Non-lamellar liquid crystal-forming composition having high safety

Abstract

To provide a non-lamellar liquid crystal-forming composition having high safety and a compound usable for the same.SOLUTION: The present invention relates to a non-lamellar liquid crystal-forming composition having improved biocompatibility due to a phospholipid, comprising an amphipathic compound represented by the following general formula (I) and a phospholipid, wherein X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2, m represents 1 or 2, and R represents a hydrophilic group having one or more hydroxyl groups, and the novel amphipathic compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a highly safe non-lamellar liquid crystal forming composition. [Background technology]

[0002] Lyotropic liquid crystals such as liposomes have been widely reported as biomimetic drug delivery system (DDS) carriers since the concept of DDS was first proposed. In recent years, non-lamellar liquid crystals (NLLCs), a type of lyotropic liquid crystal, have been reported to have advantages such as higher drug loading and easier preparation compared to conventional DDS carriers.

[0003] Various liquid crystal-forming compounds are used for various purposes in the fields of cosmetics, pharmaceuticals, and the like. In recent years, an amphiphilic compound having an isoprenoid-type fatty chain capable of forming cubic liquid crystals that are highly stable even at low temperatures (below 6°C) has been developed (Patent Document 1). An amphiphilic compound having an isoprenoid-type fatty chain that stably forms non-lamellar liquid crystals and has low viscosity, making it useful as a base for injections, has also been developed (Patent Document 2). Patent Document 3 reports that an amphiphilic compound having an isoprenoid-type fatty chain capable of forming non-lamellar liquid crystals is useful as an adhesion inhibitor.

[0004] On the other hand, glyceryl monooleate (GMO) and phytantriol (PHY), which are liquid crystal-forming compounds (self-assembling lipids / SOL) used in food additives and skin and hair cosmetics, are recognized as safe for in vitro application and oral ingestion in humans, but serious safety issues such as cytotoxicity and hemolysis have been pointed out when used in the body (e.g., Non-Patent Documents 1 and 2).

[0005] However, no general-purpose technology has been established that can improve the safety of pharmaceutical preparations containing liquid crystal-forming compounds when administered to the body while maintaining their efficacy. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2006 / 043705 [Patent Document 2] International Publication No. 2011 / 078383 [Patent Document 3] International Publication No. 2014 / 178256 [Non-patent literature]

[0007] [Non-Patent Document 1] Hinton TM, et al., Toxicology Research, Vol. 3, (2014) p.11-22 [Non-patent document 2] Wibroe PP, et al., Nanomedicine: Nanotechnology, Biology and Medicine,Vol. 11 (2015) p.1909-1914 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a highly safe non-lamellar liquid crystal forming composition. Another object of the present invention is to provide a non-lamellar liquid crystal forming composition using a novel amphiphilic compound. [Means for solving the problem]

[0009] As a result of extensive research to solve the above problems, the present inventors have found that by adding a phospholipid to an amphiphilic compound having a specific isoprenoid fatty chain, a non-lamellar liquid crystal-forming composition with improved biocompatibility and high safety that is acceptable for in vivo application can be prepared. The present inventors have also succeeded in synthesizing a new amphiphilic compound having an isoprenoid fatty chain that can be used to prepare a non-lamellar liquid crystal-forming composition. In this way, the present inventors have completed the present invention.

[0010] That is, the present invention includes the following. [1] A non-lamellar liquid crystal forming composition comprising an amphiphilic compound represented by the following general formula (I) and a phospholipid, the biocompatibility of which is improved by the phospholipid: [ka] (In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2, and m represents 1 or 2, TIFF2026001219000002.tif813 represents a single or double bond, and R represents a hydrophilic group having one or more hydroxyl groups.

[0011] [2] The composition according to [1] above, wherein the amphiphilic compound is represented by the following general formula (III) or (IV): [ka] (wherein X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2, and m represents 1 or 2).

[0012] [3] The composition according to [1] or [2] above, wherein in the general formula, n=2 and m=2. [4] The composition according to any one of the above [1] to [3], wherein the weight ratio of the amphiphilic compound to the phospholipid is 80:20 to 20:80, or 70:30 to 30:70. [5] The composition according to [4] above, wherein the weight ratio of the amphiphilic compound to the phospholipid is 50:50 to 30:70, or 45:55 to 30:70. [6] The composition according to any one of the above [1] to [5], wherein the phospholipid is phosphatidylcholine or phosphatidylethanolamine. [7] The composition according to any one of [1] to [6] above, wherein the phospholipid is selected from the group consisting of soybean phosphatidylcholine, egg yolk phosphatidylcholine, dimyristoylphosphatidylcholine, dioleylphosphatidylcholine, and dioleylphosphatidylethanolamine. [8] The composition according to any one of the above [1] to [7], wherein R in the general formula (I) represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, and glycol.

[0013] [9] The amphiphilic compound is: mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol, mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)pentaerythritol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)diglycerol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide, Mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide, Mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol, Mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan, mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan, Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl) isosorbide, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol, and Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol The composition according to [1] or [2] above, selected from the group consisting of:

[10] The composition according to any one of [1] to [9] above, wherein the improved biocompatibility is demonstrated by a reduction or elimination of toxicity compared to a control composition not containing phospholipids.

[11] The composition according to any one of the above [1] to

[10] , which contains at least one of an oil and an organic solvent.

[0014]

[12] The composition according to any one of the above [1] to

[11] , which is a non-lamellar liquid crystal composition, further comprising an aqueous medium.

[13] The composition according to

[12] above, which is a non-lamellar liquid crystal emulsion composition, further comprising a surfactant.

[14] The composition according to any one of the above [1] to

[11] , which is a liquid crystal precursor composition that does not contain an aqueous medium and is capable of forming non-lamellar liquid crystals in the presence of an aqueous medium.

[15] A pharmaceutical preparation comprising the composition according to any one of [1] to

[14] above.

[16] The pharmaceutical preparation according to

[15] above, for preventing adhesion of biological tissues.

[17] The pharmaceutical formulation according to

[15] above, wherein the composition is a sustained-release formulation further comprising a drug.

[18] The pharmaceutical formulation according to

[17] above, wherein the drug is a gonadotropin-releasing hormone (GnRH) agonist.

[19] The pharmaceutical formulation according to

[18] above, wherein the GnRH agonist is leuprolide or a salt thereof.

[20] The pharmaceutical preparation according to any one of the above

[15] to

[19] , which is a spray, an aerosol, an injection, or a depot preparation.

[0015]

[21] An amphiphilic compound represented by the following general formula (I') or a salt thereof: [ka] (In the formula, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2, and m represents 1 or 2, TIFF2026001219000005.tif813 represents a single bond or a double bond, and R represents a hydrophilic group in which one hydroxyl group has been removed from any one selected from the group consisting of sorbitan, isosorbide, and glycol.

[0016]

[22] The compound or salt thereof according to the above

[21] , wherein n=2 in the general formula (I').

