Formulation having improved absorbability of low-soluble and / or low-membrane-permeable drug

Abstract

The present invention provides: a pharmaceutical composition containing a low-soluble and / or low-membrane-permeable drug and an ionic liquid, and being characterized in that the ionic liquid contains an anionic component and a cationic component, the anionic component is oleic acid or isostearic acid, and the cationic component is selected from cationic lipids; and a transmucosal absorption promoter or intestinal absorption promoter containing an ionic liquid, and being characterized in that the ionic liquid contains an anionic component and a cationic component, the anionic component is oleic acid or isostearic acid, and the cationic component is selected from cationic lipids.

Description

Formulations with improved absorption of low-solubility and / or low-membrane-permeability drugs

[0001] The present invention relates to a preparation with improved absorbability of a low-solubility and / or low-membrane-permeable drug, and a transmucosal absorption enhancer and gastrointestinal absorption enhancer that improve the transmucosal and gastrointestinal absorption of a low-solubility and / or low-membrane-permeable drug. In particular, the present invention relates to a preparation containing a low-solubility and / or low-membrane-permeable drug and an ionic liquid, with significantly improved absorbability of a low-solubility and / or low-membrane-permeable drug, and a transmucosal absorption enhancer and gastrointestinal absorption enhancer that contain an ionic liquid, with significantly improved transmucosal and gastrointestinal absorption of a low-solubility and / or low-membrane-permeable drug.

[0002] When developing a drug as an oral formulation, if sufficient oral absorption is not achieved, it can lead to failure to achieve the pharmacological evaluation items, resulting in delays or discontinuation of drug development. In recent years, in order to evaluate such risks, the Biopharmaceutics Classification System (BCS) has been used as a method for estimating factors that limit oral absorption from the characteristics of pharmaceutical ingredients. In the BCS, compounds are classified into four classes based on the solubility and membrane permeability of the drug, and attempts have been made to clarify the gastrointestinal absorption characteristics of each class and use them in formulation development. Specifically, the BCS classifies the absorption of a drug at a pH of 1. Compounds are classified into Class 1 (HS, HP) compounds that exhibit high solubility (HS) and high membrane permeability (HP) compounds, Class 2 (LS, HP) compounds that exhibit low solubility (LS) and high membrane permeability (HP) compounds, Class 3 (HS, LP) compounds that exhibit high solubility (HS) and low membrane permeability (LP) compounds, and Class 4 (LS, LP) compounds that exhibit low solubility (HS) and low membrane permeability (LP) compounds, based on a combination of solubility in 250 mL of a 0 to 7.5 buffer solution and permeability through cell membranes such as Caco-2 and MDCK cells derived from gastrointestinal epithelial cells, or membrane absorption using the permeability of artificial membranes (Non-Patent Document 1). In particular, compounds that exhibit low solubility and / or low membrane absorption, which are poorly absorbed through mucosal membranes and the gastrointestinal tract, are difficult to apply as oral formulations, and the dosage forms in which these compounds can be used are limited. Meanwhile, in clinical settings, oral formulations that are less invasive and more convenient for patients are desired. However, currently, no useful method is known for developing oral formulations with improved absorbability for these compounds.

[0003] In recent years, absorption enhancers for compounds exhibiting low solubility and / or low membrane permeability have been investigated in an attempt to improve their absorption. Absorption enhancers are compounds that promote drug absorption by directly acting on mucous membranes, causing structural changes, etc. Numerous compounds, including surfactants, bile salts, bacterial toxins, chelating agents, and medium-chain fatty acids, have been investigated in in vitro and in vivo studies for their effectiveness in improving the absorption of molecules with low biological membrane permeability. Absorption enhancers that have been put to practical use in oral formulations include sodium caprate (C10) and sulcaprozate sodium (SNAC), but these are primarily used for protein formulations such as GLP-1, and their effectiveness is not sufficient.

[0004] JP 2020-73533 A U.S. Pat. No. 10,278,923

[0005] A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm Res. 1995 Mar;12(3):413-20.

[0006] The present inventors have previously developed numerous transdermal absorption formulations that efficiently absorb compounds such as small molecular weight drugs, medium molecular weight nucleic acids, and small molecular weight peptides through the skin using ionic liquids (ILs), which are salts composed of organic anions and organic cations and which are liquid at room temperature, and have found that it is possible to design ionic liquids that are optimal for drugs with different properties. However, the drug absorption mechanisms differ significantly between transdermal absorption, gastrointestinal absorption, and intestinal absorption (transmucosal absorption), and it is therefore unlikely that the use of ionic liquids directly in transdermal absorption formulations will improve absorbability.

