External preparation containing non-lamellar liquid crystal-forming lipid

Abstract

The present application relates to an external preparation containing a non-lamellar liquid crystal-forming lipid. The present invention relates to an external preparation which can be held satisfactorily on the surface of a living body and can increase drug permeability, and more particularly, to an external preparation containing a non-lamellar liquid crystal-forming lipid and a drug.

Description

[0001] This application is a divisional application of the application with the filing date of September 9, 2019, application number 201980058315.2, and invention title "External preparation containing non-lamellar liquid crystal-forming lipid". Technical Field

[0002] The present invention relates to an external preparation containing a non-lamellar liquid crystal-forming lipid. Background Art

[0003] Transdermal absorption-type preparations used by attaching to the skin have advantages such as ease of administration and sustained release, and the use of such preparations is increasing not only for local administration of various drugs but also for systemic administration. However, since the skin functions as a biological barrier to restrict the permeation of substances, it is known that the drug absorbability in transdermal absorption-type preparations is generally low. Therefore, various transdermal absorption enhancers are used in transdermal absorption-type preparations, but the obtained transdermal absorption enhancing effect is not necessarily sufficient.

[0004] Lyotropic liquid crystals such as liposomes have been reported to have many useful properties since the advocacy period of the DDS concept as drug delivery system (DDS) carriers that mimic organisms. In recent years, for non-lamellar liquid crystal (NLLC), which is one of the lyotropic liquid crystals, it has been reported that it has advantages such as a higher drug content rate, ease of preparation, and high stability in high-molecular drugs compared with conventional DDS carriers.

[0005] Various liquid crystal-forming compounds are used in various applications such as the cosmetic field and the pharmaceutical field. In recent years, a lipid compound of cubic-forming liquid crystal that shows high stability even at low temperatures (below 6°C) has been developed, and the use of such liquid crystal in sustained-release preparations has been reported (Patent Document 1). However, these lipid compounds have a high viscosity and cannot pass through a fine syringe needle (e.g., 30 Gage), so it is difficult to use them for injections. Therefore, a lipid compound that can stably form a non-lamellar liquid crystal and has a lower viscosity has been developed as a base for injections (Patent Document 2). Although Patent Document 3 discloses a skin external preparation containing a liquid crystal formed from such a low-viscosity lipid compound, its main dosage forms are lotions and emulsions, and the skin retention is not high. In addition, Patent Document 3 does not describe the application of this external preparation to tissues other than the skin.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: WO 2006 / 043705

[0009] Patent Document 2: WO 2011 / 078383

[0010] Patent Document 3: Japanese Patent Application Laid-Open No. 2012-17318 Summary of the Invention

[0011] Problems to be Solved by the Invention

[0012] The problem to be solved by the present invention is to provide an external preparation that can be well retained on the biological surface and can increase drug permeability.

[0013] Technical Solution for Solving the Problem

[0014] The present inventors conducted in-depth research to solve the above problems and found that when using non-lamellar liquid crystal-forming lipids to manufacture patches such as tape agents, aerosol agents, liquid crystal precursor preparations, etc., it was possible to achieve good retention of the preparation on the biological surface and an increase in drug permeability. In addition, such preparations are applied not only to the skin but also to the mucosa, thus completing the present invention.

[0015] That is, the present invention includes the following:

[0016] [1] An external preparation containing non-lamellar liquid crystal-forming lipid and a drug.

[0017] [2] The external preparation according to the above [1], which is an amphiphilic compound represented by the following general formula (I) or a salt thereof.

[0018] [Chemical Formula 1]

[0019]

[0020] In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, m represents 1 or 2.

[0021]

[0022] represents a single bond or a double bond, and R represents a hydrophilic group having two or more hydroxyl groups.

[0023] [3] The external preparation according to the above [2], wherein R in the formula represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol.

[0024] [4] The external preparation according to any one of the above [1] to [3], wherein the non-lamellar liquid crystal-forming lipid is mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) glycerol or mono-O-(5,9,13-trimethyltetradec-4-enoyl) glycerol.

[0025] [5] The topical agent according to [1] above, wherein the non-lamellar liquid crystal-forming lipid is glyceryl monooleate or phytantriol.

[0026] [6] The topical agent according to any one of [1] to [5] above, which is formulated into a patch dosage form.

[0027] [7] The topical agent according to [6] above, wherein the patch is a rubber plaster.

[0028] [8] The topical agent according to [6] or [7] above, which contains 70 w / w% or more of an adhesive.

[0029] [9] The topical agent according to any one of [1] to [5] above, which is formulated into an aerosol dosage form.

[0030]

[10] The topical agent according to any one of [1] to [9] above, wherein the non-lamellar liquid crystal-forming lipid does not form a liquid crystal in the topical agent.

[0031]

[11] The topical agent according to any one of [1] to

[10] above, which is applied to a mucosa.

[0032]

[12] The topical agent according to any one of [1] to

[11] above, which further contains a water-soluble polymer and / or an oily component.

[0033]

[13] The topical agent according to

[12] above, wherein the water-soluble polymer is hydroxypropyl cellulose.

[0034]

[14] The topical agent according to any one of [1] to

[13] above, which further contains ethanol.

[0035]

[15] The topical agent according to any one of [1] to [5] above, which contains fine particles containing the non-lamellar liquid crystal-forming lipid and the drug.

[0036]

[16] The topical agent according to any one of [1] to

[15] above, which is used for drug delivery to the brain.

[0037] This specification incorporates the content disclosed in Japanese Patent Application No. 2018-168365, which is the basis of the priority of this application.

[0038] Effects of the Invention

[0039] According to the present invention, a topical agent can be provided which can be well retained on the biological surface and can increase the skin permeability of the drug. Further, according to the present invention, a topical agent can be provided which can be applied to a mucosa and has high drug mucosal permeability. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 It is a photograph showing the observation image under a polarized light microscope. A: Preparation No. 1; B: Preparation No. 2; C: Preparation No. 3; D: Preparation No. 4; E: Preparation No. 5; F: Preparation No. 19; G: Preparation No. 25; H: Preparation No. 26.

[0041] Figure 2 It is a graph showing the results of small-angle X-ray diffraction. A: Preparation No. 1; B: Preparation No. 2; C: Preparation No. 3; D: Preparation No. 13; E: Preparation No. 25; F: Preparation No. 26; G: Preparation No. 27.

[0042] Figure 3 It is a graph showing the results of small-angle X-ray diffraction. A: Preparation No. 37; B: Preparation No. 45; C: Preparation No. 46; D: Preparation No. 47; E: Preparation No. 48; F: Preparation No. 49.

[0043] Figure 4 It is a schematic diagram of the vertical diffusion unit structure.

[0044] Figure 5 It is a graph showing the skin permeation behavior of FL-Na from the liquid crystal precursor preparation.

[0045] Figure 6 It is a graph showing the results of small-angle X-ray diffraction. A: Preparation No. 52 (with water added), B: Preparation No. 53 (with water added), C: Preparation No. 56 (with water added), D: Preparation No. 57 (with water added), E: Preparation No. 56 (without water added).

[0046] Figure 7 It is a graph showing the skin permeation behavior of FL-Na from the spray. Each value is mean ± standard error (S.E.).

[0047] Figure 8 It is a schematic diagram showing the extension of the adhesive layer on the backing. The arrow indicates the extension direction of the adhesive layer.

[0048] Figure 9 It is a photograph showing the phase diagram of the surface of the adhesive layer of the rubber plaster preparation. A: Preparation No. 73, observation field of view 1μm × 1μm; B: Preparation No. 63, observation field of view 1μm × 1μm; C: Preparation No. 73, observation field of view 0.5μm × 0.5μm; D: Preparation No. 63, observation field of view 0.5μm × 0.5μm.

[0049] Figure 10 It is a schematic diagram of the horizontal diffusion unit structure.

[0050] Figure 11 It is a graph showing the release behavior of FL-Na from the rubber plaster preparation.

[0051] Figure 12 It is a graph showing the skin penetration behavior of FL-Na from a cataplasm preparation.

[0052] Figure 13 It is a graph showing the results of small-angle X-ray diffraction. A: Preparation No. 75; B: Preparation No. 76; C: Preparation No. 77.

[0053] Figure 14 It is a graph showing the release behavior of tranilast from each preparation within 8 hours after application. Each value represents mean ± standard error (S.E.). White squares represent Preparation No. 75; black squares represent Preparation No. 76; white triangles represent Preparation No. 78.

[0054] Figure 15 It is a graph showing the change over time of the concentration of tranilast in plasma within 8 hours after intranasal administration. Each value represents mean ± standard error (S.E.). White squares represent Preparation No. 75; black squares represent Preparation No. 76; white circles represent Preparation No. 77; white triangles represent Preparation No. 78.

[0055] Figure 16 It is a graph showing the change over time of the concentration of tranilast in the brain within 8 hours after intranasal administration. Each value represents mean ± standard error (S.E.). White squares represent Preparation No. 75; black squares represent Preparation No. 76; white circles represent Preparation No. 77; white triangles represent Preparation No. 78.

[0056] Figure 17 It is a graph showing the concentration of tranilast in different regions of the brain 2 hours, 4 hours, and 8 hours after intranasal administration. A: Midbrain; B: Cortex; C: Cerebellum; D: Hippocampus.

[0057] Figure 18 It is a graph showing the concentration of tranilast in different regions of the brain 2 hours, 4 hours, and 8 hours after intranasal administration. A: Spinal cord; B: Olfactory bulb. Detailed implementation mode

[0058] Hereinafter, the present invention will be described in detail.

[0059] The present invention relates to an external preparation containing a non-lamellar liquid crystal-forming lipid and a drug. In the present invention, the external preparation refers to a drug applied to the surface of a living body (such as skin or mucous membrane) for the purpose of administering the drug. The external preparation may be a pharmaceutical composition. The external preparation of the present invention has an attachment property to the surface of a living body and is preferably stably retained on the surface of a living body. If the external preparation of the present invention is applied to the surface of a living body, the drug is released from the liquid crystal formed by the non-lamellar liquid crystal-forming lipid in the external preparation, and the drug effectively penetrates through the skin and mucous membrane and is absorbed (administered) into the body. The external preparation of the present invention can significantly promote the penetration of the drug through the skin and mucous membrane, etc.

[0060] 1. Non - lamellar liquid - crystal - forming lipid

[0061] In the present invention, a lipid capable of forming a non - lamellar liquid crystal (non - lamellar liquid - crystal - forming lipid) can be used as the liquid - crystal - forming lipid. The non - lamellar liquid - crystal - forming lipid used in the present invention is preferably a low - molecular - weight amphiphilic compound. Here, "low - molecular - weight" means having a molecular weight of about 20 to 10,000. The molecular weight of the non - lamellar liquid - crystal - forming lipid used in the present invention is preferably 50 to 5,000, more preferably 100 to 2,500, and still more preferably 200 to 1,000.

[0062] In one embodiment, an amphiphilic compound represented by the following general formula (I) or a salt thereof can be used as the non - lamellar liquid - crystal - forming lipid.

[0063] [Chemical formula 2]

[0064]

[0065] In general formula (I), X and Y each represent a hydrogen atom or together represent an oxygen atom. In general formula (I), n represents an integer of 0 to 2 (preferably 1 or 2), and m represents 1 or 2. In the amphiphilic compound represented by general formula (I), the combination of n and m can be any one of the following: n = 0, m = 1; n = 0, m = 2; n = 1, m = 1; n = 1, m = 2; n = 2, m = 1; or n = 2, m = 2.

[0066] In the formula:

[0067]

[0068] represents a single bond or a double bond.

[0069] R in general formula (I) represents a hydrophilic group having two or more hydroxyl groups, and is not limited to the following. For example, it can be mentioned: a hydrophilic group obtained by removing one hydroxyl group (OH) from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol. R in general formula (I) is more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol, pentaerythritol, erythritol, diglycerol, glyceric acid, or xylose, and particularly preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol. It should be noted that the hydrophilic group obtained by removing one hydroxyl group (OH) from glyceric acid can be a hydrophilic group obtained by removing the OH (hydroxyl group) contained in the carboxyl group of glyceric acid.

[0070] It should be noted that in the present invention, the expression in general formula (I):

[0071]

[0072] It indicates that the amphiphilic compound is the E form (cis form) or Z form (trans form) of a geometric isomer or a mixture thereof. The meaning of this expression is the same in the following general formulas (II) and (III).

[0073] As an example of the amphiphilic compound represented by the general formula (I), the amphiphilic compound represented by the following general formula (II) can be cited.

[0074] [Chemical formula 3]

[0075]

[0076] In the general formula (II), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2 (0, 1 or 2), and m represents 1 or 2.

[0077] R in the general formula (II) represents a hydrophilic group obtained by removing one hydroxyl group (OH) from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol. Preferred examples of R are hydrophilic groups obtained by removing one hydroxyl group (OH) from any one selected from glycerol, pentaerythritol, erythritol, diglycerol, glyceric acid, and xylose, and more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol. The hydrophilic group obtained by removing one hydroxyl group (OH) from glyceric acid may be a hydrophilic group obtained by removing the OH (hydroxyl group) contained in the carboxyl group of glyceric acid.

[0078] As another example of the amphiphilic compound represented by the general formula (I), the amphiphilic compound represented by the following general formula (III) can be cited.

[0079] [Chemical formula 4]

[0080]

[0081] In the general formula (III), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2 (preferably 1 or 2), and m represents 1 or 2.

[0082] In the general formula (III), R represents a hydrophilic group having two or more hydroxyl groups, and is not limited to the following, but for example, may include: a hydrophilic group obtained by removing one hydroxyl group (OH) from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol. Preferred examples of R are hydrophilic groups obtained by removing one hydroxyl group (OH) from any one selected from glycerol, pentaerythritol, erythritol, diglycerol, glyceric acid, and xylose, and more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol. The hydrophilic group obtained by removing one hydroxyl group (OH) from glyceric acid may be a hydrophilic group obtained by removing the OH (hydroxyl group) contained in the carboxyl group of glyceric acid.

[0083] As another example of the amphiphilic compound represented by the general formula (I), an amphiphilic compound represented by the following general formula (IV) can be cited.

[0084] [Chemical formula 5]

[0085]

[0086] In the general formula (IV), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2 (preferably 1 or 2), and m represents 1 or 2.

[0087] In the general formula (IV), R represents a hydrophilic group having two or more hydroxyl groups, and is not limited to the following, but for example, may include: a hydrophilic group obtained by removing one hydroxyl group (OH) from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol. Preferred examples of R are hydrophilic groups obtained by removing one hydroxyl group (OH) from any one selected from glycerol, pentaerythritol, erythritol, diglycerol, glyceric acid, and xylose, and more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol. The hydrophilic group obtained by removing one hydroxyl group (OH) from glyceric acid may be a hydrophilic group obtained by removing the OH (hydroxyl group) contained in the carboxyl group of glyceric acid.

[0088] As preferred examples of the amphiphilic compound represented by the general formula (I), the following can be cited:

[0089] mono - O - (5,9,13 - trimethyltetradec - 4 - enoyl) glycerol,

[0090] mono - O - (5,9,13 - trimethyltetradecanoyl) glycerol,

[0091] mono - O - (5,9,13 - trimethyltetradeca - 4,8,12 - trienoyl) glycerol,

[0092] mono - O - (5,9,13,17 - tetramethyloctadec - 4 - enoyl) glycerol,

[0093] mono - O - (5,9,13,17 - tetramethyloctadecanoyl) glycerol, and

[0094] mono - O - (5,9,13,17 - tetramethyloctadeca - 4,8,12,16 - tetraenoyl) glycerol,

[0095] but not limited to these.

[0096] As a further preferred example, mono - O - (5,9,13 - trimethyltetradec - 4 - enoyl) glycerol and mono - O - (5,9,13,17 - tetramethyloctadec - 4 - enoyl) glycerol can be cited.

[0097] The amphiphilic compound represented by the general formula (I) used in the present invention shows high stability under a wide range of environmental conditions. For example, the amphiphilic compound represented by the general formula (I) is characterized in that it has an isoprenoid chain as a hydrophobic group, which is different from an amphiphilic compound having a straight - chain fatty acid chain such as oleic acid as a hydrophobic group, has high resistance to hydrolysis, and also has relatively high oxidation stability. In addition, the temperature range for obtaining a liquid crystal of the amphiphilic compound represented by the general formula (I) is large, and the Kraft temperature is low, and it can stably form a liquid crystal even at a low temperature (6 °C or lower, preferably 0 °C or lower).

[0098] In addition, the amphiphilic compound represented by the general formula (I) used in the present invention itself shows a low viscosity. Specifically, the amphiphilic compound represented by the general formula (I) itself preferably has a viscosity of 15.0 Pa·s or less, more preferably 11.0 Pa·s or less, and further preferably 6.0 Pa·s or less in the measurement value at 25 °C. This viscosity can be measured, for example, at a temperature of 25 °C using a viscosity / viscoelasticity measuring device (Gemini II, Malvern).

[0099] The external preparation of the present invention may contain a salt of the amphiphilic compound represented by the general formula (I). The salt of the amphiphilic compound represented by the general formula (I) of the present invention can be any salt, and examples include salts of alkali metals or alkaline earth metals such as sodium, potassium, calcium, and magnesium, and preferably sodium salts and potassium salts. The salt of the amphiphilic compound represented by the general formula (I) of the present invention can be a pharmaceutically acceptable salt or a salt acceptable for cosmetics manufacturing.

[0100] The present invention is not limited to an external preparation using the amphiphilic compound represented by the general formula (I) or its salt, and any other non - lamellar liquid - crystal - forming lipid can be used.