[23] The amphiphilic compound is selected from the group consisting of: Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradecyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide, Mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide, mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan, Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl) isosorbide, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol, and Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol The compound or salt thereof according to

[21] or

[22] above, selected from the group consisting of:

[0017] This specification includes the disclosures of Japanese Patent Application Nos. 2020-011237 and 2020-211758, from which this application claims priority. [Effects of the Invention]

[0018] According to the present invention, a highly safe non-lamellar liquid crystal forming composition can be provided. The present invention also provides a non-lamellar liquid crystal forming composition using a novel amphiphilic compound. [Brief explanation of the drawings]

[0019] [Figure 1]Figure 1 shows photographs showing the appearance of abscesses that developed after administration of the formulations. Figures 1A-C: Precursor formulation of Formulation No. 1. Figure 1D: Precursor formulation of Formulation No. 71. A: Abscess that developed along the incision and suture wound, B: Part of the abscess removed from the inside, C: The site of the abscess after partial removal, D: Abscess that developed along the incision and suture wound. The arrows point to the partial abscess. [Figure 2] Figure 2 shows the release rate of leuprolide acetate from each precursor formulation. Precursor formulation No. 121 contains DMPC as a phospholipid, precursor formulation No. 122 contains DOPC, precursor formulation No. 123 contains DOPE, and precursor formulation No. 124 contains DOPG-Na. Aqueous solution No. 125 does not contain either a C17 glycerol ester or a phospholipid. [Figure 3] FIG. 3 is a set of photographs showing the results of a subcutaneous implantation test using precursor formulations containing DMPC (FIG. 3A) or DOPC (FIG. 3B) as the phospholipid. [Figure 4] Figure 4 shows the release rate of FD-4 from each precursor formulation. Values ​​represent the mean ± SD (n = 3). [Figure 5] Figure 5 shows the release rate of leuprolide acetate from each precursor formulation. Values ​​represent the mean ± SD (n = 3). [Figure 6] FIG. 6 is a set of photographs showing the results of a subcutaneous implantation test using an emulsion or precursor formulation containing an isoprenoid lipid and a phospholipid. [Figure 7] FIG. 7 is a photograph showing the results of a subcutaneous implantation test using a precursor formulation containing an isoprenoid lipid and a phospholipid. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be described in detail below.

[0021] The present invention relates to a composition, particularly a non-lamellar liquid crystal-forming composition, comprising an amphiphilic compound having a specific isoprenoid-type fatty acid chain. In one embodiment, the present invention relates to a non-lamellar liquid crystal-forming composition comprising an amphiphilic compound having a specific isoprenoid-type fatty acid chain and a phospholipid. The non-lamellar liquid crystal-forming composition according to the present invention is preferably a non-lamellar liquid crystal-forming composition whose biocompatibility is improved by the phospholipid. Such a non-lamellar liquid crystal-forming composition is highly safe and therefore acceptable for in vivo application.

[0022] In the present invention, an amphiphilic compound having an isoprenoid fatty chain (isoprenoid lipid) represented by the following general formula (I) can be combined with a phospholipid to produce a non-lamellar liquid crystal-forming composition. The present invention provides a composition, particularly a non-lamellar liquid crystal-forming composition, comprising an amphiphilic compound represented by general formula (I) and a phospholipid. [ka]

[0023] In one embodiment, in general formula (I), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2 (n=1 or 2), and m represents 1 or 2 (m=1 or 2). The combination of n and m may be any of n=1, m=1; n=1, m=2; n=2, m=1; or n=2, m=2, but combinations of n=2, m=1 and n=2, m=2 are preferred, and combinations of n=2, m=2 are more preferred. In one embodiment, in general formula (I), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0024] In another embodiment, in general formula (I) and general formulas (II) to (IV) described below, X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, and m represents 1 or 2.

[0025] In relation to the present invention, the amphiphilic compound is represented by the chemical formula: TIFF2026001219000007.tif813 represents a single or double bond.

[0026] R in general formula (I) represents a hydrophilic group having one or more (e.g., two, three, four, or five) hydroxyl groups. R in general formula (I) may be a residue in which one hydroxyl group (OH) has been removed from a polyol. R in general formula (I) may have an ether bond and / or a cyclic structure. Examples of R in general formula (I) include, but are not limited to, a hydrophilic group in which one hydroxyl group (OH) has been removed from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, xylitol, sorbitan, isosorbide, and glycols (including, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycols such as 1,3-butylene glycol, and isoprene glycol). Isoprene glycol is also known as 3-methyl-1,3-butanediol. More preferably, R in general formula (I) is a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, or glycol (e.g., propylene glycol, ethylene glycol, butylene glycol such as 1,3-butylene glycol, or isoprene glycol). In one embodiment, R in general formula (I) may be a hydrophilic group having one hydroxyl group obtained by removing one hydroxyl group (OH) from a glycol having no ether bond, and such an amphiphilic compound represented by general formula (I) is not a self-assembling lipid (SOL).

[0027] In relation to the present invention, the amphiphilic compound is represented by the chemical formula: TIFF2026001219000008.tif78 means that the amphiphilic compound is a geometric isomer of E form (cis form) or Z form (trans form), or a mixture thereof.

[0028] Examples of the amphiphilic compound represented by general formula (I) include the amphiphilic compound represented by the following general formula (II). [ka]

[0029] In general formula (II), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2 (n=1 or 2), and m represents 1 or 2 (m=1 or 2). The combination of n and m may be any of n=1, m=1; n=1, m=2; n=2, m=1; or n=2, m=2, but combinations of n=2, m=1 and n=2, m=2 are preferred, and combinations of n=2, m=2 are more preferred. In one embodiment, in general formula (II), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0030] R in general formula (II) represents a hydrophilic group having one or more hydroxyl groups. R in general formula (II) may be the same as R in general formula (I). Examples of R in general formula (II) include, but are not limited to, hydrophilic groups in which one hydroxyl group (OH) has been removed from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, xylitol, sorbitan, isosorbide, and glycols (including, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycols such as 1,3-butylene glycol, and isoprene glycol). R in general formula (II) is more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, or glycol (e.g., propylene glycol, ethylene glycol, butylene glycol such as 1,3-butylene glycol, isoprene glycol, etc.). In one embodiment, R in general formula (II) may be, for example, a hydrophilic group having one hydroxyl group obtained by removing one hydroxyl group (OH) from a glycol having no ether bond.

[0031] Another example of the amphiphilic compound represented by general formula (I) is the amphiphilic compound represented by the following general formula (III). [ka]

[0032] In general formula (III), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2 (n=1 or 2), and m represents 1 or 2 (m=1 or 2). The combination of n and m may be any of n=1, m=1; n=1, m=2; n=2, m=1; or n=2, m=2, but combinations of n=2, m=1 and n=2, m=2 are preferred, and combinations of n=2, m=2 are more preferred. In one embodiment, in general formula (III), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0033] R in general formula (III) represents a hydrophilic group having one or more hydroxyl groups. R in general formula (III) may be the same as R in general formula (I). Examples of R in general formula (III) include, but are not limited to, hydrophilic groups in which one hydroxyl group (OH) has been removed from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, xylitol, sorbitan, isosorbide, and glycols (including, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycols such as 1,3-butylene glycol, and isoprene glycol). More preferably, R in general formula (III) is a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, or glycol (e.g., propylene glycol, ethylene glycol, butylene glycol such as 1,3-butylene glycol, isoprene glycol, etc.). In one embodiment, R in general formula (II) may be a hydrophilic group having one hydroxyl group obtained by removing one hydroxyl group (OH) from a glycol having no ether bond, for example.

[0034] Still another example of the amphiphilic compound represented by general formula (I) is the amphiphilic compound represented by the following general formula (IV). [ka]

[0035] In general formula (IV), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2 (n=1 or 2), and m represents 1 or 2 (m=1 or 2). The combination of n and m may be any of n=1, m=1; n=1, m=2; n=2, m=1; or n=2, m=2, but combinations of n=2, m=1 and n=2, m=2 are preferred, and combinations of n=2, m=2 are more preferred. In one embodiment, in general formula (IV), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0036] R in general formula (IV) represents a hydrophilic group having one or more hydroxyl groups. R in general formula (IV) may be the same as R in general formula (I). Examples of R in general formula (IV) include, but are not limited to, hydrophilic groups in which one hydroxyl group (OH) has been removed from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, glyceric acid, triglycerol, xylose, sorbitol, ascorbic acid, glucose, galactose, mannose, dipentaerythritol, maltose, mannitol, xylitol, sorbitan, isosorbide, and glycols (including, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycols such as 1,3-butylene glycol, and isoprene glycol). R in general formula (IV) is more preferably a hydrophilic group obtained by removing one hydroxyl group (OH) from glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, or glycol (e.g., propylene glycol, ethylene glycol, butylene glycol such as 1,3-butylene glycol, isoprene glycol, etc.). In one embodiment, R in general formula (IV) may be, for example, a hydrophilic group having one hydroxyl group obtained by removing one hydroxyl group (OH) from a glycol having no ether bond.