[0007] Therefore, an object of the present invention is to design an ionic liquid that promotes transmucosal and gastrointestinal absorption of drugs that have low solubility and / or low membrane permeability and are therefore generally very difficult to administer orally, and to provide an oral preparation containing such a drug and an ionic liquid, which has significantly improved drug absorbability, as well as a transmucosal absorption enhancer and gastrointestinal absorption enhancer for drugs that have low solubility and / or low membrane permeability and are therefore poorly absorbed transmucosally and in the gastrointestinal tract.

[0008] The present inventors have investigated new ionic liquids that can enhance the intestinal and gastrointestinal absorption of low-solubility and / or low-membrane-permeable drugs. In the investigation of ionic liquids, PROTAC (e.g., BI-3663, VZ185) was used as a model compound for low-solubility and / or low-membrane-permeable drugs.

[0009] The present inventors prepared various ionic liquids capable of dissolving low-solubility and / or low-membrane-permeable drugs, and evaluated the permeability of formulations containing these ionic liquids and drugs using membrane permeability evaluation methods such as the artificial membrane permeability assay (PAMPA method) and membrane permeability evaluation methods using Caco2 cells, a cell line derived from human colon cancer that is a cell model reproducing intestinal function in the small intestine. As a result, they found that the use of specific ionic liquids improves the transmucosal and gastrointestinal absorbability of low-solubility and / or low-membrane-permeable drugs, thereby completing the present invention.

[0010] That is, the present invention provides the following aspects. [Item 1] A pharmaceutical composition comprising a low-solubility and / or low-membrane-permeable drug and an ionic liquid, wherein the ionic liquid comprises an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids. [Item 2] The pharmaceutical composition according to Item 1, wherein the cationic lipid is DODAP, DODMA, or DOTMA. [Item 3] The pharmaceutical composition according to Item 1 or 2, wherein the anionic component is oleic acid and the cationic component is DODAP or DODMA. [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, wherein the low-solubility and / or low-membrane-permeable drug is PROTAC. [Item 5] An oral formulation comprising the pharmaceutical composition according to any one of Items 1 to 4. [Item 6] A transmucosal absorption enhancer containing an ionic liquid, wherein the ionic liquid contains an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids (provided that the transmucosal absorption enhancer does not contain a drug). [Item 7] The transmucosal absorption enhancer of Item 6, wherein the cationic lipid is DODAP, DODMA, or DOTMA. [Item 8] The transmucosal absorption enhancer of Item 6 or 7, wherein the anionic component is oleic acid and the cationic component is DODAP or DODMA. [Item 9] A formulation comprising a low-solubility and / or low-membrane-permeable drug and the transmucosal absorption enhancer of any one of Items 6 to 8. [Item 10] The formulation of Item 9, wherein the low-solubility and / or low-membrane-permeable drug is PROTAC. [Item 11] A gastrointestinal absorption enhancer containing an ionic liquid, wherein the ionic liquid contains an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids (but excluding a drug). [Item 12] The gastrointestinal absorption enhancer according to Item 11, wherein the cationic lipid is DODAP, DODMA, or DOTMA.[Item 13] The gastrointestinal absorption enhancer according to Item 11 or 12, wherein the anion component is oleic acid and the cation component is DODAP or DODMA. [Item 14] An oral formulation comprising a low-solubility and / or low-membrane-permeable drug and the gastrointestinal absorption enhancer according to any one of Items 11 to 13. [Item 15] The oral formulation according to Item 14, wherein the low-solubility and / or low-membrane-permeable drug is PROTAC.

[0011] According to the present invention, even low-solubility and / or low-membrane-permeability drugs that are difficult to use as oral formulations can be prepared as oral formulations by significantly improving their absorbability. Furthermore, the transmucosal or gastrointestinal absorption enhancer containing the ionic liquid of the present invention can promote transmucosal or gastrointestinal absorption of low-solubility and / or low-membrane-permeability drugs.