[0101] The non-lamellar liquid crystal-forming lipids used in the present invention can be, for example, glycerol fatty acid monoesters. As the fatty acids constituting the glycerol fatty acid monoesters, saturated or unsaturated fatty acids having 8 to 24 carbon atoms are preferred. Other examples of glycerol fatty acid monoesters include: glyceryl monooleate (GMO; also known as: monoolein), glyceryl monoisostearate, glyceryl monoelaidate, etc., but are not limited to these. Or as the non-lamellar liquid crystal-forming lipid, glycerol monoalkyl ether can also be used. Specifically, as glycerol monoalkyl ether, examples include: glyceryl monooleyl ether (also known as: oleyl glycerol), glyceryl monoisostearyl ether (also known as: isostearyl glycerol), glyceryl monoelaidyl ether, etc., but are not limited to these. Moreover, as other non-lamellar liquid crystal-forming lipids, phytantriol (PHY) etc. can be used.

[0102] The non-lamellar liquid crystal-forming lipids used in the present invention also include combinations of two or more lipids that form non-lamellar liquid crystals by mixing, and lipids that form non-lamellar liquid crystals by combination with components such as oily components. Such non-lamellar liquid crystal-forming lipids are known to those skilled in the art.

[0103] By adding one or more predetermined components such as oily components to the non-lamellar liquid crystal-forming lipids used in the present invention, there are cases where the formed liquid crystal structure can be changed. The external preparation contains the non-lamellar liquid crystal-forming lipid and such a component. Compared with the case where the component is not contained, even when the liquid crystal structure changes, as long as non-lamellar liquid crystals are also formed after the liquid crystal structure changes, the external preparation and the non-lamellar liquid crystal-forming lipid used in the external preparation are also respectively included in the scope of the "external preparation" and "non-lamellar liquid crystal-forming lipid" in the present invention.

[0104] The non-lamellar liquid crystal-forming lipids used in the present invention can form non-lamellar liquid crystals in an aqueous medium (aqueous phase). It should be noted that in the present invention, the aqueous medium containing the non-lamellar liquid crystal-forming lipid is sometimes referred to as a "non-lamellar liquid crystal-forming lipid / aqueous system" or an "amphiphile / aqueous system".

[0105] The non-lamellar liquid crystal-forming lipids contained in the external preparation of the present invention form non-lamellar liquid crystals in the external preparation, or form non-lamellar liquid crystals on the surface of the organism due to the presence of surrounding water when applied to the surface of the organism, or form non-lamellar liquid crystals on the surface of the organism due to the volatilization of volatile components (solvents such as ethanol, propellants, etc.) when applied to the surface of the organism. The non-lamellar liquid crystals formed by the non-lamellar liquid crystal-forming lipids contained in the external preparation of the present invention are preferably type II (water-in-oil type) liquid crystals with hydrophobic groups oriented outward, more preferably cubic liquid crystals, inverse hexagonal phase liquid crystals, or a mixed system thereof, but are not limited to these.

[0106] The analysis of the liquid crystal structure formed by non-layered liquid crystal-forming lipids can be carried out by conventional methods such as observation using a polarized light microscope or small-angle X-ray scattering (SAXS) measurement.

[0107] For example, in order to confirm the formation of liquid crystals, various liquid crystal structures possessed can also be studied by the small-angle X-ray scattering (SAXS) method. Generally, first, a sample of a non-layered liquid crystal-forming lipid / aqueous system at a predetermined concentration is added to, for example, a quartz X-ray capillary, and then the capillary is sealed with an oxygen burner and subjected to SAXS measurement.

[0108] By confirming the results of the SAXS measurement and whether the following specific scattering peak ratios (peak intervals) are presented in their respective liquid crystal structures, the formation of liquid crystals can be confirmed.

[0109] Ratio of Pn3m cubic liquid crystal:

[0110]

[0111] Ratio of Ia3d cubic liquid crystal:

[0112]

[0113] Ratio of Im3m cubic liquid crystal:

[0114]

[0115] Ratio of Fd3m cubic liquid crystal:

[0116]

[0117] Ratio specific to the inverse hexagonal phase liquid crystal:

[0118]

[0119] According to the method well-known to those skilled in the art, if the peaks are calculated from the SAXS data and then the ratios of their reciprocals are obtained, the space group and lattice constant can be easily determined.

[0120] The amphiphilic compound represented by the general formula (I) for the external preparation of the present invention can be synthesized with reference to the description in the following examples or according to the synthesis method described in International Publication WO2014 / 178256. Alternatively, the amphiphilic compound represented by the general formula (III) can be synthesized, for example, according to the synthesis method described in International Publication WO2011 / 078383. Moreover, the amphiphilic compound represented by the general formula (IV) can be synthesized, for example, according to the synthesis method described in International Publication WO2006 / 043705.

[0121] For the synthesized compound, it is preferable to preliminarily confirm the target compound by conventional methods such as nuclear magnetic resonance (NMR) measurement.

[0122] In addition, various other non - lamellar liquid - crystalline lipids are commercially available. Glycerol monooleate (GMO) and phytantriol (PHY) can be commercially obtained from Tokyo Chemical Industry Co., Ltd., Kao Corporation, and Riken Vitamin Co., Ltd. (all in Japan), etc. Glyceryl oleate can be commercially obtained from Nikko Chemicals Co., Ltd. (Japan) under the trade name NIKKOL Selachyl Alcohol V, for example. Glyceryl isostearate can be commercially obtained from Kao Corporation (Japan) under the trade name Penetol GE - IS, for example.

[0123] The external preparation of the present invention contains an effective amount of non - lamellar liquid - crystalline - forming lipid. The amount of the non - lamellar liquid - crystalline - forming lipid contained in the external preparation of the present invention is not limited to the following, but relative to the total weight of the external preparation, it can generally be 0.1 w / w% or more, 0.5 w / w% or more, for example, 3 w / w% or more, 5 w / w% or more, 0.5 w / w% - 99.8 w / w%, 1 w / w% - 99.5 w / w%, 5 w / w% - 99 w / w%, 10 w / w% - 99.8 w / w%, 40 w / w% - 99.8 w / w%, 60 w / w% or more, 70 w / w% or more, 60 w / w% - 99.8 w / w%, 65 w / w% - 99.8 w / w%, 68 w / w% - 99 w / w%, 70 w / w% - 99.5 w / w%, 70 w / w% - 90 w / w%, 10 w / w% - 30 w / w%, 10 w / w% - 25 w / w%, 13 w / w% - 15 w / w%, 3 w / w% - 20 w / w%, 3 w / w% - 15 w / w%, 3 w / w% - 10 w / w% or 5 w / w% - 9 w / w%.

[0124] The "total weight of the external preparation" as mentioned here refers to the total weight of the composition (preferably a mixed or dispersed composition) that serves as the external preparation and contains at least a non - lamellar liquid - crystalline - forming lipid and a drug. The weights of other constituent parts such as the support for carrying the composition and the container for accommodating the composition are not included in the "total weight".

[0125] 2. Drug

[0126] The drug incorporated in the external preparation of the present invention is released onto the surface of a living body by applying the external preparation to the surface of the living body, and is absorbed into the body through the skin, mucous membranes, etc. The drug can be any substance (active ingredient) to be administered to a living body. However, the drug is not the non-lamellar liquid crystal-forming lipid itself. The drug can be an organic compound or an inorganic compound. The drug can be a water-soluble drug or a lipid-soluble (lipophilic, water-insoluble or poorly water-soluble) drug. The drug can be a physiologically active substance. The drug can be, for example, a protein, a peptide, an amino acid, a nucleic acid, etc., but is not limited to these. The drug can be, for example, an anticancer agent, an immunosuppressant, an analgesic (e.g., a non-opioid analgesic, an opioid analgesic such as morphine), an anti-inflammatory agent, an anti-allergic agent (e.g., Tranilast), a steroid drug (e.g., triamcinolone acetonide), an anti-obesity drug, an anti-diabetic drug, an antibiotic, an antifungal agent, an antiviral agent, a vasodilator, an anesthetic, a smoking cessation aid (e.g., nicotine), an antipsychotic drug, an antihypertensive drug, a cardiotonic, a β-blocker, an anti-anemic agent, an antihyperlipidemic agent, a bronchodilator, a dementia treatment drug, a brain central nervous system disease treatment drug for Alzheimer's disease, Parkinson's disease, cerebrovascular disorder or brain tumor, etc., a chronic obstructive pulmonary disease (COPD) treatment drug, a glaucoma treatment drug, a cataract treatment drug, an age-related macular degeneration treatment drug, an overactive bladder treatment drug, an attention deficit hyperactivity disorder treatment drug, a hormonal agent, a vaccine, etc., but is not limited to these.

[0127] 3. Dosage form and composition of the external preparation

[0128] The external preparation of the present invention can be used for systemic administration or for local administration. The external preparation of the present invention can be formulated into any dosage form. The external preparation of the present invention is not limited to the following, but can have: a patch, such as a rubber plaster (also called: a plaster), a gel patch, etc.; a spray, such as an aerosol, a pump spray (manual or powered spray), etc.; an ointment, a cream, an oral preparation, a nasal preparation, a suppository, a vaginal preparation, etc. A spray refers to a pharmaceutical preparation in a dosage form in which a drug is ejected by applying pressure manually, by power, by a propellant (gas) or by any other means. The external preparation of the present invention can contain microparticles containing a non-lamellar liquid crystal-forming lipid and a drug (e.g., microparticles or nanoparticles). The external preparation of the present invention can also be a dispersion, for example, a dispersion liquid containing such microparticles (e.g., microparticles or nanoparticles). The present invention also provides a preparation containing any of these dosage forms of the external preparation of the present invention.

[0129] The external preparation of the present invention can be used on the surface of a living body, preferably applied to the skin (skin surface). Alternatively, the external preparation of the present invention is used for application to the mucous membrane (mucous membrane surface). The external preparation of the present invention can promote the penetration of a drug through the skin or mucous membrane. The external preparation of the present invention is applied not only to the skin but also to the mucous membrane.

[0130] As other components, the external preparation of the present invention may contain an aqueous medium. As the aqueous medium, it is not limited to the following, but may be water such as sterilized water, purified water, distilled water, ion-exchanged water, ultrapure water, etc.; electrolyte aqueous solutions such as physiological saline, sodium chloride aqueous solution, calcium chloride aqueous solution, magnesium chloride aqueous solution, sodium sulfate aqueous solution, potassium sulfate aqueous solution, sodium carbonate aqueous solution, sodium acetate aqueous solution, etc.; buffer solutions such as phosphate buffer or Tris-hydrochloric acid buffer solution, etc. The aqueous medium is preferably physiologically acceptable water or aqueous solution. The aqueous medium can contain components of the external preparation such as drugs by dissolution, dispersion, suspension, etc.

[0131] As other components, the external preparation of the present invention may contain a water-soluble polymer. Examples of the water-soluble polymer include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, polyvinylpyrrolidone, carbon black, carrageenan, chitosan, chondroitin sulfate, xanthan gum, hyaluronate (such as sodium hyaluronate), alginate (such as sodium alginate), gelatin, dextran, etc. As hydroxypropyl cellulose (HPC), for example, there are 5 grades of HPC sold by Nippon Soda Co., Ltd. (Japan): HPC-SSL (molecular weight of about 40,000, viscosity of 2 - 2.9 mPa·s), HPC-SL (molecular weight of about 100,000, viscosity of 3 - 5.9 mPa·s), HPC-L (molecular weight of about 140,000, viscosity of 6 - 10 mPa·s), HPC-M (molecular weight of about 620,000, viscosity of 150 - 400 mPa·s), and HPC-H (molecular weight of about 910,000, viscosity of 1000 - 4000 mPa·s). In one embodiment, the molecular weight of hydroxypropyl cellulose can be 1,000,000 or less, or 800,000 or less, for example, 10,000 - 700,000 or 10,000 - 80,000.

[0132] The amount of the drug contained in the external preparation of the present invention is not limited to the following, but relative to the total weight of the external preparation, it can generally be 0.0001 w / w% or more, for example, 0.0001 w / w% to 10 w / w%, 0.0005 w / w% to 5 w / w%, 0.0005 w / w% to 1 w / w%, 0.001 w / w% to 5 w / w%, 0.001 w / w% to 1 w / w%, 0.001 w / w% to 0.1 w / w%, 0.001 w / w% to 0.05 w / w%, 0.001 w / w% to 0.01 w / w%, 0.01 w / w% to 5 w / w%, 0.01 w / w% to 1 w / w%, 0.01 w / w% to 0.1 w / w%, 0.05 w / w% to 1 w / w% or 0.1 w / w% to 0.5 w / w%. The meaning of "total weight of the external preparation" is as described above. It should be noted that for the present invention, w / w% means weight / weight%, and can be used interchangeably with mass / mass%.

[0133] As other components, the external preparation of the present invention may contain an oily component. As the oily component, it is not limited to the following, but for example, hydrocarbon oils, ester oils; and fats and oils such as vegetable oils and animal oils can be mentioned; higher alcohols such as behenyl alcohol and stearyl alcohol; higher fatty acids such as stearic acid and palmitic acid; fat-soluble vitamins, etc. As specific examples of the oily component, for example, squalene, squalane, isopropyl myristate, octyldodecyl myristate, castor oil, olive oil, tocopherol, and tocopheryl acetate can be mentioned, but it is not limited to these.

[0134] As other components, the external preparation of the present invention may contain a surfactant. As examples of the surfactant used in the present invention, nonionic surfactants represented by block copolymers formed by hydrophilic ethylene oxide and hydrophobic propylene oxide (polyoxyethylene polyoxypropylene glycol), polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, and polyoxyethylene hydrogenated castor oil can be mentioned. As the nonionic surfactant, the molecular weight is more preferably 1000 or more (more preferably 5000 or more). As the block copolymer formed by ethylene oxide and propylene oxide, polyoxyethylene(200)polyoxypropylene(70)glycol, polyoxyethylene(196)polyoxypropylene(67)glycol, polyoxyethylene(160)polyoxypropylene(30)glycol, polyoxyethylene(120)polyoxypropylene(40)glycol, etc. can be mentioned. These block copolymers formed by ethylene oxide and propylene oxide are known as Pluronic (R) , Poloxamer (R) , UNILUBE (R) , PLONON (R)Various names such as these are commercially available. As particularly preferred examples of the surfactant, the following can be mentioned: polyoxyethylene(200) polyoxypropylene(70) glycol, polyoxyethylene(196) polyoxypropylene(67) glycol (alias: Pluronic (R) F127; UNILUBE 70DP-950B, Poloxamer (R) 407), etc., but are not limited thereto. It should be noted that in the present invention, the non-lamellar liquid crystal-forming lipid used in the present invention is not included in the scope of the surfactant. The external preparation of the present invention may contain one or more than two kinds of such surfactants.

[0135] Relative to the total weight of the external preparation, the surfactant of the external preparation of the present invention generally may contain 0.001 w / w% or more, for example, 0.01 w / w% or more, preferably 0.05 w / w% or more, more preferably 0.1 w / w% or more, for example, 0.01 w / w% to 10 w / w%, 0.1 w / w% to 5 w / w%, 0.3 w / w% or more, 0.3 w / w% to 2 w / w%, 0.3 w / w% to 1.5 w / w%, 0.3 w / w% to 1 w / w% or 0.55 w / w% to 0.9 w / w%.

[0136] As other components, the external preparation of the present invention may contain ethanol (in the present invention, unless otherwise specified, it refers to absolute ethanol). It should be noted that ethanol (absolute ethanol) is not an aqueous medium.

[0137] As other components, the external preparation of the present invention may contain pharmaceutically acceptable water-soluble organic compounds such as propylene glycol, glycerin, ethylene glycol, and butylene glycol.

[0138] As other components, the external preparation of the present invention may contain other pharmaceutically acceptable additives. As additives, the following can be mentioned: carriers, excipients, stabilizers, buffers, preservatives, colorants, flavoring agents, pH regulators, dispersants, etc., but are not limited thereto.

[0139] In the external preparation of the present invention, the non-lamellar liquid crystal-forming lipid may or may not form a liquid crystal (especially a non-lamellar liquid crystal). When the non-lamellar liquid crystal-forming lipid does not form a liquid crystal in the external preparation, the external preparation is also called a liquid crystal precursor preparation. In the external preparation of the present invention that does not contain an aqueous medium or does not contain a sufficient amount of an aqueous medium, since the non-lamellar liquid crystal-forming lipid does not form a liquid crystal, the external preparation is a liquid crystal precursor preparation.

[0140] By applying the external preparation of the present invention to the surface of a living body, preferably to the skin or mucosa, the drug contained in the external preparation can be administered to the living body. The present invention also provides a drug delivery method or a drug administration method, which comprises applying the external preparation of the present invention to the surface of a living body, preferably to the skin or mucosa. The application object of the external preparation of the present invention is not particularly limited, but generally is an animal, preferably a mammal or a bird including primates such as humans; domestic animals; pets such as dogs, cats, rabbits, and experimental animals, etc.

[0141] Next, the external preparation in a preferred dosage form will be described in detail.

[0142] 4. Patch

[0143] The external preparation of the present invention can be formulated into a patch dosage form. The present invention also provides a patch containing the external preparation of the present invention. In the present invention, a patch refers to a pharmaceutical preparation for percutaneous or transmucosal absorption of a drug, which is attached to the skin or mucosa for use. The patch can be a local action type or a systemic action type. The patch has an adhesive layer. The adhesive layer of the patch is preferably a composition containing an adhesive (more preferably a lipophilic adhesive), and preferably contains a non-lamellar liquid crystal-forming lipid and a drug in addition to the adhesive. As patches, although not limited to the following, examples include: rubber plaster (also called: plaster), hydrogel patch (cataplasms), etc.