[0037] Preferred examples of the amphiphilic compound represented by general formula (I) used in the present invention include: mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol, mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)pentaerythritol, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)diglycerol, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan, mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)isosorbide Mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol, Mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan, mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan, Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl) isosorbide, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol, and Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol These include, but are not limited to:

[0038] Another example of the amphiphilic compound represented by general formula (I) is: mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan, Mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl) isosorbide, mono-O-(3,7,11,15-tetramethylhexadecanoyl)sorbitan, mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)propylene glycol, and Mono-O-(3,7,11,15-tetramethylhexadecanoyl)propylene glycol These include, but are not limited to:

[0039] In a preferred embodiment, the amphiphilic compound represented by general formula (I) used in the present invention may itself exhibit low viscosity. Specifically, the amphiphilic compound represented by general formula (I) itself preferably has a viscosity of 15.0 Pa s or less, more preferably 11.0 Pa s or less, and even more preferably 6.0 Pa s or less, measured at 25°C. This viscosity can be measured, for example, using a viscosity / viscoelasticity measuring device (Gemini II, Malvern Instruments) at a temperature of 25°C.

[0040] The non-lamellar liquid crystal forming composition according to the present invention may contain one or more amphiphilic compounds having an isoprenoid fatty chain represented by general formula (I). When the non-lamellar liquid crystal forming composition according to the present invention contains multiple amphiphilic compounds having an isoprenoid fatty chain, the weight ratio of these amphiphilic compounds is not particularly limited. However, in one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan and mono-O-(5,9,13-trimethyltetradec-4-enoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15. In one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan and mono-O-(5,9,13-trimethyltetradecanoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15. In one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan and mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15. In one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan and mono-O-(5,9,13,17-tetramethyloctadecanoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15.In one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain 2-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide and 5-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 50:50 to 70:30, or 55:45 to 65:35, for example 60:40. In one embodiment, the non-lamellar liquid crystal forming composition according to the present invention may contain mono-O-(4,8,12,16-tetramethylheptadeca-3-enoyl)sorbitan and mono-O-(4,8,12,16-tetramethylheptadeca-3-enoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15. In one embodiment, the non-lamellar liquid crystal forming composition may contain mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan and mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)isosorbide in a weight ratio of 50:50 to 99:1, preferably 60:40 to 90:10, 70:30 to 90:10, or 80:20 to 90:10, for example, 8:2 or 85:15.

[0041] The present invention also provides a newly discovered amphiphilic compound represented by the following general formula (I'), which is included in the scope of the amphiphilic compound represented by general formula (I). The amphiphilic compound represented by general formula (I') can also be suitably used in combination with a phospholipid to produce a non-lamellar liquid crystal-forming composition. [ka]

[0042] In one embodiment, in general formula (I'), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents 1 or 2, preferably n=2, and m represents 1 or 2; TIFF2026001219000013.tif813 represents a single bond or a double bond, and R represents a hydrophilic group formed by removing one hydroxyl group from sorbitan, isosorbide, or glycol (for example, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycol such as 1,3-butylene glycol, and isoprene glycol).

[0043] In general formula (I'), the combination of n and m may be any of n=1, m=1; n=1, m=2; n=2, m=1; or n=2, m=2. In one embodiment, in general formula (I'), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0044] In another embodiment, in general formula (I'), X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2, and m represents 1 or 2; TIFF2026001219000014.tif813 represents a single bond or a double bond, and R may represent a hydrophilic group obtained by removing one hydroxyl group from sorbitan, isosorbide, or glycol (e.g., propylene glycol, etc.). The combination of n and m may be any of 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. In one embodiment, in general formula (I'), X and Y together represent an oxygen atom, and n=2, m=2; or n=2, m=1.

[0045] The amphiphilic compound represented by general formula (I') may be a compound represented by the above general formula (II), (III), or (IV), in which X and Y each represent a hydrogen atom or together represent an oxygen atom, n represents an integer of 0 to 2 (preferably, n=1 or 2), m represents 1 or 2, and R represents a hydrophilic group in which one hydroxyl group has been removed from sorbitan, isosorbide, or glycol (e.g., propylene glycol, etc.).

[0046] Preferred examples of the amphiphilic compound represented by general formula (I') include: Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan, Mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan, Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide, Mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide, mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan, Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl) isosorbide, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol, and Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol These include, but are not limited to:

[0047] The non-lamellar liquid crystal forming composition of the present invention contains an amphiphilic compound represented by general formula (I). The amphiphilic compound represented by general formula (I) includes an amphiphilic compound represented by general formula (I'). The non-lamellar liquid crystal forming composition of the present invention may contain the amphiphilic compound represented by general formula (I) or (I') in the form of a salt thereof. The salt of the amphiphilic compound represented by general formula (I) or (I') of the present invention may be any salt, including, but not limited to, salts of alkali metals or alkaline earth metals such as sodium, potassium, calcium, and magnesium. The salt of the amphiphilic compound represented by general formula (I) or (I') of the present invention may be a pharmaceutically acceptable salt. The non-lamellar liquid crystal forming composition of the present invention containing the amphiphilic compound represented by general formula (I) or (I') of the present invention in the form of a salt thereof is also included in the scope of the non-lamellar liquid crystal forming composition containing the amphiphilic compound represented by general formula (I) or (I') of the present invention.

[0048] The amphiphilic compound represented by general formula (I) of the present invention can be used in combination with a phospholipid. If the amphiphilic compound represented by general formula (I) is toxic, the phospholipid can reduce the toxicity of the amphiphilic compound, improving the biocompatibility of the non-lamellar liquid crystal-forming composition and increasing safety when applied in vivo. In other words, the non-lamellar liquid crystal-forming composition comprising the amphiphilic compound represented by general formula (I) of the present invention and a phospholipid preferably has improved biocompatibility due to the phospholipid compared to a control composition not containing a phospholipid. In the present invention, "biocompatibility" refers to the property of causing little or no adverse reactions (side effects) in the body when applied in vivo. The improved biocompatibility due to the phospholipid in the non-lamellar liquid crystal-forming composition comprising the amphiphilic compound represented by general formula (I) of the present invention and a phospholipid can be confirmed by the reduction or elimination of toxicity when the composition is applied in vivo compared to a control composition not containing a phospholipid. In the present invention, a "control composition not containing a phospholipid" refers to a non-lamellar liquid crystal-forming composition having the same composition but without the phospholipid. "Toxicity" in the present invention includes, but is not limited to, systemic toxicity such as hepatotoxicity, foreign body reactions such as abscess formation, and local toxicity resulting in tissue damage such as bleeding and discoloration. Hepatotoxicity can be confirmed by the occurrence of at least one symptom of liver damage selected from the group consisting of ascites, liver enlargement, adhesions around the liver (particularly adhesions at non-damaged, non-inflamed sites), and liver whitening. In one embodiment, the reduction or elimination of toxicity in the nonlamellar liquid crystal-forming composition of the present invention may result in a reduction in mortality following in vivo administration of the nonlamellar liquid crystal-forming composition to small laboratory animals, including rodents such as mice and rats, compared to a control composition not containing phospholipids. The nonlamellar liquid crystal-forming composition of the present invention, comprising an amphiphilic compound represented by general formula (I) and a phospholipid, is suitable for in vivo administration (preferably parenteral administration, such as intraperitoneal administration, intramuscular administration, or subcutaneous administration).In the present invention, "acceptable for internal application" means that when administered to a living body (typically, when administered parenterally, such as intraperitoneally, intramuscularly, or subcutaneously), no toxicity occurs or the toxicity occurs at a pharmaceutically acceptable level. However, the non-lamellar liquid crystal forming composition of the present invention is not limited to compositions intended for internal application.