[0012] This figure shows the absorption-enhancing effect of various ionic liquids on VZ185 by the PAMPA method. PBS was used as a control. This figure shows the absorption-enhancing effect of various ionic liquids on BI-3663 by the PAMPA method. PBS was used as a control. This figure shows the absorption-enhancing effect of various ionic liquids on bifonazole by the PAMPA method. PBS was used as a control. This figure shows the absorption-enhancing effect (permeability coefficient) of various ionic liquids on VZ185 by a Caco-2 cell membrane permeability test. Transport Buffer (A) was used as a control. This figure shows the absorption-enhancing effect (permeability coefficient) of various ionic liquids on BI-3663 by a Caco-2 cell membrane permeability test. Transport Buffer (A) was used as a control. This figure shows the absorption-enhancing effect (permeability coefficient) of an ionic liquid (oleic acid-DODMA) on bifonazole in a Caco-2 cell membrane permeability test. Transport Buffer (A) was used as the control. This figure shows the absorption-enhancing effect (permeability coefficient) of an ionic liquid (isostearic acid-DODMA) on ritonavir in a Caco-2 cell membrane permeability test. Transport Buffer (A) was used as the control. This figure shows the absorption-enhancing effect (permeability coefficient) of various ionic liquids on furosemide in a Caco-2 cell membrane permeability test. The absorption-enhancing effect is expressed as a permeability coefficient. Transport Buffer (A) was used as the control.

[0013] The present invention relates to a preparation containing a low-solubility and / or low-membrane-permeable drug and an ionic liquid, which significantly improves the absorbability of the low-solubility and / or low-membrane-permeable drug, and to a transmucosal absorption enhancer and a gastrointestinal absorption enhancer which contain an ionic liquid and significantly improve the transmucosal absorbability and gastrointestinal absorbability of a low-solubility and / or low-membrane-permeable drug.

[0014] In the present invention, a "lowly soluble drug" is one that exhibits a solubility in 250 mL of a buffer solution having a pH of 1.0 to 7.5 that is equal to or less than the maximum drug content contained in one unit of formulation, and includes, for example, drugs that correspond to the low solubility (LS) defined by the BCS. Examples of such drugs include water-insoluble drugs that exhibit a solubility of 100 μg or less in 1 mL of water, drugs that are difficult to use as injections due to their low solubility, and drugs that have low or no solubility in buffer solutions, intestinal fluids, or the small intestine. Note that, as a result of their low solubility, "lowly soluble drugs" are poorly absorbed transmucosally and from the gastrointestinal tract, and therefore may possess the properties of "lowly membrane-permeable drugs." Therefore, in the present invention, "lowly soluble drugs" may be highly membrane-permeable drugs as long as they are poorly absorbed transmucosally and from the gastrointestinal tract.

[0015] In the present invention, a "low-membrane-permeable drug" refers to a drug with low permeability through biological membranes. Examples of such drugs include those that are poorly absorbed from the digestive tract due to poor permeability through the mucus layer present on the digestive tract mucosa, those that are poorly absorbed due to interactions with substances present in the mucus layer, those that are poorly absorbed from the digestive tract due to poor permeability through the digestive tract mucosa, those that are poorly absorbed orally due to interactions between the digestive tract mucus layer and the mucosa, and those that are poorly absorbed due to the formation of insoluble complexes with bile acids. Generally, this refers to a drug that is difficult to deliver orally. In the present invention, a "low-membrane-permeable drug" may be a drug with low digestive tract absorption, even if it is highly soluble. It also includes, for example, compounds with low bioavailability, specifically, compounds with an extent of bioavailability of 50% or less. Bioavailability can be calculated using the following formula: Bioavailability (%) = 100 × (amount reaching the blood following oral administration) / (amount reaching the blood following intravenous administration). The "amount reaching the blood" here is calculated as the area enclosed by the blood concentration and the horizontal axis (time axis) (area under the blood drug concentration-time curve: AUC). This also includes compounds determined to have low permeability using cultured cell (e.g., Caco-2, MDCK, HT-29, LLC-PK1) monolayer membrane methods, immobilized artificial membrane chromatography methods, partition coefficient methods, ribosomal membrane methods, and PAMPA (Parallel Artificial Membrane Permeation Assay) methods.