[0144] A rubber plaster is a preparation having an adhesive layer made of a pressure-sensitive adhesive as a base. The adhesive layer is preferably a composition containing a pressure-sensitive adhesive, a non-lamellar liquid crystal-forming lipid, and a drug. In one embodiment, the rubber plaster has an adhesive layer and a support, and the adhesive layer contains a pressure-sensitive adhesive, a non-lamellar liquid crystal-forming lipid, and a drug. In a preferred embodiment, the rubber plaster is a so-called matrix type preparation having an adhesive layer, a backing (release sheet), and a support, and the adhesive layer contains a pressure-sensitive adhesive, a non-lamellar liquid crystal-forming lipid, and a drug. The pressure-sensitive adhesive used for the rubber plaster is preferably a lipophilic polymer. As the pressure-sensitive adhesive, although not limited to the following, examples include: acrylic, urethane, rubber, or silicone adhesives. As the acrylic adhesive, although not limited to the following, examples include DURO-TAK (R) (Henkel Corporation), for example DURO-TAK (R) 387 - 2516.

[0145] The support can be of any shape that can be used in a patch, but is preferably a sheet substrate. As the support, for example, a known support can be used. The support can be, for example, any material suitable as a support for a patch, such as a film like a polymer film, a cloth like a non-woven fabric or a woven fabric, or paper. The support can be composed of, for example, polyester, polyethylene (such as polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), polyolefin (such as polyethylene, polypropylene, etc.), cellulose derivatives such as cellulose esters, polyurethane, polyamide, etc. The thickness of the support is not limited to the following, but is generally 5 μm to 500 μm, preferably 10 to 300 μm, for example 10 to 200 μm, 10 to 100 μm, 25 to 100 μm, 50 μm to 300 μm, or 60 μm to 200 μm.

[0146] As the release sheet, any release sheet that can be used in a patch can be used. For example, a known release film can be used. The release sheet can be composed of, for example: a polymer film such as polyester (such as polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), polyolefin (such as polyethylene, polypropylene, etc.), polyvinyl chloride, polyvinylidene chloride, etc., a cellulose derivative such as cellulose ester, or paper, etc., which has a layer of fluororesin, silicone resin, etc. on the contact surface with the adhesive layer, or a laminated film of these various materials, etc. The thickness of the release sheet is not limited to the following, but is generally 5 to 500 μm, preferably 10 to 300 μm, for example 10 to 200 μm, 25 to 100 μm, 50 μm to 300 μm, or 60 μm to 200 μm.

[0147] The thickness of the adhesive layer in the patch is not limited to the following, but is generally 5 μm to 1 mm, preferably 5 to 500 μm, for example 5 to 200 μm, 10 to 100 μm, or 20 to 50 μm.

[0148] Regarding the non-lamellar liquid crystal-forming lipid and the drug, as described above.

[0149] In one embodiment, the amount of the non-lamellar liquid crystal-forming lipid in the adhesive layer of a patch, such as a rubber plaster, is preferably an amount that forms a liquid crystal. Regarding the non-lamellar liquid crystal-forming lipid, as described above. More specifically, the amount of the non-lamellar liquid crystal-forming lipid in the adhesive layer is not limited to the following, but is generally 0.1 w / w% or more, preferably 5 w / w% or more, relative to the total weight of the adhesive layer, for example 1 w / w% to 20 w / w%, 1 w / w% to 10 w / w%, 5 w / w% to 20 w / w%, 5 w / w% to 10 w / w%, 10 w / w% to 30 w / w%, 10 w / w% to 25 w / w%, or 13 w / w% to 15 w / w%.

[0150] The amount of the drug in the adhesive layer is not limited to the following, but is generally 0.0001 w / w% or more, preferably 0.0005 w / w% to 5 w / w%, more preferably 0.001 w / w% to 5 w / w% with respect to the total weight of the adhesive layer. For example, it can be 0.001 w / w% to 1 w / w%, 0.01 w / w% to 1 w / w%, 0.05 w / w% to 1 w / w%, or 0.1 to 0.5 w / w%.

[0151] The amount of the adhesive (e.g., pressure-sensitive adhesive) in the adhesive layer is not limited to the following, but is generally 70 w / w% or more, preferably 75 w / w% or more, more preferably 75 w / w% to 90 w / w%, 75 w / w% to 85 w / w%, 80 w / w% to 95 w / w%, or 85 w / w% to 95 w / w%, 85 w / w% to 90 w / w% with respect to the total weight of the adhesive layer. For example, it can be 80 w / w% or 90 w / w%.

[0152] In one embodiment, the amounts of the non-lamellar liquid crystal-forming lipid and the adhesive in the adhesive layer of a patch such as a rubber plaster are not limited to the following, but can be 1 w / w% to 20 w / w% and 75 w / w% to 90 w / w% respectively with respect to the total weight of the adhesive layer. In another embodiment, the amounts of the non-lamellar liquid crystal-forming lipid and the adhesive in the adhesive layer of a patch such as a rubber plaster are not limited to the following, but can be 1 w / w% to 10 w / w% and 85 w / w% to 95 w / w% respectively with respect to the total weight of the adhesive layer. In another embodiment, the amounts of the non-lamellar liquid crystal-forming lipid and the adhesive in the adhesive layer of a patch such as a rubber plaster are not limited to the following, but can be 10 w / w% to 15 w / w% and 75 w / w% to 85 w / w% respectively with respect to the total weight of the adhesive layer. In another embodiment, the amounts of the non-lamellar liquid crystal-forming lipid and the adhesive in the adhesive layer of a patch such as a rubber plaster are not limited to the following, but can be 13 w / w% to 15 w / w% and 75 w / w% to 85 w / w% respectively with respect to the total weight of the adhesive layer.

[0153] The adhesive layer of a patch, such as a rubber plaster, contains a non-lamellar liquid crystal-forming lipid and a drug, and preferably contains an aqueous medium (e.g., water). By containing the aqueous medium, the non-lamellar liquid crystal-forming lipid forms a liquid crystal in the patch, and the drug is encapsulated in the liquid crystal. Regarding the aqueous medium, as described above. Alternatively, the patch itself may not contain an aqueous medium. In this case, when the patch is applied to the surface of a living body, the non-lamellar liquid crystal-forming lipid forms a liquid crystal on the surface of the living body due to the presence of water around it, and the drug can also be encapsulated in the liquid crystal. In one embodiment, the aqueous medium, as a liquid containing a drug or other components, can be admixed in the adhesive layer composition. The amount of the aqueous medium in the adhesive layer is not limited to the following, but is generally 0.1 w / w% or more, preferably 0.5 w / w% or more, more preferably 1 w / w% or more, for example 5 w / w% or more, 3 w / w% to 30 w / w%, 5 w / w% to 10 w / w%, 10 w / w% to 30 w / w%, 10 w / w% to 25 w / w%, or 13 w / w% to 15 w / w% based on the total weight of the adhesive layer. In one embodiment, the weight ratio of the non-lamellar liquid crystal-forming lipid to the aqueous medium in the adhesive layer can preferably be 1:5 to 5:1, for example, it can be 1:1 to 10:1, 1:1 to 5:1, 1:1 to 3:1, 1.5:1 to 10:1, 2:1 to 5:1, and in a preferred example, it is 2:1 to 3:1. The weight ratio of the non-lamellar liquid crystal-forming lipid to the adhesive in the adhesive layer can be, for example, 1:2 to 1:20, preferably 1:2 to 1:15, 1:3 to 1:10, 1:3 to 1:8, or 1:5 to 1:7.

[0154] The adhesive layer may further contain other components. Regarding other components, as described above for the external preparation of the present invention.

[0155] The manufacture of a patch, such as a rubber plaster, can be carried out using techniques well known to those skilled in the art. In one embodiment, a liquid crystal gel is prepared by uniformly mixing a non-lamellar liquid crystal-forming lipid, a drug, an aqueous medium, and optionally other components, and then an adhesive is mixed to prepare an adhesive layer composition. The adhesive layer composition is spread on a backing, the adhesive layer is dried, the adhesive layer is pressed and fixed to a support, and cut to a certain size as needed, whereby a patch such as a rubber plaster can be manufactured. Alternatively, a liquid crystal gel can be prepared as described above, and then an adhesive is mixed to prepare an adhesive layer composition. The adhesive layer composition is coated on a support, the adhesive layer is dried, and then the backing is adhered to the adhesive layer and cut to a certain size as needed, whereby a patch such as a rubber plaster can be manufactured. A patch, such as a rubber plaster, can be made in a size and / or shape suitable for attachment to the affected area, or can be made in a predetermined size and / or shape and cut into an appropriate size and / or shape for use when in use.

[0156] In such a patch, such as a rubber plaster, the drug is introduced into a liquid crystal formed from a lipid that forms a non-layered liquid crystal. When the patch is applied to the surface of a living body such as the skin and mucous membranes, it serves to increase the drug permeability in the skin and mucous membranes.

[0157] By applying the patch of the present invention, such as a rubber plaster, to the surface of a living body of an object (e.g., a mammal), preferably to the skin or mucous membranes (attachment), the drug contained in the patch can be administered transdermally or transmucosally to the object. Regarding the object, as described above. The present invention also provides a method for administering or delivering such a drug.

[0158] 5. Aerosol

[0159] The external preparation of the present invention can be formulated into an aerosol dosage form. The present invention also provides an aerosol containing the external preparation of the present invention. In the present invention, an aerosol refers to a pharmaceutical preparation in a dosage form in which a drug is ejected by the pressure of a propellant filled together with the drug in the same container. The external preparation of the present invention formulated into an aerosol dosage form consists of a composition containing a non-layered liquid crystal-forming lipid and a drug and a propellant. Examples of the propellant include: liquefied gas and / or compressed gas. Examples of the liquefied gas include: liquefied petroleum gas (LPG), dimethyl ether (DME), etc. Examples of the compressed gas include: carbon dioxide, nitrogen, air, etc. In the aerosol of the present invention, the propellant is more preferably a liquefied gas, and further preferably LPG.

[0160] The aerosol of the present invention preferably has a composition containing a non-layered liquid crystal-forming lipid and a drug and a propellant filled in a container. The composition containing a non-layered liquid crystal-forming lipid and a drug is preferably a liquid, and preferably aqueous. In other words, the external preparation of the present invention formulated into an aerosol dosage form preferably contains an aqueous medium in addition to a non-layered liquid crystal-forming lipid, a drug, and a propellant. By containing an aqueous medium, the non-layered liquid crystal-forming lipid forms a liquid crystal, and the drug is encapsulated within the liquid crystal. Alternatively, the external preparation of the present invention formulated into an aerosol dosage form may contain an aqueous medium, but in this case, the non-layered liquid crystal-forming lipid in the external preparation forms a non-layered liquid crystal through the aqueous medium present at the application site (e.g., body moisture or external moisture such as added water), and the drug is encapsulated within the liquid crystal. If the aerosol of the present invention is applied to the surface of a living body, the volatile components (solvents such as ethanol, propellants, etc.) in the aerosol volatilize, and a non-layered liquid crystal can be formed on the surface of the living body. In the aerosol of the present invention, the composition containing a non-layered liquid crystal-forming lipid and a drug and the propellant may be mixed in the container or separated into multiple phases. Regarding the non-layered liquid crystal-forming lipid, drug, and aqueous medium, as described above.

[0161] In one embodiment, the amount of the non-lamellar liquid crystal-forming lipid used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw material filled in the container, it is generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant (the total weight of the topical agent; the same hereinafter), usually 0.1 w / w% or more, preferably 0.5 w / w% or more, more preferably 1 w / w% or more, for example, 1 w / w% to 40 w / w%, 3 w / w% or more, 3 w / w% to 40 w / w%, 3 w / w% to 20 w / w%, 3 w / w% to 15 w / w%, 3 w / w% to 10 w / w%, 10 w / w% to 30 w / w%, or 5 w / w% to 9 w / w%.

[0162] In one embodiment, the amount of the drug used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw material filled in the container, it is generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, usually 0.0001 w / w% or more, preferably 0.0005 w / w% to 5 w / w%, for example, 0.0005 w / w% to 1 w / w%, 0.001 w / w% to 5 w / w%, 0.001 w / w% to 10 w / w%, 0.001 w / w% to 1 w / w%, 0.001 w / w% to 0.1 w / w%, 0.001 w / w% to 0.05 w / w%, 0.001 w / w% to 0.01 w / w%, 0.01 w / w% to 0.1 w / w%, 0.1 w / w% to 3 w / w%, or 0.1 w / w% to 1 w / w%.

[0163] In one embodiment, the amount of the propellant used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw material filled in the container, it is generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, usually 40 w / w% or more, preferably 50 w / w% or more, for example, 50 w / w% to 90 w / w%, 50 w / w% to 85 w / w%, 50 w / w% to 80 w / w%, 60 w / w% to 85 w / w%, 60 w / w% to 80 w / w%, 60 w / w% to 70 w / w%, or 65 w / w% to 75 w / w%.

[0164] In one embodiment, the amount of the aqueous medium used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw materials filled in the container, it is generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, usually 0.1 w / w% or more, preferably 0.5 w / w% or more, more preferably 1 w / w% or more, for example 3 w / w% or more, 5 w / w% or more, 0.1 w / w% - 30 w / w%, 1 w / w% - 30 w / w%, 3 w / w% - 30 w / w%, 3 w / w% - 20 w / w%, 3 w / w% - 15 w / w%, 1 w / w% - 10 w / w%, 3 w / w% - 10 w / w%, 5 w / w% - 10 w / w% or 5 w / w% - 9 w / w%.

[0165] In one embodiment, the weight ratio of the non-lamellar liquid crystal-forming lipid to the aqueous medium can preferably be 1:5 - 5:1, 1:2 - 2:1, 1:1.5 - 1.5:1, for example it can be 1:1.3 - 1.3:1, 1:1.1 - 1.1:1, and in a preferred example it is 1:1. Alternatively, the weight ratio of the non-lamellar liquid crystal-forming lipid to the aqueous medium can be 1:1 - 10:1 or 1.5:1 - 5:1, for example 1:1, 1.5:1, 2:1, 3:1, 4:1 or 5:1.

[0166] The external preparation of the present invention formulated into an aerosol dosage form may or may not contain a surfactant. In one embodiment, the composition containing the non-lamellar liquid crystal-forming lipid and the drug contains a surfactant. Regarding the surfactant, as described above. Preferred examples of the surfactant used in the aerosol include polyoxyethylene(196) polyoxypropylene(67) glycol (alias: Pluronic (R) F127, but not limited thereto. In one embodiment, the amount of the surfactant used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw materials filled in the container, it is generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, usually 0.01 w / w% or more, preferably 0.05 w / w% or more, more preferably 0.1 w / w% or more, for example 0.05 w / w% - 15 w / w%, 0.1 w / w% - 5 w / w%, 0.3 w / w% or more, 0.3 w / w% - 10 w / w%, 0.3 w / w% - 2 w / w%, 0.3 w / w% - 1.5 w / w%, 0.3 w / w% - 1 w / w% or 0.55 w / w% - 0.9 w / w%.

[0167] In one embodiment, the weight ratio of the non - lamellar liquid - crystal - forming lipid to the surfactant in the aerosol can be preferably 3:1 to 20:1, or 5:1 to 20:1. For example, it can be 3:1 to 11:1, 7:1 to 17:1, or 8:1 to 15:1, 8:1 to 13:1, 9:1 to 11:1. In a preferred example, it is 10:1.

[0168] The external preparation of the present invention formulated into an aerosol dosage form preferably further contains ethanol. The composition containing the non - lamellar liquid - crystal - forming lipid and the drug contains ethanol. By mixing ethanol, the skin permeability of the drug is further increased.

[0169] In one embodiment, the amount of ethanol used in the aerosol is not limited to the following, but relative to the total weight of the aerosol raw materials filled in the container, generally the total weight of the composition containing the non - lamellar liquid - crystal - forming lipid and the drug and the propellant, it can be 1 w / w% or more, preferably 3 w / w% or more. For example, it is 5 w / w% or more, 7 w / w% or more, 1 w / w% to 30 w / w%, 1 w / w% to 20 w / w%, 5 w / w% to 60 w / w%, 5 w / w% to 30 w / w%, 5 w / w% to 25 w / w%, 7 w / w% to 20 w / w%, 10 w / w% to 20 w / w%, 13 w / w% to 50 w / w%, 13 w / w% to 20 w / w%, or 15 w / w% to 18 w / w%.

[0170] In one embodiment, the amount of ethanol relative to the total weight of the composition containing the non - lamellar liquid - crystal - forming lipid and the drug (excluding the propellant) is not limited to the following, but for example, it can be 20 w / w% to 60 w / w% or 30 w / w% to 50 w / w%.