[0049] The phospholipids used in the present invention include, but are not limited to, one or more phospholipids selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerin, phosphatidic acid, and sphingomyelin, and salts thereof, or phospholipid preparations or fractions containing the same. Examples of phosphatidylcholine include, but are not limited to, dioleylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), soybean phosphatidylcholine (SPC; also known as soybean lecithin), and egg yolk phosphatidylcholine (EPC; also known as egg yolk lecithin). Examples of phosphatidylethanolamine include, but are not limited to, dioleylphosphatidylethanolamine (DOPE). An example of a phosphatidylglycerin is dioleylphosphatidylglycerin, and an example of a salt of phosphatidylglycerin is sodium dioleylphosphatidylglycerin (DOPG-Na), but these are not limited thereto. The phospholipids used in the present invention may be synthetic or naturally derived. In one embodiment, the phospholipid used in the present invention may be phosphatidylcholine, such as soybean phosphatidylcholine or egg yolk phosphatidylcholine. In another embodiment, the phospholipid used in the present invention may be phosphatidylcholine, phosphatidylethanolamine, or phosphatidylglycerin, or a salt thereof. In one embodiment, the phospholipid used in the present invention may be selected from the group consisting of soybean phosphatidylcholine (SPC), egg yolk phosphatidylcholine (EPC), dimyristoyl phosphatidylcholine (DMPC), dioleyl phosphatidylcholine (DOPC), and dioleyl phosphatidylethanolamine (DOPE). The non-lamellar liquid crystal forming composition of the present invention may contain one or more types of phospholipids.

[0050] For the purpose of improving the biocompatibility of the amphiphilic compound and increasing the safety of the non-lamellar liquid crystal forming composition, the weight ratio of the isoprenoid amphiphilic compound represented by general formula (I) to the phospholipid contained in the non-lamellar liquid crystal forming composition according to the present invention is, but is not limited to, preferably amphiphilic compound:phospholipid=90:10 to 10:90, and for example, amphiphilic compound:phospholipid=80:20 to 20:80, 80:20 to 30:70, 70:30 to 10:9 ... The ratio may be 20:80, 70:30 to 30:70, 60:40 to 10:90, 60:40 to 20:80, 60:40 to 30:70, 60:40 to 40:60, 45:55 to 10:90, 45:55 to 20:80, 45:55 to 30:70, 45:55 to 35:65, 45:55 to 55:45, 50:50 to 20:80, 50:50 to 30:70, 40:60 to 10:90, 40:60 to 20:80, 40:60 to 30:70, 35:65 to 20:80, or 35:65 to 25:75.

[0051] In one embodiment, a non-lamellar liquid crystal forming composition comprising an amphiphilic compound represented by general formula (I) (wherein n=2 and m=2, and R represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, and glycol (for example, propylene glycol, ethylene glycol, diethylene glycol, butylene glycol such as 1,3-butylene glycol, and isoprene glycol, but are not limited to these)) and a phospholipid, wherein the weight ratio of the amphiphilic compound to the phospholipid is 90:10 to 10:90. For example, the amphipathic compound:phospholipid ratio is preferably 80:20 to 20:80, 80:20 to 30:70, 70:30 to 10:90, 70:30 to 20:80, 70:30 to 30:70, 60:40 to 10:90, 60:40 to 20:80, 60:40 to 30:70, 60:40 to 40:60, 45:55 to 10 :90, 45:55 to 20:80, 45:55 to 30:70, 45:55 to 35:65, 45:55 to 55:45, 50:50 to 20:80, 50:50 to 30:70, 40:60 to 10:90, 40:60 to 20:80, 40:60 to 30:70, 35:65 to 20:80, or 35:65 to 25:75.

[0052] In one embodiment, a non-lamellar liquid crystal forming composition comprising an amphiphilic compound represented by general formula (I) (wherein n=1 and m=2, and R represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, and glycol (for example, propylene glycol, ethylene glycol, diethylene glycol, butylene glycol such as 1,3-butylene glycol, and isoprene glycol, but are not limited to these)) and a phospholipid, the weight ratio of the amphiphilic compound to the phospholipid being 90:10 to 10:90. For example, the amphipathic compound:phospholipid ratio is preferably 80:20 to 20:80, 80:20 to 30:70, 70:30 to 10:90, 70:30 to 20:80, 70:30 to 30:70, 60:40 to 10:90, 60:40 to 20:80, 60:40 to 30:70, 60:40 to 40:60, 45:55 to 10 :90, 45:55 to 20:80, 45:55 to 30:70, 45:55 to 35:65, 45:55 to 55:45, 50:50 to 20:80, 50:50 to 30:70, 40:60 to 10:90, 40:60 to 20:80, 40:60 to 30:70, 35:65 to 20:80, or 35:65 to 25:75.

[0053] In one embodiment, a non-lamellar liquid crystal forming composition comprising an amphiphilic compound represented by general formula (I) (wherein n=2 and m=1, and R represents a hydrophilic group obtained by removing one hydroxyl group from any one selected from the group consisting of glycerol, erythritol, pentaerythritol, diglycerol, sorbitan, isosorbide, and glycol (for example, propylene glycol, ethylene glycol, diethylene glycol, butylene glycol such as 1,3-butylene glycol, and isoprene glycol, but are not limited to these)) and a phospholipid, the weight ratio of the amphiphilic compound to the phospholipid being 90:10 to 10:90. For example, the amphipathic compound:phospholipid ratio is preferably 80:20 to 20:80, 80:20 to 30:70, 70:30 to 10:90, 70:30 to 20:80, 70:30 to 30:70, 60:40 to 10:90, 60:40 to 20:80, 60:40 to 30:70, 60:40 to 40:60, 45:55 to 10 :90, 45:55 to 20:80, 45:55 to 30:70, 45:55 to 35:65, 45:55 to 55:45, 50:50 to 20:80, 50:50 to 30:70, 40:60 to 10:90, 40:60 to 20:80, 40:60 to 30:70, 35:65 to 20:80, or 35:65 to 25:75.

[0054] In one embodiment, in a non-lamellar liquid crystal forming composition comprising an amphiphilic compound represented by general formula (I) (wherein n is an integer of 0 to 2, m is 1 or 2, and R represents a hydrophilic group in which one hydroxyl group has been removed from sorbitan, isosorbide, or glycol (for example, but not limited to, propylene glycol, ethylene glycol, diethylene glycol, butylene glycol such as 1,3-butylene glycol, and isoprene glycol)), and a phospholipid, the weight ratio of the amphiphilic compound to the phospholipid is preferably 90:10 to 10:90. For example, Blend:Phospholipid = 80:20-20:80, 80:20-30:70, 70:30-10:90, 70:30-20:80, 70:30-30:70, 60:40-10:90, 60:40-20:80, 60:40-30:70, 60:40-40:60, 45:55-10:90, 45:55- It may be 20:80, 45:55 to 30:70, 45:55 to 35:65, 45:55 to 55:45, 50:50 to 20:80, 50:50 to 30:70, 40:60 to 10:90, 40:60 to 20:80, 40:60 to 30:70, 35:65 to 20:80, or 35:65 to 25:75.

[0055] The weight ratio of the amphipathic compound to the phospholipid is calculated using the total weight of the isoprenoid amphipathic compounds represented by general formula (I) when multiple compounds are used, or the total weight of the phospholipids when multiple compounds are used. In this specification, the terms "weight" and "mass" are used interchangeably.

[0056] In an alternative embodiment, the non-lamellar liquid crystal forming composition of the present invention may not contain phospholipids, as long as it has sufficiently high biocompatibility (i.e., safety), depending on the application, dosage form, composition, etc. Therefore, the present invention also relates to a composition, particularly a non-lamellar liquid crystal forming composition, containing an amphiphilic compound represented by general formula (I). Such a non-lamellar liquid crystal forming composition can also be used as a sustained-release preparation, for example, when it contains a drug.

[0057] In the present invention, the term "non-lamellar liquid crystal forming composition" means a composition that forms a non-lamellar liquid crystal structure (non-lamellar liquid crystal composition), or a composition that does not form a non-lamellar liquid crystal structure by itself but has the ability to form a non-lamellar liquid crystal structure in the presence of water (i.e., upon contact with an aqueous medium) (liquid crystal precursor composition).