[0016] In the present invention, "low-solubility and / or low-membrane-permeable drugs" refer to drugs that have the properties of both the above-mentioned "low-solubility drugs" and "low-membrane-permeable drugs," and examples thereof include compounds classified as BCS Class 4 (e.g., PROTAC). Note that there are "low-solubility drugs" that have low solubility in the small intestine and are therefore poorly absorbed transmucosally and from the gastrointestinal tract, and there are also "low-membrane-permeable drugs" that are highly soluble but poorly absorbed from the gastrointestinal tract. Therefore, "low-solubility and / or low-membrane-permeable drugs" also include "low-solubility drugs" and "low-membrane-permeable drugs." Examples of such drugs include, but are not limited to, BI-3663, VZ185, ACBI1, bifonazole, hydrochlorothiazide, furosemide, acetazolamide, sulfamethoxazole, chlorothiazide, enalaprilat, mebendazole, bifonazole, methotrexate, amphotericin B, ritonavir, and the like. In the present invention, the oral absorbability of low-solubility and / or low-membrane-permeable drugs is not particularly limited. Drugs that do not provide sufficient pharmacological effects through oral administration due to low transmucosal or gastrointestinal absorbability can achieve the desired pharmacological effects by increasing their oral absorbability. Furthermore, drugs that provide sufficient pharmacological effects through oral administration despite low transmucosal or gastrointestinal absorbability can be further improved to reduce the drug dosage and reduce side effects.

[0017] In the present invention, "ionic liquid" refers to a salt formed from an anion component and a cation component that is a viscous liquid at room temperature and has a melting point of 100°C or less, or a "hydrated ionic liquid." "Hydrated ionic liquid" refers to an ionic liquid consisting of an ionic liquid and a small amount of water molecules. Ionic liquids can be prepared by mixing equimolar or excess amounts of anion component and cation component at room temperature or under heating. The excess amount of anion component and cation component is preferably within 10-fold molar amount.

[0018] In the present invention, the "anion component" refers to an organic anion, and examples thereof include organic acids such as lactic acid, citric acid, tartaric acid, succinic acid, malic acid, benzoic acid, levulinic acid, aspartic acid, glutamic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, stearic acid, behenic acid, isostearic acid, oleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, linolenic acid, adipic acid, and sebacic acid. In the present invention, the anion component is preferably a long-chain fatty acid such as oleic acid or isostearic acid.

[0019] In the present invention, the "cationic component" refers to an organic cation, such as a cationic lipid, organic amines such as diethanolamine, triethanolamine, arginine, lysine, meglumine, and trometamol, organic quaternary ammonium cations, basic amino acids, and amino sugars. In the present invention, the cationic component is preferably a cationic lipid. Cationic lipids are broadly divided into a hydrophobic portion and a hydrophilic portion, with the hydrophobic portion being a hydrophobic group such as a fatty acid residue or a sterol residue, and the hydrophilic portion being a cationic group such as an amino group or an ammonium group. In particular, structures containing two hydrophobic groups in the hydrophobic portion and one cationic group such as an amino group or an ammonium group in the hydrophilic portion (two-chain cationic lipids) are widely known.

[0020] In the present invention, examples of the cationic lipid include DODAP (1,2-dioleoyl-3-dimethylaminopropane), DODMA (1,2-dioleoyl-3-dimethylaminopropane), DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane), DLinDAP (1,2-dilinoleoyl-3-dimethylaminopropane), and salts thereof.

[0021] The ionic liquid of the present invention is composed of a combination of the above-mentioned anion component and cation component, but may be used as a mixed ionic liquid of two or more kinds (including ionic liquids in which only the anion component or the cation component differs). In addition, the ionic liquid may contain water.

[0022] In the present invention, the term "transmucosal absorption enhancer" refers to an agent that improves the transmucosal absorbability of drugs that are poorly absorbed from mucous membranes other than the digestive tract, such as oral mucosa, rectum, vagina, nasal mucosa, and lungs, such as low-solubility and / or low-membrane-permeability drugs.

[0023] In the present invention, the term "gastrointestinal absorption enhancer" refers to an agent that improves the gastrointestinal absorption of drugs that are poorly absorbed in the gastrointestinal tract and are not effective when administered orally, such as low-solubility and / or low-membrane-permeability drugs.

[0024] The preparation of the present invention may contain a pharmaceutically acceptable carrier in combination. Examples of the carrier include excipients, coating agents, binders, bulking agents, disintegrants, surfactants, lubricants, diluents, dispersants, buffers, osmotic pressure adjusters, pH adjusters, emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, moisturizers, thickeners, activity enhancers, anti-inflammatory agents, bactericides, flavoring agents, and odor enhancers. These carriers may be used alone or in combination of two or more in appropriate amounts.

[0025] It can also be made into a capsule shape with a water-soluble encapsulating agent. This water-soluble encapsulating agent serves as the capsule membrane, and by sealing the content liquid with this water-soluble encapsulating agent, it is possible to prevent the content liquid from oxidizing and other quality preservation properties, and form the capsule.