[0171] In one embodiment, the external preparation of the present invention formulated into an aerosol dosage form can contain a drug, a non - lamellar liquid - crystal - forming lipid (for example, an amphiphilic compound represented by the general formula (I) or a glycerol fatty acid monoester, preferably mono - O - (5,9,13 - trimethyltetradec - 4 - enoyl) glycerol or mono - O - (5,9,13,17 - tetramethyloctadec - 4 - enoyl) glycerol), a surfactant (preferably Pluronic (R)F127), ethanol, and a propellant (preferably LPG). In this case, relative to the total weight of the aerosol raw materials filled in the container, generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, the amount of ethanol can be as described above, but is preferably 5 w / w% to 25 w / w%, 13 w / w% to 20 w / w%, or 15 w / w% to 18 w / w%. In this case, relative to the total weight of the aerosol raw materials filled in the container, generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, the amount of the propellant is preferably 50 w / w% to 85 w / w%, 60 w / w% to 80 w / w%, or 60 w / w% to 70 w / w%. In one embodiment, relative to the total weight of the aerosol raw materials filled in the container, generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, the amount of ethanol can be 5 w / w% to 25 w / w%, and the amount of the propellant can be 60 w / w% to 80 w / w%. In one embodiment, relative to the total weight of the aerosol raw materials filled in the container, generally the total weight of the composition containing the non-lamellar liquid crystal-forming lipid and the drug and the propellant, the amount of ethanol can be 15 w / w% to 18 w / w%, and the amount of the propellant can be 60 w / w% to 70 w / w%.

[0172] The external preparation of the present invention formulated into an aerosol dosage form may also contain other components. Such other components are basically included in the composition containing the non-lamellar liquid crystal-forming lipid and the drug. Regarding other components, as described above for the external preparation of the present invention.

[0173] The production of the aerosol can be carried out using techniques well known to those skilled in the art. In one embodiment, a composition is prepared by uniformly mixing a non-lamellar liquid crystal-forming lipid, a drug, an aqueous medium, and optionally a surfactant and other components, further adding ethanol and mixing as needed, putting the aerosol stock solution into a container, and then filling the container with a propellant by using an inflation valve or the like, thereby an aerosol can be produced. In another embodiment, a composition can also be prepared by uniformly mixing a non-lamellar liquid crystal-forming lipid, a drug, and optionally a surfactant and other components, further adding ethanol and mixing as needed as the aerosol stock solution.

[0174] By using the spray of such an aerosol, the liquid crystal encapsulating the drug that is stably formed and adhered to the application site on the biological surface has excellent drug permeability.

[0175] By applying the aerosol agent of the present invention to the biological surface of an object (e.g., a mammal), preferably to the skin or mucosa (spray), the drug contained in the aerosol agent can be administered transdermally or transmucosally to the object. Regarding the object, as described above. The present invention also provides a method for administering or delivering such a drug.

[0176] 6. Liquid crystal precursor preparation

[0177] The non-lamellar liquid crystal-forming lipid of the external preparation of the present invention may not form a liquid crystal (non-lamellar liquid crystal) in the external preparation. When the external preparation of the present invention does not contain an aqueous medium or when the non-lamellar liquid crystal-forming lipid does not contain an amount of aqueous medium sufficient to form a liquid crystal, the non-lamellar liquid crystal-forming lipid does not form a liquid crystal in the external preparation. However, if such an external preparation is applied to the biological surface in the presence of water, the non-lamellar liquid crystal-forming lipid forms a liquid crystal on the biological surface and stably adheres to the biological surface. The present invention also provides an external preparation of the present invention in which the non-lamellar liquid crystal-forming lipid does not form a liquid crystal, that is, a liquid crystal precursor preparation.

[0178] The external preparation of the present invention as a liquid crystal precursor preparation is preferably a composition containing a non-lamellar liquid crystal-forming lipid and a drug and not containing an aqueous medium or not containing a sufficient amount of aqueous medium. Regarding the non-lamellar liquid crystal-forming lipid, the drug, and the aqueous medium, as described above.

[0179] In one embodiment, the amount of the non-lamellar liquid crystal-forming lipid used in the liquid crystal precursor preparation is not limited to the following, but relative to the total weight of the liquid crystal precursor preparation (external preparation), it can be 10 w / w% or more, preferably 30 w / w% or more, or 50 w / w% or more, more preferably 60 w / w% or more, for example, 70 w / w% or more, 50 w / w% - 99.8 w / w% or more, 60 w / w% - 99.8 w / w% or more, 65 w / w% - 99.8 w / w%, 65 w / w% - 99.5 w / w%, 68 w / w% - 99 w / w%, 70 w / w% - 99.5 w / w%, or 50 w / w% - 90 w / w%, or 70 w / w% - 90 w / w%.

[0180] In one embodiment, the amount of the drug used in the liquid crystal precursor preparation is not limited to the following, but relative to the total weight of the liquid crystal precursor preparation (external preparation), it is usually 0.0001 w / w% or more, preferably 0.0001 w / w% - 10 w / w%, for example, 0.0005 w / w% - 5 w / w%, 0.0005 w / w% - 1 w / w%, 0.001 w / w% - 5 w / w%, 0.001 w / w% - 1 w / w%, or 0.001 w / w% - 0.1 w / w%.

[0181] The external preparation of the present invention as a liquid crystal precursor preparation preferably further contains a water-soluble polymer. Regarding the water-soluble polymer, as described above. Preferred examples of the water-soluble polymer include: hydroxypropyl cellulose (HPC), such as HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H, but are not limited to these.

[0182] In one embodiment, the amount of the water-soluble polymer in the liquid crystal precursor preparation is not limited to the following, but is, for example, 0.01 w / w% or more, preferably 0.1 w / w% or more, relative to the total weight of the liquid crystal precursor preparation (external preparation), and is, for example, 0.1 w / w% to 10 w / w%, 1 w / w% to 5 w / w%, or 0.5 w / w% to 2 w / w%.

[0183] The external preparation of the present invention as a liquid crystal precursor preparation may further contain or not contain ethanol. In one embodiment, the amount of ethanol in the liquid crystal precursor preparation is not limited to the following, but may be 1 w / w% or more, preferably 4 w / w% or more, relative to the total weight of the liquid crystal precursor preparation (external preparation), and is, for example, 5 w / w% to 40 w / w%, 5 w / w% to 30 w / w%, 10 w / w% to 30 w / w%.

[0184] The external preparation of the present invention as a liquid crystal precursor preparation may further contain or not contain an oily component. Regarding the oily component, as described above. Preferred examples of the oily component include: squalene, squalane, isopropyl myristate, tocopherol, etc., but are not limited to these. In one embodiment, the amount of the oily component in the liquid crystal precursor preparation is not limited to the following, but is, for example, 0.01 w / w% or more, and is, for example, 0.01 w / w% to 60 w / w%, 0.1 w / w% to 40 w / w%, 1 w / w% to 30 w / w%, 1 w / w% to 10 w / w%, or 1 w / w% to 8 w / w% relative to the total weight of the liquid crystal precursor preparation (external preparation).

[0185] In one embodiment, the external preparation of the present invention as a liquid crystal precursor preparation may contain a drug, a non-lamellar liquid crystal-forming lipid (for example, an amphiphilic compound represented by the general formula (I) or a glycerol fatty acid monoester, preferably mono-O-(5,9,13-trimethyltetradec-4-enoyl) glycerol or mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) glycerol), a water-soluble polymer (preferably hydroxypropyl cellulose), and ethanol.

[0186] The external preparation of the present invention as a liquid crystal precursor preparation may further contain other components. Regarding other components, as described above for the external preparation of the present invention.

[0187] The production of the liquid crystal precursor preparation can be carried out using techniques well-known to those skilled in the art. The liquid crystal precursor preparation can be produced by sufficiently mixing the above-mentioned raw materials. In one embodiment, the liquid crystal precursor preparation can be produced by sufficiently mixing a water-soluble polymer, ethanol, and, optionally, an oily component, etc. in a non-lamellar liquid crystal-forming lipid, adding a drug thereto, and sufficiently mixing. Alternatively, the liquid crystal precursor preparation can also be produced by sufficiently mixing a drug, ethanol, and, optionally, a water-soluble polymer and an oily component, etc., adding a non-lamellar liquid crystal-forming lipid thereto, and mixing. In addition, the liquid crystal precursor preparation can also be produced simply by sufficiently mixing a non-lamellar liquid crystal-forming lipid, a medicament, a water-soluble polymer, an oily component, etc.

[0188] When such a liquid crystal precursor preparation is applied to the surface of a living body, in the presence of water, it forms a liquid crystal encapsulating the drug, stably adheres to the application site, and has excellent drug permeability.

[0189] The liquid crystal precursor preparation of the present invention can also be applied to the skin, but is more preferably applied to the mucosa. By applying the liquid crystal precursor preparation of the present invention to the mucosa, the non-lamellar liquid crystal-forming lipid comes into contact with water from the living body, and self-formation of a liquid crystal (non-lamellar liquid crystal) formed from the non-lamellar liquid crystal-forming lipid occurs on the mucosal surface. Thereby, the liquid crystal encapsulating the drug stably adheres to the mucosa and has excellent drug mucosal permeability. Therefore, the present invention provides not only a preparation for application to the skin but also a preparation for application to the mucosa. The external preparation of the present invention as a liquid crystal precursor preparation is particularly preferably applied to the mucosa.

[0190] By applying the liquid crystal precursor preparation of the present invention to the surface of a living body of an object (for example, a mammal), preferably applied to the mucosa or skin (for example, spraying, coating, dropping, etc.), the drug contained in the liquid crystal precursor preparation can be administered to the object through the mucosa or transdermally. When applying the liquid crystal precursor preparation of the present invention to the skin, it is preferably applied to the skin pre-wetted with an aqueous medium or an aqueous medium is added to the preparation after applying the preparation to the skin. Regarding the object and the aqueous medium, as described above. The present invention also provides such a method for administering or delivering a drug.

[0191] 7. External preparation containing microparticles

[0192] The present invention also provides an external preparation containing microparticles, and the microparticles contain the above non-lamellar liquid crystal-forming lipid and the above drug. The external preparation of the present invention can be a dispersion (emulsion) or other dispersions. The external preparation of the present invention can also contain a dispersion of microparticles, such as a dispersion liquid (microparticle dispersion liquid), and the microparticles contain a non-lamellar liquid crystal-forming lipid and a drug. The dispersion, such as a dispersion liquid, preferably contains the above non-lamellar liquid crystal-forming lipid and the above drug in a dispersion medium such as an aqueous medium like water, and also preferably contains a dispersant such as a surfactant. The dispersion, such as a dispersion liquid, may also contain a solvent such as ethanol and / or an oily component as the case may be.

[0193] In the present invention, "microparticles" refer to particles having an average particle diameter of less than 1 mm. The "microparticles" of the present invention can be microparticles or nanoparticles. In the present invention, "microparticles" refer to particles having an average particle diameter of 1 μm or more and less than 1 mm. In the present invention, "nanoparticles" refer to particles having an average particle diameter of 1 nm or more and less than 1 μm. In the present invention, "dispersion" refers to a dispersion medium containing microparticles in a dispersed state. In the present invention, "microparticle dispersion liquid" refers to a liquid medium (for example, an aqueous medium such as water or a physiologically acceptable aqueous solution such as physiological saline) containing microparticles in a dispersed state. "Microparticle dispersion liquid" and "nanoparticle dispersion liquid" refer to a liquid medium (for example, an aqueous medium such as water or a physiologically acceptable aqueous solution such as physiological saline) containing microparticles or nanoparticles in a dispersed state, respectively. The microparticles of the present invention, such as microparticles or nanoparticles, are mainly composed of a non-lamellar liquid crystal-forming lipid and can contain a drug inside. The microparticles, such as microparticles or nanoparticles, can be prepared by dispersing a liquid crystal phase. In one embodiment, the microparticles, such as microparticles or nanoparticles, can be prepared as a dispersion liquid (emulsion) obtained by dispersing a suspension containing a non-lamellar liquid crystal-forming lipid, a drug, an aqueous medium, a dispersant such as a surfactant, and other components as needed by high-pressure dispersion, ultrasonic treatment, etc.

[0194] The non-lamellar liquid crystal-forming lipid used in the preparation of the microparticles can be any of the above non-lamellar liquid crystal-forming lipids. In one embodiment, the non-lamellar liquid crystal-forming lipid can be an amphiphilic compound represented by the general formula (I), for example, it can be mono-O-(5,9,13-trimethyltetradec-4-enoyl) glycerol. In another embodiment, the non-lamellar liquid crystal-forming lipid can be a glycerol fatty acid monoester, such as glycerol monooleate.

[0195] The microparticles can contain any of the above drugs, but in one embodiment, it can be said to be a lipophilic (oleophilic) drug.

[0196] The "fine particles" of the present invention are not limited to the following, but preferably have an average particle size of 1 nm or more and less than 1 mm. For example, the average particle size can be 1 nm to 500 μm, 10 nm to 500 μm, 50 nm to 500 μm, 10 nm to 1 μm, or 50 nm to 50 μm. The nanoparticles of the present invention are not limited to the following, but preferably have an average particle size of 1 nm to 500 nm. For example, the average particle size can be 50 nm to 500 nm, 100 nm to 400 nm, or 100 nm to 300 nm.

[0197] In addition to containing non - lamellar liquid - crystal - forming lipids and drugs, the above - mentioned fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, may also contain any of the above - mentioned other components. In one embodiment, the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, also preferably contains any of the above - mentioned surfactants. For example, block copolymers formed from ethylene oxide and propylene oxide such as polyoxyethylene(196) polyoxypropylene(67) glycol (alias: Pluronic (R) F127). In one embodiment, the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, may contain a solvent such as ethanol. In one embodiment, the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, may contain a surfactant and ethanol. In one embodiment, the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, may contain the above - mentioned oily component, the above - mentioned water - soluble organic compound, and / or other pharmaceutically acceptable additives.

[0198] In one embodiment, the weight ratio of the non - lamellar liquid - crystal - forming lipid to the dispersant in the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, is not limited to the following, but is preferably non - lamellar liquid - crystal - forming lipid:dispersant = 1:1 to 100:1. For example, it can be 3:1 to 50:1, 3:1 to 10:1, 5:1 to 40:1, 10:1 to 30:1, 10:1 to 25:1, or 15:1 to 25:1.

[0199] In one embodiment, when using a solvent such as ethanol in the fine - particle dispersion, such as a fine - particle dispersion liquid like a nanoparticle dispersion liquid, the weight ratio of the non - lamellar liquid - crystal - forming lipid to the solvent (such as ethanol) is not limited to the following, but is preferably non - lamellar liquid - crystal - forming lipid:solvent (such as ethanol) = 1:10 to 10:1. For example, it can be 1:1 to 10:1, 1.5:1 to 5:1, 2:1 to 10:1, or 5:1 to 10:1.

[0200] In one embodiment, the amounts of non - lamellar liquid - crystal - forming lipid, drug, dispersant (such as surfactant), and solvent (such as ethanol) relative to the total weight of the microparticle dispersion, such as nanoparticle dispersion, etc., can be, for example, 1 w / w% - 40 w / w%, 0.001 w / w% - 10 w / w%, 0.05 w / w% - 15 w / w%, and 1 w / w% - 30 w / w% respectively. In another embodiment, the amounts of non - lamellar liquid - crystal - forming lipid, drug, dispersant (such as surfactant), and solvent (such as ethanol) relative to the total weight of the microparticle dispersion, such as nanoparticle dispersion, etc., can be, for example, 10 w / w% - 30 w / w%, 0.1 w / w% - 3 w / w%, 0.3 w / w% - 10 w / w%, and 1 w / w% - 20 w / w% respectively.

[0201] In one embodiment, the amounts of non - lamellar liquid - crystal - forming lipid, drug, and dispersant (such as surfactant) relative to the total weight of the microparticle dispersion, such as nanoparticle dispersion, etc., can be, for example, 1 w / w% - 40 w / w%, 0.001 w / w% - 10 w / w%, and 0.05 w / w% - 15 w / w% respectively. In another embodiment, the amounts of non - lamellar liquid - crystal - forming lipid, drug, and dispersant (such as surfactant) relative to the total weight of the microparticle dispersion, such as nanoparticle dispersion, etc., can be, for example, 10 w / w% - 30 w / w%, 0.1 w / w% - 3 w / w%, and 0.3 w / w% - 10 w / w% respectively.

[0202] The external preparation of the present invention containing the above - mentioned microparticles or microparticle dispersion can be any of the above - mentioned dosage forms. In one embodiment, the external preparation of the present invention containing microparticles or microparticle dispersion can be applied to the biological surface of an object (e.g., a mammal), preferably to the skin or mucosa. In one embodiment, the external preparation of the present invention containing microparticles or microparticle dispersion can be used for application to the mucosa (mucosal surface), for example, it can be a nasal preparation. In another embodiment, the external preparation of the present invention containing microparticle dispersion or microparticle dispersion can be a spray such as an aerosol.

[0203] 8. Intracerebral delivery

[0204] The external preparation of the present invention can be particularly advantageously used for delivering drugs into the brain. In one embodiment, the external preparation of the present invention for intracerebral drug delivery may be an external preparation containing the above-mentioned microparticles or microparticle dispersion. In one embodiment, the external preparation of the present invention for application to mucous membranes (mucous membrane surfaces), for example, the external preparation of the present invention as a nasal preparation, is particularly suitable for delivering drugs into the brain. Such an external preparation of the present invention may be an external preparation of the present invention containing the above-mentioned microparticles or microparticle dispersion, and may also be the above-mentioned patch, aerosol, or liquid crystal precursor preparation. The external preparation of the present invention can effectively deliver drugs into the brain by transdermal administration or transmucosal administration, such as intranasal administration. The external preparation of the present invention can greatly improve the drug delivery efficiency into the brain (especially including the olfactory bulb, cortex, brainstem, cerebellum, midbrain, and / or hippocampus).