[0058] When the non-lamellar liquid crystal-forming composition according to the present invention is a liquid crystal precursor composition, it does not contain an aqueous medium or does not contain an amount of aqueous medium sufficient to form a non-lamellar liquid crystal structure. When the non-lamellar liquid crystal-forming composition according to the present invention is a non-lamellar liquid crystal composition, it contains an aqueous medium, preferably an amount of aqueous medium sufficient to form a non-lamellar liquid crystal structure. The aqueous medium is not particularly limited and may be sterilized water, purified water, distilled water, ion-exchanged water, ultrapure water, water for injection, physiological saline, phosphate buffer solution, etc. The non-lamellar liquid crystal-forming composition according to the present invention may be a liquid crystal emulsion (more specifically, a non-lamellar liquid crystal emulsion composition). The non-lamellar liquid crystal-forming composition according to the present invention, which is a liquid crystal emulsion, preferably further contains a surfactant. Note that non-lamellar liquid crystal emulsion compositions are also referred to as dispersants. The non-lamellar liquid crystal emulsion composition according to the present invention, which contains the above-mentioned amphiphilic compound and phospholipid, also exhibits high stability.

[0059] An example of a surfactant used in the non-lamellar liquid crystal forming composition according to the present invention is P80 (polyoxyethylene sorbitan monooleate (20E.O.)). Other examples of surfactants include nonionic surfactants such as block copolymers of hydrophilic ethylene oxide and hydrophobic propylene oxide (polyoxyethylene polyoxypropylene glycol), polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, and polyoxyethylene hydrogenated castor oil. Nonionic surfactants having a molecular weight of 1,000 or more (more preferably, 5,000 or more) are more preferred. Examples of block copolymers of ethylene oxide and propylene oxide include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (120) polyoxypropylene (40) glycol. These block copolymers of ethylene oxide and propylene oxide are available from Pluronic (R) , poloxamer (R) , Unilube (R) , Pronon (R) Particularly preferred examples of nonionic surfactants include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol (also known as Pluronic (R) F127; Unilube 70DP-950B, Poloxamer (R) 407). In the present invention, the amphiphilic compounds represented by general formulas (I) and (I') used in the present invention are not included in the scope of surfactants. The non-lamellar liquid crystal forming composition of the present invention may contain one or more of such surfactants.

[0060] The non-lamellar liquid crystal forming composition according to the present invention may contain at least one of an oil component and an organic solvent.

[0061] Examples of oils that can be used in the non-lamellar liquid crystal forming composition of the present invention include, but are not limited to, vegetable oils such as sesame oil, soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, and cottonseed oil, animal oils such as egg yolk oil, fish oil, and lanolin, medium-chain triglycerides (MCT), triglycerides, mineral oils such as liquid paraffin, hydrocarbon oils such as squalene and squalane, ester oils such as isopropyl myristate (IPM), cholesterol, tocopherol, tocopherol acetate, glyceryl dioleate (GDO), gelling hydrocarbons, tetrahydrofarnesyl methyl acetate, and hexahydrogeranylgeranyl methyl acetate. The oil is preferably pharmaceutically acceptable.

[0062] The non-lamellar liquid crystal forming composition according to the present invention contains an isoprenoid-type amphiphilic compound represented by general formula (I), a phospholipid, and an oil in a total amount, which is not limited to the following: in the case of a liquid crystal precursor composition, it may contain 30% or more of the total amount of the composition, typically 60 to 100%, preferably 65 to 95%, for example, 75 to 95%, 75 to 93%, or 80 to 95%; in the case of a liquid crystal emulsion composition, it may contain 0.01 to 40%, preferably about 1 to 30%, for example, 20 to 30%, 20 to 23%, or 25 to 30%, of the total amount of the composition.

[0063] In this specification, the percentage (%) of a component in the non-lamellar liquid crystal forming composition means % by weight, and can be expressed in units of w / w%.

[0064] Examples of organic solvents used in the non-lamellar liquid crystal forming composition of the present invention include, but are not limited to, alcohols such as ethanol, propylene glycol, and isopropanol; ethers such as diethyl ether and polyethylene glycol; dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP); and dimethylacetamide (DMA). The organic solvent is preferably pharmaceutically acceptable. In the non-lamellar liquid crystal forming composition of the present invention, protic organic solvents or aprotic organic solvents may be used alone, or in combination with aprotic organic solvents. Examples of protic organic solvents include alcohols such as ethanol and propylene glycol, and polyethylene glycol. Examples of aprotic organic solvents include ethers such as diethyl ether, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and dimethylacetamide (DMA).

[0065] The non-lamellar liquid crystal forming composition according to the present invention may contain a water-soluble polymer, such as, but not limited to, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, polyvinylpyrrolidone, carbopol, carrageenan, chitosan, chondroitinate, xanthan gum, hyaluronate (such as sodium hyaluronate), alginate (such as sodium alginate), gelatin, and dextran. Hydroxypropyl cellulose (HPC) includes, for example, five grades of HPC commercially available from Nippon Soda Co., Ltd. (Japan): HPC-SSL (molecular weight approximately 40,000, viscosity 2-2.9 mPa s), HPC-SL (molecular weight approximately 100,000, viscosity 3-5.9 mPa s), HPC-L (molecular weight approximately 140,000, viscosity 6-10 mPa s), HPC-M (molecular weight approximately 620,000, viscosity 150-400 mPa s), and HPC-H (molecular weight approximately 910,000, viscosity 1000-4000 mPa s). In one embodiment, the hydroxypropyl cellulose may have a molecular weight of 1,000,000 or less, or 800,000 or less, e.g., 10,000-700,000 or 10,000-80,000.

[0066] The non-lamellar liquid crystal forming composition of the present invention may contain an antioxidant, such as ascorbic acid or sodium sulfite, but is not limited to these.

[0067] The non-lamellar liquid crystal forming composition of the present invention can form a gel containing water or in the presence of water. This gel formation means that non-lamellar liquid crystals (liquid crystal gels) are formed. The non-lamellar liquid crystals can retain and sustainably release substances such as drugs. The present invention also relates to a gel (gel-like composition) containing the non-lamellar liquid crystal forming composition of the present invention.

[0068] The non-lamellar liquid crystal is a liquid crystal structure that is not a lamellar liquid crystal, and specifically may be, for example, a cubic liquid crystal, a reversed hexagonal liquid crystal (HII), a reversed micellar cubic phase (Fd3m), or a sponge phase (L3). The non-lamellar liquid crystal may include two or more types of non-lamellar liquid crystal phases.

[0069] The cubic liquid crystal may be a cubic liquid crystal belonging to the crystallographic space group Ia3d (hereinafter referred to as Ia3d cubic liquid crystal), a cubic liquid crystal belonging to the crystallographic space group Pn3m (hereinafter referred to as Pn3m cubic liquid crystal), or a cubic liquid crystal belonging to the crystallographic space group Im3m (hereinafter referred to as Im3m cubic liquid crystal).

[0070] The liquid crystal structure can be analyzed by a conventional method, for example, by small angle X-ray scattering (SAXS) measurement using the following method.

[0071] When the sample to be measured is an emulsion, for example, the sample can be placed in an X-ray capillary tube made of soda glass or quartz, and the capillary can be sealed with an oxygen burner before being subjected to SAXS measurement. SAXS measurement can be performed using commercially available equipment, such as the NANO Viewer nanoscale X-ray structure evaluation system (manufactured by Rigaku).

[0072] By checking whether the SAXS measurement results show the ratio of the following scattering peaks (peak intervals) that are specific to each liquid crystal structure, it is possible to confirm whether the non-lamellar liquid crystal forming composition of the present invention has formed or will form a liquid crystal structure in the presence of water. PN3M Cubic LCD Ratio: √2:√3:√4:√6:√8:√9:√10: ,,,, Ia3d Cubic LCD Ratio: √3:√4:√7:√8:√10:√11: ,,,, Im3m Cubic LCD Ratio: √2:√4:√6:√8:√10:√12:√14: ,,,, Fd3m Cubic LCD Ratio: √3:√8:√11:√12:√16:√19:√24:√27: ,,,, Ratio specific to inverted hexagonal liquid crystal: 1:√3:2: ,,,, Furthermore, the space group and lattice constant can be easily determined by calculating peak values ​​from SAXS intensity distribution data and then calculating the ratio of their reciprocals according to a method well known to those skilled in the art.