[0026] When forming the capsule, a water-soluble polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone may be used.

[0027] The following examples are provided to aid in a better understanding of the present invention and are not intended to limit the scope of the present invention.

[0028] The physical properties and structures of BI-3663 and VZ185, which are low-solubility and / or low-membrane-permeability drugs used in the following examples, are shown in the table below, but the drugs targeted by the present invention are not limited to these compounds.

[0029] The drugs used in the following examples, bifonazole, ritonavir, and furosemide, were purchased from Tokyo Chemical Industry Co., Ltd.

[0030] Example 1: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (1) To investigate whether ionic liquids enhance the intestinal absorption of low-solubility and / or low-membrane permeability drugs, various ionic liquids were prepared, and the membrane permeability of the drugs was evaluated in compositions containing these ionic liquids and low-solubility and / or low-membrane permeability drugs. Specifically, using VZ185, a protacin (PROTAC) drug, as a model drug with low solubility and / or low membrane permeability, the membrane permeability of the drugs was evaluated for compositions containing various ionic liquids by a Caco-2 cell membrane permeability test according to the following procedure. As controls, EDTA, SNAC, sodium caprylate, sodium oleate, which are used as absorption enhancers, and CAGE and lactic acid, which have been reported to enhance the mucosal absorption of insulin, were used instead of ionic liquids.

[0031] (1) Preparation of Transport Buffer Sodium hydroxide (0.4 g) was dissolved in water (100 mL) to prepare a 0.1 N NaOH solution. MES (2-morpholinoethanesulfonic acid, 1.493 g) and D-glucose (2.453 g) were dissolved in HBSS(+) (phenol red-free) (600 mL), and the pH was adjusted to 6.5 using 0.1 N NaOH solution. HBSS(+) (phenol red-free) was then added to make a total volume of 700 mL. This was sterilized by filtration using a 0.22 μm membrane filter, and this was designated Transport Buffer (A). Next, HEPES (1.192 g), D-glucose (1.752 g), and BSA (1.25 g) were dissolved in HBSS(+) (phenol red-free) (400 mL), and the pH was adjusted to 7.4 using 0.1 N NaOH solution. Then, HBSS(+) (phenol red-free) was added to make a total volume of 500 mL. The solution was sterilized by filtration using a 0.22 μm membrane filter, and this was used as Transport Buffer (B).

[0032] (2) Preparation of test solution VZ185 (1.5 mg) was mixed with 1% TWEEN 80 (1.5 mL) to prepare a 1 mg / mL VZ185 solution. Each organic acid (0.05 mmol) as an anionic component and each cationic lipid (0.05 mmol) as a cationic component were mixed with Transport Buffer (A) (4.98 mL) to prepare an ionic liquid composition containing 10 mM of each component. In addition, as a control, 0.05 mmol of EDTA, SNAC, sodium caprylate, sodium oleate, CAGE (choline geranate), and lactic acid were each mixed with Transport Buffer (A) (4.98 mL) to prepare a 10 mM control composition. A 1 mg / mL VZ185 solution (25 μL) and the ionic liquid composition or control composition (475 μL) were mixed to prepare a 50 μg / mL drug-ionic liquid composition or drug-control composition. Caco-2 cells were then cultured on a 24-well transport well for 3 weeks. After that, 100 μL of a 50 μg / mL drug-ionic liquid composition was added to the apical side of each well, and 600 μL of Transport Buffer (B) was added to the basolateral side. The cells were then incubated at 37°C, 5% CO ２ After 15, 30, 60, 120, and 240 minutes, 200 μL of sample was taken from the basolateral side of each well and used as a test solution. After the sample was taken, 200 μL of Transport Buffer (B) was added to each well, and the wells were again incubated at 37°C, 5% CO ２ The mixture was incubated in an incubator. A control solution was also prepared in the same manner, except that the drug-control composition was used instead of the drug-ionic liquid composition.