[0205] Therefore, the present invention also provides a method for delivering drugs into the brain, which includes transdermal administration or transmucosal administration of the external preparation of the present invention to any of the above-mentioned subjects such as humans, for example, intranasal administration. Transdermal administration is not limited to the following, but patches, sprays (such as aerosols), ointments, or creams can also be used for transdermal administration. Transmucosal administration can also be carried out using patches, sprays (such as aerosols), nasal preparations, oral preparations, suppositories, or vaginal preparations, etc.

[0206] The dosage of the external preparation of the present invention for delivering drugs into the brain can be appropriately set by those skilled in the art according to the drug. For example, the dosage per administration of the external preparation of the present invention is 1 ng to 10 g per kilogram of the body weight of the subject, and can be, for example, 10 ng to 100 mg. For example, the dosage per administration of the external preparation of the present invention containing a microparticle dispersion is preferably 1 μL to 500 μL per kilogram of the body weight of the subject, based on the amount of the microparticle dispersion, and can be, for example, 10 μL to 100 μL.

[0207] The drug contained in the external preparation for intracerebral drug delivery can be any drug expected to be delivered into the brain, which can be an organic compound, an inorganic compound, or can also be a protein, peptide, amino acid, nucleic acid, etc. The drug can be selected from the above-mentioned drugs. As drugs, for example, drugs for treating central nervous system diseases of the brain such as Alzheimer's disease, Parkinson's disease, cerebrovascular disorders, brain tumors, antipsychotics, anesthetics, etc. can be cited, but are not limited to these.

[0208] Examples

[0209] Hereinafter, the present invention will be further specifically described with reference to examples. However, the technical scope of the present invention is not limited to these examples.

[0210] [Example 1] Synthesis of mono - O - (5,9,13 - trimethyltetradec - 4 - enoyl) glycerol

[0211] [Chemical Formula 6]

[0212]

[0213] At 80 °C, 1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate (methyl tetrahydrofarnesoate) was slowly added dropwise to a solution of 0.65 g (7.1 mmol) of glycerol and 0.59 g (4.3 mmol) of potassium carbonate in 3.5 mL of anhydrous N,N-dimethylformamide. The mixture was stirred at 100 °C for 18 hours, then 1 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane mixture) to obtain the title compound as a colorless transparent liquid.

[0214] For the obtained compound, 1 1H-NMR measurement and viscosity measurement were carried out, and the results are shown below.

[0215] 1 1H-NMR spectrum (300 MHz, CDCl 3 , TMS) δ: 0.80 - 0.90 (m, 9H), 1.00 - 1.70 (m, 15H), 1.97 (td, J = 7.8, 17.0 Hz, 2H), 2.13 (t, J = 6.1 Hz, 1H, OH), 2.25 - 2.45 (m, 4H), 2.55 (d, J = 5.2 Hz, 1H, OH), 3.50 - 4.00 (m, 3H), 4.10 - 4.25 (m, 2H), 5.08 (t, J = 6.7 Hz, 1H) Viscosity: 0.48 Pa·s (shear rate 92 1 / s)

[0216] The synthesized mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol is also known as C17MGE or C17 glyceride.

[0217] [Example 2] Synthesis of mono-O-(5,9,13-trimethyltetradecanoyl)glycerol

[0218] [Chemical Formula 7]

[0219]

[0220] To 50.3 g (177 mmol) of methyl 5,9,13-trimethyltetradecanoate, 70 g (0.53 mol) of 2,2-dimethyl-1,3-dioxolane-4-methanol and 36.7 g (266 mmol) of potassium carbonate were added, and the mixture was stirred at 85 °C for 3 hours under a reduced pressure of 200 mmHg to 250 mmHg. During this period, methanol formed in the reaction was distilled off. The resulting reaction solution was concentrated under reduced pressure (50 °C → 210 °C, 1.4 kPa → 0.38 kPa), and then purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 43.0 g (yield 63%) of methyl 5,9,13-trimethyltetradecanoate (2,2-dimethyl-1,3-dioxolan-4-yl) ester.

[0221] To a solution of 32.7 g (85.0 mmol) of methyl 5,9,13-trimethyltetradecanoate (2,2-dimethyl-1,3-dioxolan-4-yl) ester in tetrahydrofuran (340 mL) at room temperature, 85 mL of 3 M hydrochloric acid was added, and the mixture was stirred at the same temperature for 5 hours. The reaction solution was added to ethyl acetate (300 mL) and saturated aqueous sodium hydrogen carbonate solution (400 mL) for liquid separation. The obtained organic layer was washed with saturated brine and then dried over magnesium sulfate. The residue was obtained by concentration after filtration, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 28.7 g (yield 98%) of the title compound as a colorless transparent liquid. For the obtained compound, the 1 results of 1H-NMR measurement are shown below.

[0222] 1 1H-NMR spectrum (270 MHz, CDCl 3 3, TMS) δ: 0.7 - 0.9 (m, 12H), 0.95 - 1.45 (m, 16H), 1.45 - 1.75 (m, 3H), 2.34 (t, J = 7.4 Hz, 2H), 3.60 (dd, J = 5.8, 11.5 Hz, 1H), 3.70 (dd, J = 4.0, 11.5 Hz, 1H), 3.94 (m, 1H), 4.15 (dd, J = 5.9, 11.7 Hz, 1H), 4.21 (dd, J = 4.7, 11.7 Hz, 1H)

[0223] The synthesized mono-O-(5,9,13-trimethyltetradecanoyl)glycerol is also called saturated C17 glyceride.

[0224] [Example 3] Synthesis of mono-O-(5,9,13-trimethyltetradeca-4,8,12-trienoyl)glycerol

[0225] [Chemical formula 8]

[0226]

[0227] Under a reduced pressure of 200 mmHg to 250 mmHg, 13.9 g (50.0 mmol) of methyl 5,9,13-trimethyltetradeca-4,8,12-trienoate (farnesyl acetate) was slowly added dropwise to an anhydrous N,N-dimethylformamide (20 mL) solution of 9.2 g (0.10 mol) of glycerol and 0.28 g (2.0 mmol) of potassium carbonate at 85 °C, and the mixture was stirred at the same temperature for 3 hours. During this period, methanol generated in the reaction was distilled off. The resulting reaction solution was diluted with a mixed solvent of ethyl acetate / hexane (1:1, 150 mL), and then washed with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue was obtained by concentration after filtration, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100:0 to 0:100), thereby obtaining 8.22 g (yield 49%) of the title compound as a colorless transparent liquid. For the obtained compound, 1 1H-NMR measurement and viscosity measurement were carried out, and the results are shown below.

[0228] 1 1H-NMR spectrum (270 MHz, CDCl 3 , TMS) δ: 1.5 - 1.8 (m, 12H), 1.9 - 2.1 (m, 8H), 2.1 (brs, 1H, OH), 2.25 - 2.45 (m, 4H), 2.56 (brs, 1H, OH), 3.59 (dd, J = 5.6, 11.2 Hz, 1H), 3.68 (dd, J = 3.6, 11.2 Hz, 1H), 3.92 (m, 1H), 4.14 (dd, J = 6.0, 11.6 Hz, 1H), 4.21 (dd, J = 4.8, 11.6 Hz, 1H), 5.02 - 5.16 (m, 3H)

[0229] Viscosity: 0.26 Pa·s (shear rate 92 1 / s)

[0230] The synthesized mono-O-(5,9,13-trimethyltetradeca-4,8,12-trienoyl)glycerol is also called farnesyl acetate glycerol ester.

[0231] [Example 4] Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol

[0232] [Chemical Formula 9]

[0233]

[0234] Under reduced pressure of 60 mmHg to 70 mmHg and a nitrogen stream, 28.2 g (80.0 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 23.5 g (255 mmol) of glycerol and 0.55 g (4.0 mmol) of potassium carbonate in 48 mL of anhydrous N,N-dimethylformamide at 80 °C, and the mixture was stirred at the same temperature for 3 hours. The resulting reaction solution was diluted with a mixed solvent of ethyl acetate / hexane (1:1, 200 mL), washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by concentration after filtration was purified by silica gel column chromatography (hexane / ethyl acetate = 100:0 to 30:70) to give 13.3 g (yield 40%) of the title compound as a slightly yellow transparent liquid. For the obtained compound, 1 1H-NMR measurement was carried out, and the results are shown below.

[0235] 1 1H-NMR spectrum (300 MHz, CDCl 3 , TMS) δ: 0.80 - 0.95 (m, 12H), 1.00 - 1.70 (m, 22H), 1.85 - 2.15 (m, 2H), 2.15 - 2.55 (m, 4H), 3.53 - 3.78 (m, 3H), 3.80 - 4.00 (m, 1H), 4.10 - 4.25 (m, 2H), 5.08 (dd, J = 6.9 Hz, J = 6.9 Hz, 1H)

[0236] The synthesized mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol is also known as C22MGE or C22 glyceride.

[0237] [Example 5] Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol

[0238] [Chemical Formula 10]

[0239]

[0240] Under a nitrogen atmosphere, 2.5 g of 5% palladium on carbon was added to a solution of 20.6 g (50.0 mmol) of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol in 62 mL of ethyl acetate. The nitrogen in the reaction system was replaced with hydrogen, and then the mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 42 hours. The hydrogen in the reaction system was replaced with nitrogen, and then 5% palladium on carbon was filtered out. The filtrate was purified by silica gel column chromatography (ethyl acetate) to give 20.2 g (yield 98%) of the title compound as a colorless transparent liquid. For the obtained compound, 1The H-NMR measurement results are as follows.

[0241] 1 H-NMR spectrum (300 MHz, CDCl 3 , TMS) δ: 0.7 - 0.9 (m, 15H), 0.95 - 1.75 (m, 26H), 2.13 (t, J = 6.0 Hz, OH), 2.34 (t, J = 7.7 Hz, 2H), 2.56 (d, J = 5.1 Hz, OH), 3.55 - 3.75 (m, 2H), 3.94 (m, 1H), 4.15 (dd, J = 6.0, 11.7 Hz, 1H), 4.20 (dd, J = 4.7, 11.7 Hz, 1H)

[0242] The synthesized mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol is also known as saturated C22 glyceride.

[0243] [Example 6] Synthesis of mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol

[0244] (1) Synthesis of methyl 5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoate (geranylgeranyl acetate)

[0245] Under a nitrogen atmosphere, at 135 °C, a solution of 58.1 g (200 mmol) of 3,7,11,15-tetramethylhexadec-1,6,10,14-tetraen-3-ol (geranyl linalool) and 19 mL (0.15 mol) of trimethyl orthoacetate was added dropwise with a solution of 53 mL (0.42 mol) of trimethyl orthoacetate and 5.0 mL (40 mmol) of hexanoic acid over 8 hours. The mixture was stirred at the same temperature for 6 hours, and then, a solution of 5.3 mL (42 mmol) of trimethyl orthoacetate and 0.5 mL (4 mmol) of hexanoic acid was further added dropwise, and the mixture was further stirred at the same temperature for 2 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (3:1, 300 mL), washed with saturated aqueous sodium bicarbonate (twice) and saturated brine, and then dried over magnesium sulfate. After filtration and concentration, 67.24 g of methyl 5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoate (geranylgeranyl acetate) was obtained as a crude liquid. This crude product was directly used in the next reaction.

[0246] (2) Synthesis of mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol

[0247] [Chemical formula 11]

[0248]

[0249] Under a reduced pressure of 200 mmHg to 250 mmHg, 13.9 g (40.0 mmol) of methyl 5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoate (geranylgeranyl acetate) was slowly added dropwise to an anhydrous N,N-dimethylformamide (16 mL) solution of 7.4 g (80 mmol) of glycerol and 5.5 g (40 mmol) of potassium carbonate at 85°C, and the mixture was stirred at the same temperature for 6 hours. During this period, methanol generated in the reaction was distilled off. The resulting reaction solution was diluted with a mixed solvent of ethyl acetate / hexane (1:1, 200 mL), washed with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by concentration after filtration was purified by silica gel column chromatography (hexane / ethyl acetate = 100:0 to 0:100), thereby obtaining 5.44 g (yield 33%) of the title compound as a transparent liquid. For the obtained compound, 1 1H-NMR measurement and viscosity measurement were carried out, and the results are shown below.

[0250] 1 1H-NMR spectrum (270 MHz, CDCl 3 3, TMS) δ: 1.55 - 1.72 (m, 15H), 1.9 - 2.2 (m, 13H), 2.27 - 2.45 (m, 4H), 2.53 (brs, 1H, OH), 3.59 (dd, J = 5.4, 11.4 Hz, 1H), 3.68 (dd, J = 3, 11.4 Hz, 1H), 3.92 (m, 1H), 4.15 (dd, J = 6.0, 11.6 Hz, 1H), 4.21 (dd, J = 4.8, 11.6 Hz, 1H), 5.05 - 5.15 (m, 4H)

[0251] Viscosity: 0.37 Pa·s (shear rate 92 1 / s)

[0252] The synthesized mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl) glycerol is also called glycerol geranylgeranyl acetate.

[0253] [Example 7] Preparation of Liquid Crystal Precursor Formulation

[0254] 1. Reagents

[0255] Rhodamine B (RB) and triamcinolone acetonide (tA) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan), and hydroxypropyl cellulose (HPC) was purchased from Nippon Soda Co., Ltd. (Tokyo, Japan). The structural formula and physicochemical parameters of TA are shown in Table 1. The ClogP, which is an index of hydrophobicity, was calculated using Chem Draw Ultra 10.0 (R) (PerkinElmer Informatics, Cambridge, MA, U.S.A.).

[0256] [Table 1]

[0257]

[0258] It is known that the viscosity of HPC increases correspondingly with the increase in the average number of substituted hydroxyl groups (hydroxypropoxy groups) of each cellulose (degree of substitution). HPC with a degree of substitution of 0.2% to 0.4% is called low degree of substitution, and HPC with a degree of substitution of 53.4% to 77.5% is called high degree of substitution. Five grades of HPC, namely low-degree-of-substitution SSL, SL, and L, and high-degree-of-substitution M and H, were used. Among the viscosities (20 °C, 2% aqueous solution) of these five HPCs, SSL is 2 to 2.9 mPa·s, SL is 3 to 5.9 mPa·s, L is 6 to 10 mPa·s, M is 150 to 400 mPa·s, and H is 1000 to 4000 mPa·s.

[0259] 2. Preparation of liquid crystal precursor formulations (1)

[0260] Formulations containing RB or TA as drugs were prepared as follows.

[0261] First, HPC was added in small portions each time to a vial containing ethanol. Then, the vial was placed in a warm water bath set at 60 °C and stirred overnight to completely dissolve the HPC in the vial, obtaining an ethanol solution containing HPC.

[0262] C17MGE was mixed with the ethanol solution containing HPC obtained above at a weight ratio of 7:3 and stirred thoroughly for 1 hour. In addition, C17MGE and ethanol were added to a vial and mixed, and stirred thoroughly to prepare a solution without HPC as well.

[0263] In the solutions prepared as described above, RB was added at a final concentration of 0.001% to prepare Formulations 1 to 6 containing RB, and TA was added at a final concentration of 0.1% to prepare Formulations 7 to 12 containing TA. It should be noted that these formulations can also be prepared by adding the drug to a pre-existing ethanol solution or ethanol containing HPC and then mixing with C17MGE.

[0264] In addition, in the absence of ethanol, Formulations No. 13 to 18 containing no ethanol but containing C17MGE were prepared by adding a drug and HPC to C17MGE and stirring.

[0265] The Formulations No. 1 to 18 prepared as described above are water-free liquid crystal precursor formulations.

[0266] Moreover, as a comparative control, instead of C17MGE, water was used and mixed and stirred together with ethanol, a drug, and HPC to prepare Formulations No. 19 to 23 containing no C17MGE. In addition, an aqueous solution of TA No. 24 was prepared.

[0267] The composition ratios (weight ratios) of the prepared Formulations No. 1 to 24 are shown in Table 2.

[0268] [Table 2]

[0269]

[0270]

[0271] 3. Preparation of Liquid Crystal Precursor Formulations (2)

[0272] Using glyceryl monooleate (GMO) to replace C17MGE in the above 2., according to the composition ratio (weight ratio) in Table 3, and following the same operating steps as in the above 2., Formulations No. 25 to 36 containing RB or TA were prepared. In addition, in the absence of ethanol, by adding a drug and HPC to GMO and heating and stirring, Formulations No. 37 and 38 containing no ethanol but containing GMO were prepared.

[0273] [Table 3]

[0274]

[0275]

[0276] 4. Preparation of Liquid Crystal Precursor Formulations (3)

[0277] Using an oily component (squalene) + C17MGE, C22MGE, or an oily component (IPM or tocopherol) + C22MGE, according to the composition ratio (weight ratio) in Table 4, and following the same operating steps as in the above 2., Formulations No. 39 to 49 and 79 to 81 containing RB or TA were prepared.

[0278] [Table 4]

[0279]

[0280]

[0281] [Example 8] Characteristic Tests of the Preparation

[0282] 1. Spray Test

[0283] Add the No. 1 - 5, 13, 19 - 23, and 46 preparations prepared in Example 7 into a 5 mL spray bottle (No. 2, Maruemu Co., Ltd., Japan), and spray vertically downward once from a distance of 3 cm onto a Kimwipe wipe that has been wetted with water. When using the spray bottle with purified water, it can manually spray approximately 60 μL per press. Measure the diameter of the area (spray area) where the preparation is sprayed on the Kimwipe wipe. If the spray can be ejected and the diameter of the spray area is 1 cm or more, it is determined as a fog-like spray; if it is less than 1 cm, it is determined as a rod-like spray. If no spray can be ejected from the ejection port of the spray bottle, it is determined as unable to spray.