[0073] On the other hand, in the SAXS measurement of the sponge phase (L3 phase), a broad scattering peak is observed.

[0074] By analyzing the scattering vector values ​​of the peaks of the measured sample, including the scattering vector value q1 [nm-1] of the peak located at the smallest angle, it is possible to determine not only the type of liquid crystal phase but also its interplanar spacing and lattice constant. Based on such analysis results, the size of the liquid crystal phase and unit cell can be changed by modifying the composition of the non-lamellar liquid crystal-forming composition, thereby controlling the sustained release (sustained release rate) of a drug from a composition or formulation (e.g., precursor formulation, emulsion) containing the non-lamellar liquid crystal-forming composition and a drug. For example, by changing the size of the liquid crystal phase and unit cell depending on the amphiphilic compound represented by general formula (I), phospholipid, and other components, and their ratio (weight ratio), it is possible to obtain a corresponding sustained release rate. Amphiphilic compounds represented by general formula (I) with similar R and the same carbon chain length (same values ​​for n and m) or close carbon chain lengths (same value for m only) and the same R exhibit the same or similar liquid crystal phase and sustained release characteristics (such as sustained release rate) when used in combination with the same phospholipid and at similar weight ratios to the phospholipid in a non-lamellar liquid crystal-forming composition. Generally, the release rate increases in the following order (from lowest to highest): reverse micellar cubic phase (Fd3m), reverse hexagonal liquid crystal (HII), and cubic liquid crystal.

[0075] The non-lamellar liquid crystal forming composition according to the present invention can be used as a medical substrate for application to the body. The non-lamellar liquid crystal forming composition according to the present invention has an anti-adhesion effect on biological tissues, and can therefore be used to prevent adhesion of biological tissues. Therefore, the non-lamellar liquid crystal forming composition according to the present invention may be used for preventing adhesion of biological tissues. The non-lamellar liquid crystal forming composition according to the present invention can be applied (administered) in vivo as an agent for preventing adhesion of biological tissues.

[0076] The non-lamellar liquid crystal forming composition of the present invention can prevent adhesion of biological tissues by applying it to biological tissues that are prone to adhesion. In the present invention, the "adhesion prevention effect" refers to the effect of preventing adhesion of tissues that are prone to adhesion to other tissues or organs, making them difficult to separate, and completely or at a low level of adhesion. Therefore, the non-lamellar liquid crystal forming composition of the present invention can be used to prevent adhesion of biological tissues.

[0077] The adhesion prevention effect of the non-lamellar liquid crystal forming composition according to the present invention is achieved by the amphiphilic compound contained in the non-lamellar liquid crystal forming composition forming a coating on the surface of the tissue to which it is applied, due to the formation of non-lamellar liquid crystals. The formed coating prevents contact between the tissue and other tissues or organs, thereby reducing adhesion.

[0078] The adhesion prevention effect of the nonlamellar liquid crystal-forming composition according to the present invention can be confirmed, for example, by applying the nonlamellar liquid crystal-forming composition to the tissue incision in an animal model after abdominal surgery, closing the abdomen, and then observing the progress. Specifically, a rat is subjected to a midline abdominal incision (e.g., approximately 30 mm), and approximately 20 mm incisions are made in the left and right upper abdominal parietal peritoneum. After complete hemostasis, the peritoneal incision is closed with continuous sutures (e.g., using 5-0 silk suture). A nonlamellar liquid crystal-forming composition sample is then applied to either the left or right peritoneal incision, covering the sutured incision. If the nonlamellar liquid crystal-forming composition is a liquid crystal precursor composition, an aqueous medium (e.g., water for injection) may be added to the sample application site by spraying, etc., to induce liquid crystal formation. No medium is applied to the other peritoneal incision. The abdominal wall is then closed in two layers. After a certain period of time (e.g., 7 days) following this surgery, the abdomen is opened and the presence of adhesions at the incision site is evaluated.

[0079] The application of the non-lamellar liquid crystal forming composition may be carried out in a manner appropriate for the formulation. The amount of the non-lamellar liquid crystal forming composition applied in this evaluation is typically preferably an amount equivalent to 5 to 50 mg of the amphiphilic compound.

[0080] Adhesion evaluation can be performed, for example, by assigning an evaluation score regarding adhesion strength as follows.

[0081] Grade 0: No adhesion Grade 1: Adhesion that can be separated with light traction (no tissue damage) Grade 2: Adhesion that can be separated with strong traction (without tissue damage) Grade 3: Adhesion with tissue damage due to strong traction separation When the evaluation score of the incision site to which the non-lamellar liquid crystal forming composition sample was applied is lower than that of the incision site to which the non-lamellar liquid crystal forming composition sample was not applied on the same animal, it can be determined that an adhesion prevention effect is observed.

[0082] Furthermore, for example, the adhesion area rate of each incision is calculated as the ratio (%) of the adhesion length to the approximately 20 mm incision suture, and based on this, the ratio of the adhesion area of ​​the incision where the non-lamellar liquid crystal forming composition sample was applied to the incision where no sample was applied to the incision where no sample was applied (adhesion area rate on the side where the sample was applied / adhesion area rate on the side where no sample was applied × 100) can be judged as A if it is 40% or less, B+ if it is 41 to 60%, B- if it is 61 to 80%, and C if it is 81% or more. In this case, a rating of A or B+ is preferable in terms of adhesion prevention effect.

[0083] In the present invention, "adhesion prevention" can be determined by the reduction in the frequency and / or severity of adhesions at the application site by application (treatment) of the non-lamellar liquid crystal forming composition compared to an untreated control.

[0084] It should be noted that it has been demonstrated in Patent Document 3 and the like that many of the amphiphilic compounds represented by general formula (I) have an anti-adhesion effect.

[0085] The present invention also provides a method for preventing adhesions in biological tissues, comprising applying the non-lamellar liquid crystal-forming composition of the present invention to biological tissues. More specifically, the present invention also provides a method for preventing tissue adhesions in an affected area, comprising applying an effective amount of the non-lamellar liquid crystal-forming composition of the present invention to an affected area of ​​a patient, specifically a site at risk of adhesions, specifically a site where tissue repair is expected to occur (e.g., an inflamed or damaged site within the body). Specific examples of such sites at risk of adhesions include sites of exogenous or endogenous inflammation within the body, wound sites such as surgical incisions, and sites where the tissue surface has been damaged by artificial manipulation such as touching during surgery. In the present invention, the term "damaged site" refers to a portion of a tissue or organ damaged by surgery, trauma, disease, or the like. Examples of tissues or organs to which the adhesion inhibitor can be applied include, but are not limited to, the peritoneum, small intestine, large intestine, rectum, stomach, duodenum, cecum, liver, uterus, fallopian tubes, lymphatic vessels, heart, pericardium, lungs, brain, ovaries, and tendons. In a typical example, the non-lamellar liquid crystal forming composition of the present invention is applied to an incision site, the area around an incision site, or the entire organ having an incision site during surgery. The non-lamellar liquid crystal forming composition of the present invention may also be applied to an internal site that comes into contact with a wound site, an inflamed site, or the like.

[0086] Application to affected areas such as injury sites (e.g., wound sites) and inflammation sites can be performed using a method appropriate for the dosage form. For example, the adhesion inhibitor can be sprayed onto affected areas such as injury sites (e.g., wound sites) and inflammation sites using a gas-propelled aerosol container. Furthermore, in the case of a pump spray, the non-lamellar liquid crystal-forming composition can be sprayed onto affected areas such as injury sites (e.g., wound sites) and inflammation sites using a non-gas-propelled spray container, such as a general-purpose manual type. In the case of endoscopic or laparoscopic surgery, the non-lamellar liquid crystal-forming composition can also be sprayed onto affected areas such as injury sites (e.g., wound sites) using a spray nozzle or the like used in endoscopic or laparoscopic surgery. In the present invention, "spraying" refers to applying pressure to eject (atomize and / or jet) the target substance in the form of droplets, mist, fine particles, foam, or the like. When the non-lamellar liquid crystal-forming composition is a liniment, an appropriate amount can be applied to affected areas such as injury sites (e.g., wound sites) and inflammation sites. When the non-lamellar liquid crystal forming composition is an injection, the non-lamellar liquid crystal forming composition may be injected into an affected area such as an injured site (for example, a wound site) or an inflamed site.