[0033] (3) Evaluation of Cell Membrane Integrity The integrity of Caco-2 cell membranes was confirmed using transepithelial electrical resistance (TEER) and Lucifer Yellow. (3-1) Transepithelial electrical resistance (TEER) was measured before and after the completion of the following procedure for evaluating Caco-2 membrane permeability. Specifically, Transport Buffer (A) (100 μL) was added to the apical side of each well, and Transport Buffer (B) (600 μL) was added to the basolateral side, and the TEER value of each well was measured using a Millicell ERS-2 (Merck Millipore Corporation, Darmstadt, Germany). (3-2) After the completion of the following procedure for evaluating Caco-2 membrane permeability, the permeability of Lucifer Yellow was measured. Specifically, Lucifer Yellow CH Dipotassium Salt (5.2 mg) was dissolved in Transport Buffer (A) (100 mL) to prepare a 100 μM Lucifer Yellow solution. Then, 100 μL of the 100 μM Lucifer Yellow solution was added to the apical side of each well, and 600 μL of Transport Buffer (B) was added to the basolateral side. The wells were then incubated at 37°C, 5% CO ２ After 60 minutes of incubation in an incubator, 200 μL of a sample was taken from the basolateral side of each well and used as a sample for measuring fluorescence intensity. The sample for measuring fluorescence intensity (100 μL) was mixed with acetonitrile (400 μL) and centrifuged at 4°C and 3,000 × g for 5 minutes. The Lucifer Yellow concentration in the supernatant was then measured using HPLC-FL under the conditions shown in the table below.

[0034] (4) Membrane Permeability Evaluation Donepezil hydrochloride (10 mg) was dissolved in methanol (100 mL) to prepare a 100 μg / mL donepezil hydrochloride solution. Exactly 1 mL of the 100 μg / mL donepezil hydrochloride solution was measured, and methanol was added to make exactly 100 mL. This was used as the IS standard stock solution. Exactly 2 mL of the IS standard stock solution was measured, and acetonitrile was added to make exactly 200 mL. This was used as the IS-acetonitrile solution (10 ng / mL donepezil / acetonitrile solution). The test solution or control solution (100 μL) and the IS-acetonitrile solution (400 μL) were mixed and centrifuged at 4°C and 3,000 × g for 10 minutes. The drug concentration in the supernatant was then measured using LC-MS / MS under the conditions shown in the table below.

[0035] The results are shown in Table 6. The TEER value >1000Ω and the Lucifer Yellow value <1% were used as the standard values ​​to evaluate the membrane integrity. Regarding membrane permeability, the membrane permeability coefficient (P ａｐｐ ) (x10 ６ The membrane permeability coefficient (P ａｐｐ )=(dQ / dt)×{1 / (A×C ０ )} dQ / dt: cumulative permeation amount on the basolateral side A: membrane area of ​​the transwell (0.33 cm ２ ) C ０ : Initial concentration on the apical side

[0036] The test results show that the ionic liquid group had a higher TEER value and a lower Lucifer Yellow transmittance than the control group, but ａｐｐ The permeability coefficients of the drugs tended to be high, and in particular, the ionic liquids of decanoic acid-DODAP, oleic acid-DODAP, and isostearic acid-DODAP had significantly high drug permeability coefficients, suggesting that the permeation-enhancing effect of ionic liquids that combine long-chain fatty acids and cationic lipids is significant.

[0037] Example 2: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (2) The results of Example 1 suggested that the permeation-enhancing effect of ionic liquids combining long-chain fatty acids and cationic lipids was significant. Therefore, Caco-2 membrane permeability and cell membrane integrity were evaluated for various ionic liquids using combinations of DHA (C22), EPA (C20), arachidonic acid (C20), isostearic acid (C18), linoleic acid (C18), and linolenic acid (C18) as anionic components, and DODAP, DODMA, and DOTMA as cationic components. Specifically, drug membrane permeability was evaluated according to the same method as in Example 1. As a control, Transport Buffer (A) prepared in Example 1 was used instead of the ionic liquid.

[0038] The results are shown in Table 7 below. Regarding membrane integrity, a TEER value of >1000Ω and a Lucifer Yellow value of <1% are desirable values, so these values ​​were used as the standard values, and values ​​exceeding the standard values ​​were considered good. Regarding membrane permeability, the membrane permeability coefficient (P ａｐｐ ) (x10 ６ The viscosity (cm / s) was calculated.

[0039] The results of this test showed that all ionic liquids had higher permeability coefficients than the control, promoting membrane permeation, and that the combination of isostearic acid and cationic lipid was particularly significant.

[0040] Example 3: Evaluation of drug membrane permeability using the artificial membrane permeability assay (PAMPA) method (1) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations using the PAMPA method. In this experiment, VZ185 and BI-3663 were used as low-solubility and / or low-membrane permeability drugs, and isostearic acid-DODMA, isostearic acid-DODAP, and oleic acid-DODMA were used as ionic liquids. PBS was used as a control. Specifically, the membrane permeability of the drugs was evaluated using a Parallel Artificial Membrane Permeability Assay-Skin Kit (manufactured by BioAssay Systems) according to the following procedure.