[0284] The result is that when using the above spray bottle, any preparation can be sprayed. The No. 1, 19, and 20 preparations are fog-like sprays, and the No. 2 - 5, 13, 21 - 23, and 46 preparations are rod-like sprays.

[0285] 2. Liquid Crystal Structure Formation Test

[0286] Use a 5 mL spray bottle in the same way as in the spray test. Add the No. 1 - 5, 19, 25, and 26 preparations prepared in Example 2 to 150 μL of purified water dropped in a glass-bottom culture dish (Matsunami Glass Industry Co., Ltd., Japan), and spray vertically downward once from a distance of 15 cm from the bottom surface of the culture dish. To determine whether a liquid crystal is formed, use a digital microscope VHX-5000 (KEYENCE Corporation, Japan) to observe the preparation in contact with water in the culture dish in polarized light microscope mode.

[0287] Figure 1 The observation results of the polarized light microscope are shown. In all of the No. 1 - 5, 25, and 26 preparations containing C17MGE or GMO, polarized light images showing a liquid crystal structure can be confirmed (A - E, G, H in Figure 1 ). However, in the No. 19 preparation containing HPC but not C17MGE, no polarized light image showing a liquid crystal structure could be confirmed (F in Figure 1 ). This indicates that the preparation containing C17MGE forms a liquid crystal structure in the sprayed water. In addition, the clearer the polarized light image can be confirmed for the preparation using HPC with a lower degree of substitution.

[0288] Moreover, regarding C17MGE and GMO, when comparing the time from spraying to liquid crystal formation (formation of a polarized image), it was found that under the condition without HPC, the C17MGE formulation No. 1 formed liquid crystal within 5 seconds, and the GMO formulation No. 25 formed liquid crystal within 10 seconds. In addition, under the condition of mixing HPC of the same level of SSL, the C17MGE formulation No. 2 formed liquid crystal within 20 seconds, and the GMO formulation No. 26 formed liquid crystal within 90 seconds. The liquid crystal formation of the formulations containing C17MGE (No. 1 and No. 2) was significantly faster. The formulations containing either C17MGE or GMO were rapidly fixed on the mucosal surface after spraying, but the formulations containing C17MGE were fixed on the mucosal surface faster and more easily than the formulations containing GMO after spraying, and it is considered that it is also easier to obtain the effect of promoting the release and absorption of the active ingredient.

[0289] 3. Small-angle X-ray scattering diffraction

[0290] When conducting the above-mentioned liquid crystal structure formation test using formulations No. 1 to No. 3, No. 13, No. 45 to No. 49 containing C17MGE or C22MGE and formulations No. 25 to No. 27, No. 37 containing GMO, the formulations sprayed into water formed a gel-like substance. For this gel-like substance, small-angle X-ray scattering (SAXS) measurement was performed using a small-angle X-ray scattering (SAXS) device (manufactured by Rigaku Corporation, Nano-Viewer) to determine the non-lamellar liquid crystal structure.

[0291] In the small-angle X-ray scattering diffraction of the gel-like substances containing formulations No. 1, No. 13, No. 37, No. 45 to No. 47 Figure 2 in A and D, and Figure 3 in A to D), at least 3 scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of inverse hexagonal phase liquid crystal From this, it was confirmed that these formulations formed inverse hexagonal phase liquid crystal.

[0292] In addition, in the small-angle X-ray scattering diffraction of the gel-like substances containing formulations No. 2, No. 3, No. 25 to No. 27 Figure 2 in B, C and E to G), at least 6 scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of cubic liquid crystal belonging to the crystallographic space group Pn3m and the ratio characteristic of inverse hexagonal phase liquid crystal From this, it was confirmed that when using these formulations, cubic liquid crystal belonging to the crystallographic space group Pn3m and inverse hexagonal phase liquid crystal were mixed and formed.

[0293] In the small-angle X-ray scattering diffraction of the gel-like substances containing formulations No. 48 and No. 49 Figure 3In E and F), at least eight scattering peaks were observed, and the peak ratio exhibited a ratio characteristic of an inverse cubic liquid crystal belonging to the crystallographic space group Fd3m. Therefore, it was confirmed that these preparations formed an inverse cubic liquid crystal belonging to the crystallographic space group Fd3m.

[0294] [Example 9] Retention test of preparations on mucosa

[0295] Three kinds of mixed anesthetics (medetomidine hydrochloride 0.15 mg / kg, midazolam 2 mg / kg, butorphanol tartrate 2.5 mg / kg) were intraperitoneally administered to male hairless rats of the WBN / ILA-Ht strain (body weight 200 - 250 g, 8 weeks old), and the back skin was excised. The stratum corneum (stratum corneum) of the excised back skin (3 cm × 3 cm) of this rat was removed by tape stripping treatment, and the obtained stratum corneum-stripped skin (epidermis-exposed skin) was used as a mucosa model.

[0296] To the mucosa model fixed on a plate covered with aluminum foil, the preparations No. 1 - 6, 13 - 17, 19 - 23, 25 - 28, 30, 39 - 41, 45, and 46 prepared in Example 7 were vertically sprayed downward once from a distance of 3 cm using a spray bottle. Immediately after spraying, the area of the preparation attached to the mucosa model (= area immediately after spraying) was measured. 15 seconds after spraying, water at 37°C was continuously flowed over the mucosa model at an angle of 45° from the horizontal for 1 hour at a flow rate of 200 mL / min, and then the area of the preparation attached to the mucosa model (= area after the flowing water test) was measured. It should be noted that in the measurement of the area immediately after spraying and the area after the flowing water test, a digital microscope VHX-5000 (KEYENCE CORPORATION, Japan) in the stereomicroscope mode equipped with a manual XY measurement system VH-M100 was used.

[0297] The reduction rate of the preparation attachment area after the flowing water test was calculated according to the following formula.

[0298] Reduction rate (%) = (area after the flowing water test - area immediately after spraying) / area immediately after spraying × 100

[0299] When the reduction rate (%) ≤ -50%, it was judged that the test sample of the preparation was peeled off from the mucosa model.

[0300] For each preparation, the flowing water test was performed more than 3 times, and they were divided into 4 groups according to the following criteria, and thus the preparation retention of each preparation was determined.

[0301] s: Samples without peeling;

[0302] a: The number of peeled samples accounted for 40% or less of the total number of samples;

[0303] b: The number of peeled specimens is greater than 40% and less than 70% of the total number of specimens;

[0304] c: The number of peeled specimens accounts for more than 70% of the total number of specimens.

[0305] For comparison, instead of the preparation prepared in Example 7, one tablet of the commercially available oral mucosa adhesion preparation Aftach (R) (Teijin Pharma Limited, Japan) or 60 mg of the oral mucosa ointment preparation KENALOG (R) (Bristol-Myers Squibb Company, USA) was respectively adhered or coated on the mucosal model, and the same running water test was carried out. The results are shown in Table 5.

[0306] [Table 5]

[0307]

[0308]

[0309] As shown in Table 5, the preparations using C17MGE or C22MGE still remained good after the 1-hour running water test, showing high mucosal adhesiveness. In particular, the preparations containing HPC and C17MGE or C22MGE showed very high mucosal adhesiveness (retentivity) and had higher mucosal adhesiveness compared with the commercially available preparations. It should be noted that the ethanol solution of HPC that did not use liquid crystal-forming lipids was completely peeled off in the running water test.

[0310] [Example 10] Preparation retention test on the skin

[0311] Using Preparation No. 2 and Preparation No. 46, instead of the mucosal model (stratum corneum-stripped skin), the skin cut from the back of a rat before tape stripping was used as the skin model, and the running water test was carried out in the same manner as in Example 9 except for this.

[0312] The results were that although both Preparation No. 2 and Preparation No. 46 were temporarily peeled off from the skin at the beginning of the running water test, the peeled gel reattached to the skin and was fixed. It is considered that by the preparation coming into contact with water completely, the reattachment on the skin surface was promoted. This result shows that the preparation of the present invention is easy to be peeled off before forming liquid crystals on the skin with less moisture (oily surface) and showing biological adhesiveness, but shows high biological adhesiveness on the skin with sufficient moisture.

[0313] [Example 11] In vitro release test

[0314] To the vertical diffusion cell as Figure 4 shown (cell volume: 6.0 mL, effective diffusion area: 1.77 cm 2; The receiving unit of Kobayashi Glass Co., Ltd. added 6.0 mL of 20% aqueous ethanol solution, and a dialysis membrane (cellulose tube 24 / 32, Wako Pure Chemical Industries, Ltd., Japan) was set. Artificial saliva Saliveht was added onto the dialysis membrane (supply unit side). (R) (Teijin Pharma Limited, Japan) 200 μL, and then the preparation was applied to start the in vitro release test of the preparation.

[0315] As the preparation, Formulations No. 7 to 12, 18, 24, 31 to 36, 38, 79, 80, and 81 prepared in Example 7 containing 0.2 mg of TA as an active ingredient (each 200 mg), KENALOG (R) ointment preparation (200 mg) and Aftach (R) Formulation 1 tablet. It should be noted that the KENALOG (R) ointment preparation was applied according to the usage method after wiping off the artificial saliva on the dialysis membrane.

[0316] To measure the release amount of TA from the preparation, the aqueous solution in the receiving unit was sampled at 500 μL at different times, and the same amount of 20% aqueous ethanol solution was supplemented each time. The temperature in the unit was maintained at 37 °C, and it was continuously stirred in the receiving unit with a magnetic stirrer. During the test, the vertical diffusion unit was set in an environment with high humidity maintained above 90% humidity using a humidifier.

[0317] At different times, acetonitrile was added to each collected sample solution at a ratio of 1:1 (v / v), stirred, and then centrifuged (21,500 × g, 5 minutes, 4 °C), and the supernatant was recovered. The supernatant was measured by high performance liquid chromatography (HPLC) to determine the TA concentration. The HPLC system and conditions used in this measurement are shown in Tables 6 and 7.

[0318] [Table 6]

[0319] HPLC system (Shimadzu Corporation, Kyoto, Japan)

[0320] System Controller SCL-10A Pump LC-10AD Autosampler SIL-10A Column Oven CTO-10AC UV Detector SPD-10AV Analysis Software LC solution Degassing Device DGU-12A3

[0321] [Table 7]

[0322] HPLC measurement conditions

[0323]

[0324] Table 8 shows the unit effective diffusion area (1.77 cm 2 ) calculated based on the measured value of the TA concentration, and the cumulative release amount of TA per unit effective release area (μg / cm 2, the average value of more than 3 tests), and the relative release amount compared with the KENALOG (R) ointment preparation.

[0325] [Table 8]

[0326]

[0327]

[0328] Preparations containing C17MGE, GMO or C22MGE showed substantially the same TA release properties as the commercially available KENALOG (R) ointment preparation. In addition, among the preparations containing C17MGE, the TA release properties of the preparations containing HPC (No. 8 to 12, No. 18) tended to be higher than those of the preparations without HPC (No. 7).

[0329] [Example 12] In vitro mucosal permeability test

[0330] In the same manner as in Example 11, 6.0 mL of phosphate buffered saline (PBS) at pH 6.75 was added to the receiving unit of the vertical diffusion cell (cell volume: 6.0 mL, effective diffusion area: 1.77 cm 2 )( Figure 4 ). Instead of the dialysis membrane used in Example 11, the hamster oral mucosa (Syrian strain (male, 8 weeks old), Sankyo Laboratory Services Co., Ltd.) was set. 200 μL of artificial saliva Saliveht (R) (Teijin Pharma Limited, Japan) was added to the oral mucosa (supply unit side), and then the preparation was applied to start the measurement.

[0331] As the preparations, No. 7, No. 8, No. 24, No. 31 to No. 33, No. 38 and No. 80 preparations (each 200 mg) prepared in Example 7 containing 0.2 mg of TA as the active ingredient, KENALOG (R) ointment preparation (200 mg) and Aftach (R) preparation 1 tablet were used. It should be noted that the KENALOG (R) ointment preparation was applied after wiping off the artificial saliva on the oral mucosa according to the usage method.

[0332] To measure the mucosal permeation amount of TA from the preparations, 500 μL of the aqueous solution in the receiving unit was sampled at different times, and the same amount of PBS was replenished each time. The temperature in the cell was maintained at 37 °C, and the solution in the receiving unit was continuously stirred with a magnetic stirrer. The vertical diffusion cell was set in an environment with high humidity maintained at 90% or more by a humidifier for the test.

[0333] Acetonitrile was added to each of the collected sample solutions at a ratio of 1:1 (v / v) over time. After stirring, centrifugation was performed (21,500×g, 5 minutes, 4°C), and the supernatant was recovered. The supernatant was measured by high performance liquid chromatography (HPLC) to determine the TA concentration. The HPLC system and conditions used in this measurement are shown in Tables 6 and 7.

[0334] Figure 5 The mucosal permeation behavior of TA from the formulations was shown for each evaluation. The vertical axis of the graph represents the cumulative mucosal permeation amount of TA per unit effective permeation area (μg / cm 2 ) calculated from the measured values of the TA concentration, based on the unit effective diffusion area (1.77 cm 2 ), and is the average value (average of more than 3 tests).

[0335] Table 9 shows the cumulative mucosal permeation amount of TA per unit effective permeation area and the relative permeation amount compared to the KENALOG (R) ointment formulation 4 hours and 8 hours after application of the formulations.

[0336] [Table 9]

[0337]

[0338] Formulations 7, 8, 31 - 33, 38, and 80 all showed high mucosal permeability. In particular, Formulations 8 and 80 containing C17MGE or C22MGE and HPC also showed significantly higher mucosal permeability compared to the commercially available mucosal formulations (Aftach (R) , KENALOG (R) ), indicating a significant improvement in the mucosal absorption of the active ingredient.

[0339] In addition, the relative permeation amount of Formulations 8 and 80 at 4 hours was more than that at 8 hours, enabling more effective drug delivery in a short time.

[0340] From these results, it can be seen that the formulations containing the liquid crystal-forming lipid and the water-soluble polymer such as HPC of the present invention not only show high mucosal adhesion and skin adhesion, but also have high drug mucosal permeability, and can significantly improve drug mucosal absorption.

[0341] [Example 13] Preparation of a spray

[0342] C17MGE, which is a lipid for forming liquid crystals, was mixed with Pluronic F-127 and mixed for 5 minutes using a vortex mixer. Then, an aqueous solution of sodium fluorescein (FL-Na) with a concentration of 790 μg / g was added, and homogenization was performed (8000 rpm, 5 minutes) using a high-speed disperser (POLYTRON PT-3100, KINEMATICA, Switzerland) to prepare a liquid crystal gel (Formulation No. 58). In the composition of Formulation No. 58, the lipid for forming liquid crystals: Pluronic F-127: aqueous FL-Na solution = 1:0.1:1 (weight ratio). The concentration of FL-Na in Formulation No. 58 was 376 μg / g.

[0343] Ethanol was added to Formulation No. 58 at a ratio of Formulation No. 58: ethanol = 1:0.5 or 1:1 (weight ratio), and the resulting solution was mixed for 5 minutes using a vortex mixer. This solution was filled into a manual 5 mL spray bottle (No. 2, Maruemu Co., Ltd., Japan) to prepare Pump Sprays No. 50 and No. 51, respectively.

[0344] In addition, Formulation No. 50 or Formulation No. 51 (solution) was added to an aerosol container (Daiso Co., Ltd., Japan), a valve for filling liquefied petroleum gas (LPG) was installed, and LPG as a propellant was filled into the container to prepare Aerosols No. 52 and No. 53. In the composition of Formulation No. 52, Formulation No. 50: LPG = 1.5:4 (weight ratio). In the composition of Formulation No. 53, Formulation No. 51: LPG = 1:2 (weight ratio).

[0345] In addition, C22MGE was used instead of C17MGE, and except for this, Sprays No. 54 to No. 57 were prepared according to the same composition and the same method as Formulations No. 50 to No. 53.

[0346] It should be noted that the concentration of FL-Na in Formulations No. 50 to No. 57 was set to be the same as that in Formulation No. 58, which is 376 μg / g, when all the ethanol and LPG had volatilized after spraying.

[0347] As a comparative control, Formulation No. 59 (FL-Na concentration 376 μg / g) in which an aqueous FL-Na solution and ethanol were mixed at a weight ratio of 1:1, and Formulation No. 60 (FL-Na concentration 376 μg / g) which is a 1 mM aqueous FL-Na solution were prepared.

[0348] The composition ratios (weight ratios) of Formulations No. 50 to No. 60 are shown in Table 10.

[0349] [Table 10]

[0350]

[0351] [Example 14] Characteristic Tests of Sprays

[0352] 1. Spray test

[0353] The aerosol agents No. 52, No. 53, No. 56, and No. 57 prepared in Example 13 were shaken 5 times immediately before spraying, and then sprayed vertically downward from a distance of 10 cm onto the glass surface.

[0354] For these aerosol agents, the spray volume per second was calculated for each spray time within 1 to 5 seconds. As a result, the spray volume per second (g / sec) is expressed as an approximate value. The preparation No. 52 is 0.723 g / sec, the preparation No. 53 is 0.868 g / sec, the preparation No. 56 is 0.726 g / sec, and the preparation No. 57 is 0.711 g / sec.

[0355] The preparations No. 52, No. 53, No. 56, and No. 57 were all sprayed into a very fine mist. As a result, ethanol volatilized instantaneously. After spraying for 1 second each and tilting the glass surface by 45 degrees after 60 seconds, the sprayed preparations did not flow down on the glass surface and were fixed.