[0087] The non-lamellar liquid crystal forming composition according to the present invention is preferably applied to an affected area such as an injured area (e.g., a wound area) or an inflamed area in an amount sufficient to sufficiently cover the affected area such as an injured area (e.g., a wound area) or an inflamed area. In a preferred embodiment, the specific application amount of the non-lamellar liquid crystal forming composition according to the present invention is 10 mg to 100 g, or 50 mg to 50 g (more preferably 0.1 g to 10 g) for humans.

[0088] When the non-lamellar liquid crystal-forming composition of the present invention contains a sufficient amount of aqueous medium (e.g., when it is a liquid crystal emulsion), the non-lamellar liquid crystal-forming composition can form non-lamellar liquid crystals on the surface of tissue to which it is applied. When the non-lamellar liquid crystal-forming composition of the present invention does not contain a sufficient amount of aqueous medium (e.g., when it is a liquid crystal precursor composition), non-lamellar liquid crystals are formed by moisture in the body. To promote film formation, however, it is preferable to apply an aqueous medium in addition to the non-lamellar liquid crystal-forming composition to an affected area such as an injury site (e.g., a wound site) or an inflammation site. The aqueous medium may be, for example, water such as sterilized water, purified water, distilled water, ion-exchanged water, ultrapure water, or water for injection, or a physiologically acceptable aqueous solution. Examples of physiologically acceptable aqueous solutions include physiological saline; electrolyte solutions such as aqueous sodium chloride solution, aqueous calcium chloride solution, aqueous magnesium chloride solution, aqueous sodium sulfate solution, aqueous potassium sulfate solution, aqueous sodium carbonate solution, and aqueous sodium acetate solution; buffer solutions such as phosphate buffer and Tris-HCl buffer; aqueous solutions containing sugar molecules such as glucose, sucrose, maltose, and hyaluronic acid; and aqueous solutions containing water-soluble polymers such as polyethylene glycol and polyvinyl alcohol. A preferred example of a physiologically acceptable aqueous solution is an aqueous hyaluronic acid solution containing hyaluronic acid or a salt thereof (such as sodium hyaluronate).

[0089] After applying the non-lamellar liquid crystal-forming composition, which is a liquid crystal precursor composition, it is preferable to apply an aqueous medium on top of the non-lamellar liquid crystal-forming composition, but this is not a limitation. The aqueous medium can be applied by the same application method as for the non-lamellar liquid crystal-forming composition, for example, by spraying, coating, or injection. After applying the aqueous medium to the tissue or organ in this manner, it is preferable to leave it for a predetermined time (for example, but not limited to, 1 to 30 minutes, preferably 5 to 10 minutes) to promote film formation.

[0090] The subject (patient) to whom the adhesion prevention method using the non-lamellar liquid crystal forming composition of the present invention is applied is typically a mammal such as a human, livestock, pet animal, laboratory animal, etc. Particularly preferred is a subject whose tissue (organ) has been or is expected to be damaged by surgery, trauma, disease, etc. Surgical operations include open surgery, endoscopic surgery, laparoscopic surgery, etc.

[0091] The non-lamellar liquid crystal forming composition of the present invention has significantly reduced or no toxicity, and therefore the adhesion prevention method according to the present invention is highly safe for patients undergoing treatment.

[0092] The non-lamellar liquid crystal-forming composition of the present invention may contain a drug in addition to the amphiphilic compound represented by general formula (I) and, if necessary, the above-mentioned components such as phospholipids. In the present invention, a drug refers to any substance (active ingredient) to be administered to a living body and retained in the non-lamellar liquid crystal structure for sustained (controlled) release by inclusion in the non-lamellar liquid crystal-forming composition. However, the drug is not the amphiphilic compound represented by general formula (I) itself. The drug may be an organic or inorganic compound. The drug may be a water-soluble drug or a lipid-soluble (lipophilic, water-insoluble, or poorly water-soluble) drug. The drug may be a physiologically active substance. The drug may be, for example, a protein, peptide, amino acid, nucleic acid, etc., but is not limited to these. The drug may be, for example, a gonadotropin-releasing hormone (GnRH) agonist. The gonadotropin-releasing hormone (GnRH) agonist may be, for example, but is not limited to, leuprolide or a salt thereof. The salt of leuprolide may be any pharmaceutically acceptable salt, including, but not limited to, carboxylic acid salts such as acetate (i.e., leuprolide acetate). Leuprolide acetate is also known by other names such as leuprorelin acetate. Such non-lamellar liquid crystal forming compositions can be used for sustained release of drugs.

[0093] The present invention also provides a pharmaceutical formulation comprising the non-lamellar liquid crystal-forming composition of the present invention. The pharmaceutical formulation of the present invention preferably comprises a non-lamellar liquid crystal-forming composition comprising an amphiphilic compound represented by general formula (I) and a phospholipid, the biocompatibility of which is improved by the phospholipid. In one embodiment, the pharmaceutical formulation of the present invention comprises a non-lamellar liquid crystal-forming composition comprising an amphiphilic compound represented by general formula (I), a phospholipid, and a drug. The "pharmaceutical formulation" of the present invention may be a pharmaceutical composition. The pharmaceutical formulation or pharmaceutical composition of the present invention may further comprise other substances such as pharmaceutically acceptable additives (e.g., carriers, excipients, lubricants, disintegrants, humectants, buffers, flavoring agents, preservatives, colorants, fragrances, propellants, etc.), as long as the pharmaceutical formulation or pharmaceutical composition maintains its ability to form non-lamellar liquid crystals.

[0094] The pharmaceutical preparation according to the present invention may be formulated into any dosage form, such as a spray, an aerosol, an injection, or a depot.

[0095] The pharmaceutical preparation of the present invention may be used to prevent adhesion of biological tissues. The pharmaceutical preparation of the present invention may also be a sustained-release preparation such as a depot preparation, which further contains the above-mentioned drug.

[0096] The present invention also provides a method for sustained delivery of a drug into a living organism (in the body) or living cells or tissues, comprising applying a pharmaceutical formulation containing the drug of the present invention or a non-lamellar liquid crystal-forming composition containing the drug of the present invention to a living organism such as a subject (patient), for example, the body (particularly, a living tissue within the body) or body surface, or to living cells or tissues. When using a non-lamellar liquid crystal-forming composition that is a liquid crystal precursor composition or a pharmaceutical formulation containing the same, an aqueous medium may be applied over the non-lamellar liquid crystal-forming composition or pharmaceutical formulation after application, but this is not limited thereto; liquid crystal formation due to water in the body may also be utilized. Application to a living organism (in the body or body surface, etc.) or living cells or tissues is preferably performed parenterally (e.g., intravenously, intraarterially, intraperitoneally, intramuscularly, subcutaneously, or intradermally). The method of the present invention enables sustained delivery of a drug into the body or living cells or tissues with high safety. [Example]

[0097] The present invention will be described in more detail below using examples, although the technical scope of the present invention is not limited to these examples.