[0041] (1) Preparation of Phosphate Buffered Saline (PBS) One Phosphate Buffered Saline Tablet (Sigma) was dissolved in 200 mL of water to prepare PBS.

[0042] (2) Preparation of Test Solutions: VZ185 (1.5 mg) was mixed with 1% TWEEN 80 (1.5 mL) to prepare a 1 mg / mL VZ185 solution. The anionic organic acid (0.025 mmol) and cationic lipid (0.025 mmol) were mixed with the PBS (4.98 mL) prepared in (1) to prepare an ionic liquid composition containing 5 mM of each component. A 50 μg / mL drug-ionic liquid composition was prepared by mixing 25 μL of a 1 mg / mL VZ185 solution with 475 μL of the ionic liquid composition. A 50 μg / mL drug-control solution was also prepared by mixing 25 μL of a 1 mg / mL VZ185 solution with 475 μL of PBS. Next, 4% lecithin / dodecane solution (5 μL) was added to each donor well and allowed to stand. PBS (300 μL) was added to each acceptor well, and then a 50 μg / mL drug-ionic liquid composition (200 μL) was added to each donor well, followed by incubation in a 37°C incubator. 300 μL of sample was taken from each acceptor well after 30, 240, and 1440 minutes, and this was used as the test solution. After sampling, PBS (300 μL) was added to each acceptor well, followed by incubation again in a 37°C incubator. A test solution for BI-3663 was also prepared according to the same method. A control solution was also prepared according to the same method, using the drug-control solution instead of the drug-ionic liquid composition.

[0043] (3) Test Method Donepezil hydrochloride (10 mg) was dissolved in methanol (100 mL) to prepare a 100 μg / mL IS solution. Exactly 1 mL of the 100 μg / mL IS solution was measured, and methanol was added to make exactly 100 mL. This was used as the IS standard stock solution. Exactly 2 mL of the IS standard stock solution was measured, and acetonitrile was added to make exactly 200 mL. This was used as the IS-acetonitrile solution (10 ng / mL donepezil / acetonitrile solution). The test solution or control solution (100 μL) and the IS-acetonitrile solution (400 μL) were mixed and centrifuged at 4°C and 3,000 × g for 10 minutes. The drug concentration in the supernatant was then measured using LC-MS / MS under the conditions shown in the table below.

[0044] The results are shown in Figures 1 and 2. The test results demonstrate that the absorbability of VZ185 and BI-3663 is significantly improved by using an ionic liquid.

[0045] Example 4: Evaluation of drug membrane permeability using the artificial membrane permeability assay (PAMPA) method (2) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations using the PAMPA method. In this experiment, bifonazole was used as the low-solubility and / or low-membrane permeability drug, and isostearic acid-DODMA, isostearic acid-DODAP, and oleic acid-DODMA were used as the ionic liquids. PBS was used as a control. Specifically, the membrane permeability of bifonazole was evaluated using a Parallel Artificial Membrane Permeability Assay-Skin Kit (BioAssay Systems) in the same manner as in Example 3.

[0046] The results are shown in Figure 3. The test results demonstrate that the use of an ionic liquid significantly improves the absorbability of bifonazole.

[0047] Example 5: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (3) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations by a Caco-2 cell membrane permeability test. In this experiment, VZ185 was used as the low-solubility and / or low-membrane permeability drug, and oleic acid-DODMA and oleic acid-DODAP were used as the ionic liquids. Transport Buffer (A) was used as a control. Specifically, the membrane permeability of VZ185 was evaluated according to the method of Example 1.

[0048] The results are shown in Figure 4. The results of this test demonstrated that oleic acid-DODMA and oleic acid-DODAP have a significant effect of enhancing gastrointestinal absorption, and that the use of these ionic liquids significantly improved the absorbability of VZ185.

[0049] Example 6: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (4) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations by a Caco-2 cell membrane permeability test. In this experiment, BI-3663 was used as the low-solubility and / or low-membrane permeability drug, and isostearic acid-DODMA, oleic acid-DODMA, and oleic acid-DODAP were used as the ionic liquids. Transport Buffer (A) was used as a control. Specifically, the membrane permeability of BI-3663 was evaluated according to the method of Example 1.