[0356] However, when the pump sprays No. 50, No. 51, No. 54, and No. 55 without LPG were sprayed with 0.19 g, 0.29 g, 0.19 g, and 0.24 g respectively, and the glass surface was tilted by 45 degrees after 60 seconds, all 4 sprayed preparations flowed down on the glass surface.

[0357] The aerosol agent of the present invention shows that it does not flow down from the application site even immediately after spraying, and the preparation can be applied very effectively.

[0358] 2. Measurement of particle size distribution

[0359] The spray of the present invention can form nano microparticles immediately after spraying.

[0360] The compositions obtained by spraying the sprays No. 50 to No. 57 into a beaker for 1 second each were diluted with distilled water by about 1000 times as the measurement samples. Using a Zetasizer Nano-ZS (manufactured by Malvern) and the dynamic light scattering method, the particle size distribution and the ζ potential representing the surface charge of the particles were measured.

[0361] Table 11 shows the average particle size (nm) (Z-average), PdI (polydispersity coefficient), and ζ potential (mV) obtained as the average value of 3 measurements. It shows an emulsion in a good state.

[0362] [Table 11]

[0363]

[0364] 3. Small angle X-ray diffraction

[0365] Spray aerosol agents No. 52, No. 53, No. 56, and No. 57 into centrifuge tubes for 3 seconds respectively, and then add 5 mL of purified water to obtain a composition. Enclose this composition in a labeled tube, and use a small-angle X-ray scattering (SAXS) device (manufactured by Rigaku Corporation, Nano-Viewer) to perform small-angle X-ray scattering diffraction measurement, thereby determining the non-layered liquid crystal structure.

[0366] In the small-angle X-ray scattering diffraction ( Figure 6 A, C, D) of the compositions obtained by spraying preparations No. 52, No. 56, and No. 57, at least 3 scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of the inverse hexagonal phase liquid crystal From this, it was confirmed that these samples formed an inverse hexagonal phase liquid crystal.

[0367] In addition, in the small-angle X-ray scattering diffraction ( Figure 6 B) of the composition obtained by spraying preparation No. 53, at least 8 scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of the cubic liquid crystal belonging to the crystallographic space group Pn3m and the ratio characteristic of the inverse hexagonal phase liquid crystal From this, it was confirmed that this sample was formed by mixing the cubic liquid crystal belonging to the crystallographic space group Pn3m and the inverse hexagonal phase liquid crystal.

[0368] Moreover, a white sample obtained by spraying preparation No. 56 onto a petri dish for 1 second and then leaving it for about 3 minutes was directly embedded in a pinhole slit, and small-angle X-ray scattering diffraction measurement was carried out in the same way to determine the non-layered liquid crystal structure. As a result, at least 3 scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of the inverse hexagonal phase liquid crystal ( Figure 6 E). From this, it was confirmed that this sample formed an inverse hexagonal phase liquid crystal.

[0369] These aerosol agents showed the ability to form a non-layered liquid crystal structure, and could form a non-layered liquid crystal structure whether or not additional water was added after spraying.

[0370] [Example 15] In vitro skin permeability test

[0371] Administer 3 kinds of mixed anesthetics (medetomidine hydrochloride 0.15 mg / kg, midazolam 2 mg / kg, butorphanol tartrate 2.5 mg / kg) intraperitoneally to male hairless rats of the WBN / ILA-Ht strain (body weight 200 - 250 g, 8 weeks old). After shaving the abdominal skin, cut out a total of 4 pieces (2 cm × 2 cm each) on the left and right with the midline as the center, and carefully remove the subcutaneous fat and blood on the dermal side with scissors to prepare the abdominal skin of the rats.

[0372] In the same manner as in Example 11, 6.0 mL of phosphate buffer (PB) at pH 7.4 was added to the receiving unit of the vertical diffusion unit (unit volume: 6.0 mL, effective diffusion area: 1.77 cm 2 )( Figure 4 ). Instead of the dialysis membrane used in Example 11, the abdominal skin of the above rat was set. 1.0 mL of PB was added to the stratum corneum (supply unit side) and hydrated for 1 hour, and then the preparation was applied to start the measurement.

[0373] As the preparations, Preparations Nos. 50 to 53 and 56 to 60 prepared in Example 13 were used. Regarding the application amount of the preparations, the 50th preparation was 0.218 g (containing 54 μg of FL-Na), the 51st preparation was 0.290 g (containing 54 μg of FL-Na), the 52nd preparation was 0.723 g per 1-second spray (containing 49 μg of FL-Na), the 53rd preparation was 0.868 g per 1-second spray (containing 54 μg of FL-Na), the 56th preparation was 0.726 g per 1-second spray (containing 49 μg of FL-Na), the 57th preparation was 0.711 g per 1-second spray (containing 44 μg of FL-Na), the 58th preparation was 0.145 g (containing 54 μg of FL-Na), the 59th preparation was 1 mL (containing 376 μg of FL-Na), and the 60th preparation was 1 mL (containing 376 μg of FL-Na).

[0374] In order to measure the skin permeation amount of FL-Na from the preparations, 500 μL of the aqueous solution in the receiving unit was sampled at different times, and the same amount of PB was replenished each time. The temperature in the unit was maintained at 32 °C, and the solution in the receiving unit was continuously stirred with a magnetic stirrer.

[0375] Each sample solution collected over time was centrifuged (21,500×g, 5 minutes, 4 °C), and then the supernatant was measured using a fluorescence spectrophotometer (RF-5300PC: Shimadzu Corporation, Japan) (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) to determine the concentration of FL-Na in the sample solution.

[0376] Figure 7 The skin permeation behavior of FL-Na from each preparation is shown. The vertical axis of the graph represents the average value (average of 3 or 4 test values) of the cumulative skin permeation amount of FL-Na per unit effective permeation area (μg / cm 2 ) based on the unit effective diffusion area (1.77 cm 2 ) calculated from the measured value of the FL-Na concentration.

[0377] Table 12 shows the cumulative skin permeation amount of FL-Na per unit effective permeation area after 4 hours and 8 hours of applying the preparation, and the relative permeation amount compared with Preparation No. 60 (control).

[0378] [Table 12]

[0379]

[0380] Preparations No. 50 - 53, 56 and 57 of the spray showed significantly higher skin permeability compared with the aqueous solution of FL-Na (Preparation No. 60), further compared with the liquid crystal gel (Preparation No. 58) and the 50% aqueous ethanol solution (Preparation No. 59). The cumulative skin permeation amount of FL-Na after 4 hours of applying Pump Sprays No. 50 and 51 showed 27-fold and 184-fold higher values respectively compared with Preparation No. 60. Moreover, the cumulative skin permeation amount of FL-Na after 4 hours of Aerosols No. 52, 53, 56 and 57 showed 104-fold, 345-fold, 33-fold and 138-fold further higher values respectively compared with Preparation No. 60. In addition, the cumulative skin permeation amount of FL-Na after 8 hours of application also showed a high value with the same trend.

[0381] Aerosols No. 52, 53, 56 and 57 did not flow down from the application site immediately after spraying as shown in Example 14, and were more effective in applying the preparation than Pump Sprays No. 50 and 51 without LPG. Considering the above, it was shown that they could be further used as extremely useful skin permeation promoting preparations.

[0382] [Example 16] Preparation of Rubber Patch Preparation

[0383] C17MGE, phytantriol (PHY, Tokyo Chemical Industry Co., Ltd., Japan) or C22MGE as the lipid forming liquid crystal and the aqueous solution of FL-Na in which FL-Na was dissolved in phosphate buffer (PB) at pH 7.4 were filled into an airtight syringe (mS-GAN025, Ito Seisakusho Co., Ltd., Japan) at a weight ratio of 1:1, 2:1, 3:1 respectively, and uniformly mixed to obtain a liquid crystal gel. The FL-Na concentration of the aqueous solution of FL-Na was set so that the FL-Na concentration of the final adhesive layer described later was 10 mM. It should be noted that since PHY is semi-solid at room temperature, it was melted using a heating stirrer (100 °C, 30 minutes) before use.

[0384] Acrylic adhesive DURO-TAK was added to the liquid crystal gel (R) (387-2516, Henkel AG & Co. KGaA, Germany) so that it was 80% by weight relative to the whole adhesive layer, and mixed using a magnetic stirrer (500 rpm, 5 minutes). The mixture was placed on the back lining of a silicone-processed polyethylene terephthalate (PET) film (FILMBYNA(R) At the left end (0%) of 75E-0010BD, Fujimori Kogyo Co., Ltd., Japan), using a No. 510 BAKER coater (Yasuda Seiki Seisakusho Co., Ltd., Japan) with a set coating thickness of 1 miL (25.4 μm), extend from the left end (0%) to the right end (100%) ( Figure 8 ). The extended adhesive layer is dried in a room at a temperature of 20 ± 2°C and a humidity of 20 ± 5% for 30 minutes, and further dried in an incubator at a temperature of 32°C and a humidity of 20 ± 2% for 30 minutes. For the dried adhesive layer, use an SN-engraved rubber roller No. 3 (Taniguchi Matsuo-do Co., Ltd., Japan) to press-bond a PET film support with a thickness of 75 μm (FILMBYNA (R) , Fujimori Kogyo Co., Ltd., Japan), thereby preparing rubber plaster preparations (Preparations No. 61 to No. 69).

[0385] The final composition ratios (weight ratios) in the adhesive layers of Preparations No. 61 to No. 69 are shown in Table 13.

[0386] [Table 13]

[0387]

[0388]

[0389] In addition, by the same method as above and according to the composition ratios (weight ratios) shown in Table 14, prepare rubber plaster preparations No. 70 to No. 72 by mixing the liquid crystal-forming lipid (C17MGE) and the above acrylic adhesives (pressure-sensitive adhesives) DURO-TAK with weight ratios of 90%, 70%, and 20%, (R) and prepare rubber plaster preparation No. 73 by mixing the above acrylic adhesive DURO-TAK with a weight ratio of 90% without mixing the liquid crystal-forming lipid. (R)

[0390] [Table 14]

[0391] Preparation Number 70 71 72 73 Code Name T-D90M5 T-D70M15 T-D20M40 T-D90M0 C17MGE 5 15 40 PHY C22MGE DURO-TAK 90 70 20 90 FL-Na Aqueous Solution 5 15 40 10 Total 100 100 100 100

[0392] [Example 17] Characteristic tests of rubber plaster preparations

[0393] 1. Image analysis

[0394] For rubber plaster preparations No. 61 to No. 73 after drying the adhesive layer and before press-bonding the PET film support in Example 16, generally perform image analysis using photography and a fluorescence microscope.

[0395] The images taken generally are obtained by photographing the entire rubber plaster preparation from 20 cm above using a digital camera (D5300, Nikon Corporation, Japan).​

[0396] Images of the fluorescence microscope were obtained by taking three pictures at positions 1 (25% of the position starting from the center of the left end of the rubber plaster preparation), 2 (50% of the position), and 3 (75% of the position) using a fluorescence microscope (BZ-X700, KEYENCE CORPORATION, Japan). The shooting conditions of the fluorescence microscope were set as follows: objective lens CFIPlan Apoλ2x, fluorescence filter GFP (OP-87763BZ-X filter), excitation wavelength 470 / 40 nm, absorption wavelength 525 / 50 nm, dichroic mirror wavelength 495 nm, gain +6 dB. Note that the exposure time was set to 1 / 175 s for the preparation containing the liquid crystal-forming lipid and 1 / 5 s for the preparation without the liquid crystal-forming lipid. Figure 8 of the position 1), 50% ( Figure 8 of the position 2), 75% ( Figure 8 of the position 3).

[0397] The adhesive layers of the rubber plaster preparations No. 61 to No. 70, which were prepared by mixing DURO-TAK at a mixing weight ratio of 80% and 90%, were uniformly extended. However, the adhesive layer of the rubber plaster preparation No. 71, which was prepared by mixing DURO-TAK at a mixing weight ratio of 70%, was slightly less uniform than that of the preparations No. 61 to No. 70. Moreover, the adhesive layers of the rubber plaster preparation No. 72, which was prepared by mixing DURO-TAK at a mixing weight ratio of 20%, and the rubber plaster preparation No. 73, which was prepared by mixing DURO-TAK at a mixing weight ratio of 90% without mixing the liquid crystal-forming lipid, were not uniformly extended. (R) The adhesive layers of the rubber plaster preparations No. 61 to No. 70, which were prepared by mixing DURO-TAK at a mixing weight ratio of 80% and 90%, were uniformly extended. However, the adhesive layer of the rubber plaster preparation No. 71, which was prepared by mixing DURO-TAK at a mixing weight ratio of 70%, was slightly less uniform than that of the preparations No. 61 to No. 70. Moreover, the adhesive layers of the rubber plaster preparation No. 72, which was prepared by mixing DURO-TAK at a mixing weight ratio of 20%, and the rubber plaster preparation No. 73, which was prepared by mixing DURO-TAK at a mixing weight ratio of 90% without mixing the liquid crystal-forming lipid, were not uniformly extended. (R) The adhesive layer of the rubber plaster preparation No. 71, which was prepared by mixing DURO-TAK at a mixing weight ratio of 70%, was slightly less uniform than that of the preparations No. 61 to No. 70. Moreover, the adhesive layers of the rubber plaster preparation No. 72, which was prepared by mixing DURO-TAK at a mixing weight ratio of 20%, and the rubber plaster preparation No. 73, which was prepared by mixing DURO-TAK at a mixing weight ratio of 90% without mixing the liquid crystal-forming lipid, were not uniformly extended. (R) The adhesive layers of the rubber plaster preparation No. 72, which was prepared by mixing DURO-TAK at a mixing weight ratio of 20%, and the rubber plaster preparation No. 73, which was prepared by mixing DURO-TAK at a mixing weight ratio of 90% without mixing the liquid crystal-forming lipid, were not uniformly extended. (R) The adhesive layers of the rubber plaster preparation No. 72, which was prepared by mixing DURO-TAK at a mixing weight ratio of 20%, and the rubber plaster preparation No. 73, which was prepared by mixing DURO-TAK at a mixing weight ratio of 90% without mixing the liquid crystal-forming lipid, were not uniformly extended.

[0398] From this result, it can be seen that by mixing DURO-TAK (R) (preferably 70% or more, more preferably 80% or more) and the liquid crystal-forming lipid of the present invention, a uniform rubber plaster preparation can be prepared.

[0399] 2. Thickness of the adhesive layer

[0400] The thickness of the entire rubber plaster preparation was measured using a Hand Clipper (thickness gauge, Teclock Corporation, Japan), and the thickness of the adhesive layer of the rubber plaster preparation was calculated by subtracting the thickness of the support (20 μm) and the backing (80 μm) from the measured value.

[0401] From the center of the left end of the preparations No. 63, No. 66, and No. 69 ( Figure 8 ) to 25% ( Figure 8 of the position 1), 50% ( Figure 8 of the position 2), 75% ( Figure 8The thickness of the three adhesive layers at the position) is 15 ± 5 μm (average value of 6 measurements).

[0402] Thus, it was confirmed that the thickness of the adhesive layer of the above-mentioned rubber plaster preparation was uniform.

[0403] 3. Analysis of the phase diagram

[0404] For the rubber plaster preparation, a scanning probe microscope (SPM-9700HT, Shimadzu Corporation, Japan) was used to observe the shape with observation fields of 1 μm × 1 μm and 0.5 μm × 0.5 μm, and then phase observation was carried out.

[0405] For Formulations 63 and 73, shape observations were carried out, and as a result, smooth surface shapes were observed for both. Moreover, for these formulations, phase observations were carried out, and the results were as Figure 9 shown. No phase diagram was observed in Formulation 73, while a characteristic phase diagram was observed in Formulation 63.

[0406] From this result, it can be seen that the physical properties of the adhesive layer surface differ depending on the presence or absence of the mixed liquid crystal-forming lipid, and the rubber plaster preparation formed by the mixed liquid crystal-forming lipid and DURO-TAK (R) has characteristic surface properties on a structure with a certain regularity.

[0407] [Example 18] In vitro release test

[0408] Into the receiving unit of the horizontal diffusion cell as Figure 10 shown (cell volume: 3.0 mL, effective diffusion area: 0.95 cm 2 ; Kobayashi Glass Co., Ltd.), 3.0 mL of PB was added, the preparation was attached to the supply unit side, and the in vitro release test of the preparation was started. As the preparations, Formulations 61 to 69 and 73 were used.

[0409] To measure the release amount of FL-Na from the preparation, 500 μL of the aqueous solution in the receiving unit was sampled at different times, and the same amount of PB was replenished each time. The temperature in the unit was maintained at 32 °C, and the solution in the receiving unit was continuously stirred with a magnetic stirrer.

[0410] The sample solutions collected over time were centrifuged (21,500 × g, 5 minutes, 4 °C), and then the supernatant was measured using a fluorescence spectrophotometer (RF-5300PC: Shimadzu Corporation, Japan) (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) to determine the concentration of FL-Na in the sample solution.

[0411] Figure 11The release behavior of FL-Na from each preparation is shown. The vertical axis of the figure represents the average value (average of 3 or 4 test values) of the cumulative release rate (%) of FL-Na based on the extraction test, calculated from the measured values of the FL-Na concentration.

[0412] Table 15 shows the cumulative release rates (%) of FL-Na 1 hour and 4 hours after the application of the preparation. The cumulative release rate (%) of FL-Na is calculated according to the following formula.