[0050] The results are shown in Figure 5. The test results demonstrate that isostearic acid-DODMA, oleic acid-DODMA, and oleic acid-DODAP have a significant gastrointestinal absorption-enhancing effect, and that the use of these ionic liquids significantly improves the absorbability of BI-3663.

[0051] Example 7: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (5) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations by a Caco-2 cell membrane permeability test. In this experiment, bifonazole was used as the low-solubility and / or low-membrane permeability drug, and oleic acid-DODMA was used as the ionic liquid. Transport Buffer (A) was used as a control. Specifically, the membrane permeability of bifonazole was evaluated according to the method of Example 1.

[0052] The results are shown in Figure 6. The results of this test demonstrated that oleic acid-DODMA has a significant effect of promoting gastrointestinal absorption, and that the use of this ionic liquid significantly improves the absorbability of bifonazole.

[0053] Example 8: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (6) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations by Caco-2 cell membrane permeability test. In this experiment, ritonavir (a low-solubility drug that is practically insoluble in water) was used as the low-solubility and / or low-membrane permeability drug, and isostearic acid-DODMA was used as the ionic liquid. Transport Buffer (A) was used as a control. Specifically, the membrane permeability of ritonavir was evaluated according to the method of Example 1.

[0054] The results are shown in Figure 7. The results of this test demonstrated that isostearic acid-DODMA has a significant effect of promoting gastrointestinal absorption, and that the use of this ionic liquid significantly improves the absorbability of ritonavir.

[0055] Example 9: Evaluation of drug membrane permeability by Caco-2 cell membrane permeability test (7) The membrane permeability of low-solubility and / or low-membrane permeability drugs was evaluated for various ionic liquid formulations by Caco-2 cell membrane permeability test. In this experiment, furosemide (a low-solubility drug that is practically insoluble in water) was used as the low-solubility and / or low-membrane permeability drug, and isostearic acid-DODAP and oleic acid-DODAP were used as the ionic liquid. Transport Buffer (A) was used as a control. Specifically, the membrane permeability of furosemide was evaluated according to the method of Example 1.

[0056] The results are shown in Figure 8. The test results demonstrate that isostearic acid-DODAP and oleic acid-DODAP have a significant effect of enhancing gastrointestinal absorption, and that the use of these ionic liquids significantly improves the absorbability of furosemide.

[0057] The above test results demonstrate that the use of ionic liquids significantly improves the absorbability of low-solubility and / or low-membrane-permeability drugs.

[0058] According to the present invention, even low-solubility and / or low-membrane-permeability drugs that are difficult to use as oral formulations can be prepared as oral formulations by significantly improving their absorbability. Furthermore, the transmucosal or gastrointestinal absorption enhancer containing the ionic liquid of the present invention can promote transmucosal or gastrointestinal absorption of low-solubility and / or low-membrane-permeability drugs.

Claims

1. A pharmaceutical composition comprising a low-solubility and / or low-membrane-permeability drug and an ionic liquid, wherein the ionic liquid comprises an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids.

2. 2. The composition of claim 1, wherein the cationic lipid is DODAP, DODMA, or DOTMA.

3. 3. The pharmaceutical composition according to claim 1, wherein the anionic component is oleic acid and the cationic component is DODAP or DODMA.

4. 3. The pharmaceutical composition according to claim 1, wherein the low-solubility and / or low-membrane-permeability drug is a protacin.

5. An oral formulation comprising the pharmaceutical composition of claim 1.

6. A transmucosal absorption enhancer (but excluding a drug) comprising an ionic liquid, characterized in that the ionic liquid comprises an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids.

7. A formulation comprising a low-solubility and / or low-membrane-permeability drug and the transmucosal absorption enhancer of claim 6.

8. A gastrointestinal absorption enhancer comprising an ionic liquid, characterized in that the ionic liquid comprises an anionic component and a cationic component, the anionic component being oleic acid or isostearic acid, and the cationic component being selected from cationic lipids (but not including a drug).

9. 9. The gastrointestinal absorption enhancer according to claim 8, wherein the cationic lipid is DODAP, DODMA, or DOTMA.

10. 10. The gastrointestinal absorption enhancer according to claim 8 or 9, wherein the anion component is oleic acid and the cation component is DODAP or DODMA.

11. An oral formulation comprising a low-solubility and / or low-membrane-permeability drug and the gastrointestinal absorption enhancer according to claim 8 or 9.

12. 12. The oral formulation of claim 11, wherein the low-solubility and / or low-membrane-permeability drug is a PROTAC.