[0413] Cumulative release rate (%) of FL-Na = Cumulative release amount of FL-Na ÷ Applied amount of FL-Na × 100

[0414] [Table 15]

[0415]

[0416]

[0417] Preparations Nos. 61 to 69 release FL-Na rapidly over time. In particular, preparations Nos. 62, 63, 65, and 66 show higher cumulative release rates 1 hour after application and reach a release rate close to 100% 4 hours after application. In particular, preparations Nos. 62 and 63 have already reached a release rate close to 100% 1 hour after application and release FL-Na very rapidly.

[0418] However, the rubber plaster preparation No. 73 that does not contain a liquid crystal-forming lipid releases FL-Na slowly, reaching a release rate of about 25% 4 hours after application, and no further release of FL-Na is observed thereafter. Thus, it is shown that the encapsulated drug cannot be effectively released without the inclusion of a liquid crystal-forming lipid.

[0419] [Example 19] In vitro skin permeability test

[0420] According to the method described in Example 15, preparations Nos. 61 to 69 were applied to the stratum corneum of the abdominal skin of rats (on the supply unit side) of a vertical diffusion cell ( Figure 4 ) for an in vitro skin permeability test. In addition, as a control, a 10 mM aqueous solution of FL-Na No. 74 prepared by dissolving FL-Na in PB was used.

[0421] Figure 12 The skin permeation behavior of FL-Na from each preparation is shown. The vertical axis of the figure represents the average value (average of 3 or 4 test values) of the cumulative skin permeation rate (%) of FL-Na based on the extraction test, calculated from the measured values of the FL-Na concentration.

[0422] Table 16 shows the cumulative skin permeation rate (%) of FL-Na 1 hour and 4 hours after application of the preparation. The cumulative release rate (%) of FL-Na was calculated according to the following formula.

[0423] Cumulative release rate of FL-Na (%) = Cumulative permeation amount of FL-Na ÷ Applied amount of FL-Na × 100

[0424] [Table 16]

[0425]

[0426]

[0427] Compared with the FL-Na aqueous solution preparation No. 74, the skin permeability of the rubber plaster preparations Nos. 61 to 69 was significantly improved. Moreover, compared with the rubber plaster preparations Nos. 64 to 66 containing PHY, the skin permeability of the preparations Nos. 61 to 63 containing C17MGE was very high. Considering that in Example 18, there was little difference in in vitro release between the rubber plaster preparations containing C17MGE or C22MGE and the rubber plaster preparations containing PHY, the high skin permeability shown by the rubber plaster preparations containing C17MGE or C22MGE was an unexpected result. Moreover, after 4 hours and later of application, the skin permeability of the preparations Nos. 62 to 63 was improved above what was expected based on the content ratio of the liquid crystal-forming lipid compared with the preparation No. 61 ( Figure 12 ).

[0428] [Example 20] Preparation of emulsion

[0429] According to the mixing ratio (weight ratio) shown in Table 17, C17MGE or glycerol monooleate (GMO, RIKEMAL XO-100, NOF Corporation, Japan), tranilast (Tokyo Chemical Industry Co., Ltd., Japan) as the drug, and ethanol (only No. 76) were mixed and then dissolved in a hot water bath at 80 °C. For the obtained lipid mixture, Pluronic (R) F127 (UNILUBE (R)An aqueous solution prepared by dissolving 70DP-950B, Nisshin Oil, or Aldrich P2443 in purified water was added, and after adding this aqueous solution, it was stirred with a spatula or a vortex mixer to prepare a suspension. Moreover, this suspension was ultrasonically treated for 5 minutes at an amplitude of 20% using an ultrasonic disperser (Sonics Vibra-Cell VCX-750, manufactured by Sonics&Materials, Inc.) to prepare white emulsions numbered 75 to 77 containing microparticles. 10 g of each of these emulsions was prepared. It should be noted that tranilast is known as an antiallergic agent, but its therapeutic effect on neurological diseases has also been studied (US2011 / 0112187A1).

[0430] It should be noted that in an emulsion with 20% lipid, C17MGE can be dispersed in 1% Pluronic (R) F127, but GMO cannot be dispersed. Therefore, GMO is dispersed in 5% Pluronic (R) F127 (emulsion number 77). As a control, Preparation No. 78 was prepared by adding 0.5% tranilast to physiological saline (Table 17).

[0431] [Table 17]

[0432]

[0433] [Example 21] Evaluation of Physical Properties of Emulsions

[0434] The particle size distribution, small-angle X-ray scattering diffraction, viscosity of Emulsions numbered 75 to 77, and encapsulation efficiency of tranilast prepared in Example 20 were measured.

[0435] The particle size distribution was measured using a Zetasizer Nano-ZS (manufactured by Malvern) and the dynamic light scattering method. The measurement samples were prepared by diluting each emulsion 1000-fold in distilled water. For each measurement sample, the average particle size (nm) (Z-average), PdI (polydispersity coefficient), and ζ potential (mV) obtained as the average of three measurements are shown in Table 18.

[0436] Each emulsion was stable and no visible aggregates were observed through experiments. This was confirmed by the appropriate average particle size, PdI, and ζ potential.

[0437] Small-angle X-ray scattering diffraction was measured using a small-angle X-ray scattering (SAXS) device (Nano-Viewer, manufactured by Rigaku Corporation) with each emulsion encapsulated in a labeled tube.

[0438] In the small-angle X-ray scattering diffraction of Emulsion No. 75Figure 13 In A) of [reference], at least three scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of an inverse hexagonal phase liquid crystal. Therefore, it was shown that this emulsion is a liquid crystal emulsion (hexosome) in which microparticles of an inverse hexagonal phase liquid crystal are dispersed in an aqueous phase.

[0439] In addition, in the small-angle X-ray scattering diffraction of Emulsion No. 76 ( Figure 13 in B) of [reference]), at least four scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of a cubic liquid crystal belonging to the crystallographic space group Pn3m. Therefore, it was shown that this emulsion is a liquid crystal emulsion (cubosome) in which microparticles of a cubic liquid crystal belonging to the crystallographic space group Pn3m are dispersed in an aqueous phase.

[0440] In addition, in the small-angle X-ray scattering diffraction of Emulsion No. 77 ( Figure 13 in C) of [reference]), at least three scattering peaks were observed, and the ratio of the peaks showed the ratio characteristic of a cubic liquid crystal belonging to the crystallographic space group Im3m. Therefore, it was shown that this emulsion is a liquid crystal emulsion (cubosome) in which microparticles of a cubic liquid crystal belonging to the crystallographic space group Im3m are dispersed in an aqueous phase.

[0441] Regarding viscosity, a viscometer (RE215H; cone-plate type 0.8°xR24, Toki Sangyo Co., Ltd.) was used. For each emulsion, the viscosity (mPa·s) measured at a temperature of 25°C and a rotation speed of 50 rpm is shown in Table 18. These viscosities are all within the range that can be ejected.

[0442] To calculate the encapsulation efficiency, each emulsion was centrifuged (21,500×g, 15 minutes, 4°C), and then the obtained supernatant was taken out, diluted 10 times with acetonitrile, and tranilast was quantified by liquid chromatography tandem mass spectrometry (LC-MS / MS). The encapsulation efficiency was calculated according to the following formula.

[0443] [Equation 1]

[0444]

[0445] In the above formula, %EE, TL 总 , TL 游离 represent the encapsulation efficiency, the total tranilast concentration in the emulsion, and the tranilast concentration in the supernatant, respectively.

[0446] As shown in Table 18, the encapsulation efficiency of each emulsion was high, indicating a high absorption ability of tranilast into the liquid crystal structure inside the microparticles.

[0447] [Table 18]

[0448]

[0449] [Example 22] In vitro release test

[0450] Xiang Ru Figure 4 The vertical diffusion unit shown (unit volume: 6.0 mL, effective diffusion area: 1.77 cm 2 ; Kobayashi Glass Co., Ltd.) was added with 6.0 mL of phosphate buffered saline (PBS; pH 7.4), and a dialysis membrane (molecular weight cutoff = 12,000-14,000 Da, Sanko Pure Chemical Industries, Ltd., Japan) pre-soaked in water was set. The preparation was applied to the dialysis membrane (supply unit side) and the in vitro release test of the preparation was started. As the preparation, 1 mL of each of the emulsion preparations No. 75 and No. 76 and the comparative control preparation No. 78 were used.

[0451] In order to measure the release amount of Tranilast from the preparation, 500 μL of the aqueous solution in the receiving unit was sampled over time, and the same amount of PBS was added each time. The unit was maintained at 32° C. and stirred with a magnetic stirrer.

[0452] Acetonitrile was added to each sample solution collected over time at a ratio of 1:1 (v / v), stirred, and centrifuged (21,500×g, 5 minutes, 4°C) to collect the supernatant. 10 μL of the supernatant was injected into the LC / MS / MS system to quantify Tranilast.

[0453] The LC / MS / MS system used in this measurement is composed of the following: system controller (CBM-20A, Shimadzu Corporation), pump (LC-20AD, Shimadzu Corporation), autosampler (SIL-20ACHT, Shimadzu Corporation), column oven (CTO-20A, Shimadzu Corporation), mass spectrometer (4000QTRAP, AB SCIEX), and analysis software (Analyst (registered trademark) version 1.4.2, Shimadzu Corporation).

[0454] The measurement conditions of LC / MS / MS are as follows: the chromatographic column (Shodex ODP2HPG-2A 2.0 mm×10 mm, Showa Denko K.K.) was maintained at 40°C. The mobile phase was acetonitrile: 5 mM ammonium acetate aqueous solution containing 0.05% formic acid = 80:20. The flow rate was maintained at 0.2 mL / min. Mass spectrometry was performed in the multiple reaction monitoring (MRM) mode, and the transition ions from m / z 328.0 to m / z 191.2 were monitored at a collision energy of 36 eV.

[0455] Figure 14The release behavior of tranilast from each preparation within 8 hours after application is shown in FIG. The vertical axis of the graph represents the cumulative release amount of tranilast (μmol / cm 2 ) is the average value (average of 4 test values).

[0456] The release behavior of tranilast from each preparation was closely related to the Higuchi equation (Higuchi T., J. Pharm. Sci., 52, 1145-1148 (1963)). Figure 14 Calculated release rate of tranilast (μmol / cm 2 / h 0.5 ) was as high as 0.17 in Preparation No. 76, and was 0.05 in Preparations No. 75 and No. 78. Figure 14 The calculated cumulative tranilast release rate (%) after 8 hours of application of the formulations was 1.82, 3.67, and 2.35, respectively, for formulations 75, 76, and 78. Formulations 75 and 76 having tranilast encapsulated in a liquid crystal structure showed clear release properties.

[0457] [Example 23] Pharmacokinetic evaluation of intranasal administration

[0458] Sprague-Dawley rats (male 7 weeks old, weight 230 g ± 10 g) were used to evaluate the pharmacokinetics of intranasal administration of preparations No. 75 to 78. First, three mixed anesthetics (0.375 mg / kg of medetomidine hydrochloride, 2.5 mg / kg of butorphanol tartrate, and 2 mg / kg of midazolam) were administered intraperitoneally to the rats for general anesthesia. The tip of the micropipette was inserted 0.5 cm into the nostrils of the rats in the supine position, and 10 μL of the preparation was dripped, thereby performing intranasal administration.

[0459] Approximately 200 μL of blood was collected from the jugular vein of rats at predetermined time points (0.17 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, and 8 hours after administration), directly transferred into heparinized tubes, and immediately centrifuged (21,500×g, 10 minutes, 4 °C) to obtain plasma. Each time blood was collected, an equal volume of physiological saline was injected into the rats via the tail vein. In some rats, 3 kinds of mixed anesthetics were intraperitoneally administered after blood collection 2 hours, 4 hours, or 8 hours after administration to perform general anesthesia, and cardiopulmonary perfusion was performed with cold PBS, and then the rat brains were excised. The excised brains were dissected into specific regions (olfactory bulb, cortex, brainstem, cerebellum, midbrain, hippocampus) on ice. The spinal cord was also collected from the dead rats. The collected brain samples were weighed, then cut with scissors, 0.5 mL of acetonitrile was added, and homogenized at 12,000 rpm for 5 minutes at 4 °C using a disperser (POLYTRON PT1200E, KINEMATICA, Switzerland). The brain homogenate was centrifuged (21,500×g, 5 minutes, 4 °C), and the supernatant was recovered. The supernatants obtained from plasma and brain homogenate were stored at -30 °C before analysis.

[0460] To 50 μL of the supernatant obtained from plasma or brain homogenate, acetonitrile was added at a ratio of 1:1 (v / v), stirred, and then centrifuged (21,500×g, 5 minutes, 4 °C), and the supernatant was recovered. By the same method as in Example 22, 10 μL of the obtained supernatant was injected into the LC / MS / MS system to quantify tranilast.

[0461] Figure 15 and Figure 16 show the time-course changes in the plasma and brain tranilast concentrations within 8 hours after intranasal administration of each formulation. The vertical axis of the figure represents the average value of the tranilast concentration (ng / mL or ng / g) (average value of 3 - 5 test values).

[0462] Based on Figure 15 、 Figure 16 the results shown, as the pharmacokinetic parameters related to tranilast in plasma and brain within 8 hours after intranasal administration of each formulation, the time to reach the maximum concentration (Tmax), the maximum concentration (Cmax), and the area under the drug concentration-time curve (AUC 0-8 ) were determined. These values are shown in Table 19.

[0463] [Table 19]

[0464]

[0465]

[0466] *For plasma, ng / mL; for brain, ng / g

[0467] For plasma, ng·h / mL; for brain, ng·h / g

[0468] The Tmax in plasma was 0.17 hours after the first blood sampling after intranasal administration for emulsions Nos. 75 to 77 and control preparation No. 78, showing rapid systemic absorption. The Tmax in the brain was 2 hours after the first blood sampling after intranasal administration for control preparation No. 78, and 8 hours after intranasal administration for emulsions Nos. 75 to 77.

[0469] In plasma, the Cmax was not significantly different among emulsion Nos. 75 and 76 using C17MGE and control preparation No. 78, but the AUC of emulsion Nos. 75 and 76 0-8 was more than 3 times higher than that of No. 78. In addition, in the brain, the Cmax of emulsion Nos. 75 and 76 was about 8 times higher than that of No. 78, and the AUC 0-8 of emulsion Nos. 75 and 76 was about 15 times higher. However, compared with control preparation No. 78, for emulsion No. 77 using GMO, although the Cmax and AUC 0-8 in plasma were both lower, the Cmax and AUC 0-8 in the brain were both about 5 times higher.

[0470] As described above, in emulsion Nos. 75 and 76 using C17MGE, tranilast was detected at high concentrations both in plasma and in the brain, higher than the concentrations shown in emulsion No. 77 using GMO. In addition, it is particularly noteworthy that the tranilast concentration in the brain in emulsion Nos. 75 and 76 increased significantly compared with No. 78. Thus, it can be seen that the emulsions using C17MGE are excellent in delivering drugs to the brain by intranasal administration.

[0471] Figure 17 and Figure 18 show the tranilast concentrations in different regions of the brain 2 hours, 4 hours, and 8 hours after intranasal administration of each preparation. The vertical axis of the figure represents the average value of the tranilast concentration (ng / g) (average value of 3 to 5 test values).

[0472] Emulsions Nos. 75 to 77 and control preparation No. 78 all showed absorption of tranilast starting 2 hours after the first cut in all brain regions. In all brain regions, the tranilast concentrations from these preparations in the olfactory bulb and spinal cord were generally higher than those in other brain regions ( Figure 17 、 18 ). Since the olfactory bulb is adjacent to the nasal cavity and the spinal cord is the brain entrance of the systemic conduction pathway, this result indicates that the migration of tranilast into the brain occurs via both the olfactory conduction pathway and the systemic conduction pathway.

[0473] In all brain regions, the tranilast concentration in emulsions Nos. 75 and 76 using C17MGE was generally higher within 8 hours after intranasal administration and significantly higher 8 hours after intranasal administration, compared with emulsion No. 77 using GMO and formulation No. 78 as a control. Figure 17 , 18 ). From this, it can be seen that, compared with emulsion No. 77 and formulation No. 78 as a control, the high concentration of tranilast in emulsions Nos. 75 and 76 accumulates in the entire brain region for a long time.

[0474] Industrial Applicability

[0475] According to the present invention, an external preparation excellent in drug absorbability in a living body can be provided.

[0476] All publications, patents, and patent applications cited in this specification are hereby incorporated by reference directly into this specification.

Claims

1. An external preparation containing a non-lamellar liquid crystal-forming lipid and a drug.

2. The external preparation according to claim 1, wherein the non-lamellar liquid crystal-forming lipid is an amphiphilic compound represented by the following general formula (I) or a salt thereof, [Chemical 1] In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, m represents 1 or 2, represents a single bond or a double bond, and R represents a hydrophilic group having two or more hydroxyl groups.

3. The external preparation according to claim 2, wherein R in the formula represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, and xylitol.

4. The external preparation according to any one of claims 1 to 3, wherein the non-lamellar liquid crystal-forming lipid is mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) glycerol or mono-O-(5,9,13-trimethyltetradec-4-enoyl) glycerol.

5. The external preparation according to claim 1, wherein the non-lamellar liquid crystal-forming lipid is glycerol monooleate or phytantriol.

6. The external preparation according to any one of claims 1 to 5, which is formulated into a patch dosage form.

7. The external preparation according to claim 6, wherein the patch is a rubber plaster.

8. The external preparation according to claim 6 or 7, which contains 70 w / w% or more of an adhesive.

9. The external preparation according to any one of claims 1 to 5, which is formulated into an aerosol dosage form.

10. The external preparation according to any one of claims 1 to 9, wherein the non-lamellar liquid crystal-forming lipid does not form a liquid crystal in the external preparation.

Images