[0098] [Example 1] Synthesis of amphiphilic compound (1) (1) Synthesis of mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan

[0099] [ka]

[0100] 14.1 g (50.0 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate and 10.9 g of a 90 wt% aqueous sorbitan solution (60.0 mmol, Sorbitan M-90, Sanko Chemical Industry Co., Ltd., 90% solids and 10% water, solids content: 79-84% sorbitan, 15-18% isosorbide) were added to a reaction vessel at room temperature and stirred at 120 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.27 g (5.0 mmol) of sodium methoxide and 0.01 g of sodium phosphinate monohydrate were added, followed by stirring at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.27 g (5.0 mmol) of sodium methoxide was added, followed by stirring at 160 °C and 8 kPa for an additional 1 hour. After cooling to 60 °C, 50 mL of ethyl acetate and 50 mL of 0.5 M hydrochloric acid were added with stirring. 150 mL of ethyl acetate was added to the resulting reaction solution, followed by extraction. The extract was washed successively with saturated sodium bicarbonate water and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / hexane mixture) to obtain 8.96 g (43% yield) of a fraction containing the title compound as a light brown, transparent liquid. The resulting fraction contained mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan and mono-O-(5,9,13-trimethyltetradec-4-enoyl)isosorbide in a weight ratio of approximately 8:2 (calculated from the TIC area value obtained by GC-MS measurement in ion mode EI+). The resulting fraction also contained a small amount of a diester derived from sorbitan (estimated from GC-MS measurement and TLC analysis). Regarding the resulting fraction, 1 The results of H-NMR measurement are as follows:

[0101] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.7-0.9 (m, 9H), 0.9-1.7 (m, 15H), 1.8-2.0 (m, 2H), 2.2-2.5 (m, 4H), 3.5-4.9 (m, 6.1H), 5.04 (m, 1H), 5.0-5.2 (m, 0.6H)

[0102] Mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan is also called C17 sorbitan ester.

[0103] The obtained fraction was used as a mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan fraction (C17 sorbitan ester fraction) in the Examples described later.

[0104] (2) Synthesis of mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan

[0105] [ka]

[0106] Under a nitrogen atmosphere, 0.48 g of 5% palladium on carbon was added to a solution of 4.14 g (10.0 mmol) of mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan in 12 mL of ethyl acetate. After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature for 2 days under atmospheric pressure and a hydrogen atmosphere. After replacing the hydrogen in the system with nitrogen, the 5% palladium on carbon was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 4.02 g (97% yield) of a fraction containing the title compound as a colorless, transparent liquid. The resulting fraction contained mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan and mono-O-(5,9,13-trimethyltetradecanoyl)isosorbide in a weight ratio of approximately 8:2 (calculated from the TIC area value measured by GC-MS in ion mode EI+). The obtained fraction also contained a small amount of sorbitan-derived diesters (estimated from GC-MS measurement and TLC analysis). 1 The results of H-NMR measurement are as follows:

[0107] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.7-0.9 (m, 12H), 0.9-1.7 (m, 19H), 2.2-2.4 (m, 2H), 3.5-4.9 (m, 6.4H), 5.0-5.2 (m, 0.6H)

[0108] Mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan is also referred to as saturated C17 sorbitan ester.

[0109] (3) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan

[0110] [ka]

[0111] 70.5 g (200 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate and 54.7 g of a 90 wt% aqueous sorbitan solution (300 mmol, Sorbitan M-90, Sanko Chemical Industry Co., Ltd., 90% solids with 10% water, solids content: 79-84% sorbitan, 15-18% isosorbide) were added to a reaction vessel at room temperature and stirred at 120 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 2.2 g (40 mmol) of sodium methoxide and 0.04 g of sodium phosphinate monohydrate were added, followed by stirring at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 1.1 g (20 mmol) of sodium methoxide was added, followed by stirring at 160 °C and 8 kPa for an additional 1 hour. The vacuum was released with nitrogen, and 1.1 g (20 mmol) of sodium methoxide was added again, followed by stirring at 160°C and 8 kPa for an additional 1.5 hours. After cooling to 60°C, 200 mL of ethyl acetate and 200 mL of 0.5 M hydrochloric acid were added with stirring. 600 mL of ethyl acetate was added to the resulting reaction solution for extraction. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / hexane mixture) to obtain 36.1 g (37% yield) of a fraction containing the title compound as a light brown, transparent liquid. The obtained fraction contained mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan and mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide in a ratio of approximately 8:2 (weight ratio) (calculated from the TIC area value obtained by GC-MS measurement in ion mode EI+). The obtained fraction also contained a small amount of sorbitan-derived diesters (estimated from GC-MS measurement and TLC analysis). 1 The results of H-NMR measurement are as follows:

[0112] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.7-0.9(m,12H),0.9-1.8(m,22H),1.85- 2.0(m,2H),2.0-2.5(m,4H),3.5-4.9(m,6.4H),5.04(m,1H),5.0-5.2(m,0.6H)

[0113] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan is also called C22 sorbitan ester.

[0114] The obtained fraction was used as a mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan fraction (C22 sorbitan ester fraction) in the Examples described later.

[0115] Furthermore, 13.00 g of the C22 sorbitan ester fraction was purified using a silica gel column (mobile phase: ethyl acetate / hexane mixture) to remove low-polarity components such as sorbitan-derived diesters and mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide from the C22 sorbitan ester fraction, yielding 6.78 g of a purified fraction as a pale yellow, transparent liquid. Its purity was 99% or more mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan (calculated from the TIC area value obtained by GC-MS measurement in ion mode EI+). Furthermore, it contained almost no low-polarity components such as sorbitan-derived diesters (estimated from GC-MS measurement and TLC analysis). Regarding the obtained compound, 1 The results of H-NMR measurement are as follows:

[0116] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.8-0.9(m,12H),0.9-1.7(m,22H),1.9-2.0(m,2H),2. 2-2.5(m,4H),2.93(brs,OH),3.6-4.5(m,7.5H),5.06(brd,J=5.0Hz,1H),4.9-5.2(m,0.5H)

[0117] The purified fraction obtained as described above is referred to as high-purity mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan or high-purity C22 sorbitan ester.

[0118] (4) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan

[0119] [ka]

[0120] Under a nitrogen atmosphere, 0.70 g of 5% palladium-carbon was added to a solution of 5.82 g (12.0 mmol) of the C22 sorbitan ester fraction in ethyl acetate (17.4 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere at atmospheric pressure. After replacing the hydrogen in the system with nitrogen, the 5% palladium-carbon was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 5.69 g (97% yield) of a fraction containing the title compound as a colorless, transparent liquid. The resulting fraction contained mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan and mono-O-(5,9,13,17-tetramethyloctadecanoyl)isosorbide in a weight ratio of approximately 8:2 (calculated from the TIC area value obtained by GC-MS analysis in ion mode EI+). The obtained fraction also contained a small amount of sorbitan-derived diesters (estimated from GC-MS measurement and TLC analysis). 1 The results of H-NMR measurement are as follows:

[0121] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.7-0.9 (m, 15H), 0.9-1.7 (m, 26H), 2.2-2.4 (m, 2H), 3.5-4.9 (m, 6.4H), 5.0-5.2 (m, 0.6H)

[0122] Mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan is also referred to as saturated C22 sorbitan ester.

[0123] The obtained fraction was used as a mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan fraction (saturated C22 sorbitan ester fraction) in the Examples described later.

[0124] (5) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide

[0125] [ka]

[0126] 35.3 g (100 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate and 29.2 g (200 mmol) of isosorbide (Sanko Chemical Industry Co., Ltd., purity ≥ 98.0%, moisture ≤ 1.0%) were added to a reaction vessel at room temperature. The mixture was heated to 120 °C while stirring at 8 kPa, then the vacuum was released with nitrogen, and 1.1 g (20 mmol) of sodium methoxide and 0.02 g of sodium phosphinate monohydrate were added. The mixture was heated to 180 °C under a nitrogen atmosphere, then the pressure was reduced to 8 kPa and the mixture was stirred for 1 hour. The vacuum was released with nitrogen, and 0.54 g (10 mmol) of sodium methoxide was added, followed by further stirring at 180 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and another 0.54 g (10 mmol) of sodium methoxide was added, followed by further stirring at 180 °C and 8 kPa for 1 hour. After cooling to 60°C, 100 mL of ethyl acetate and 100 mL of 0.5 M hydrochloric acid were added with stirring. 300 mL of ethyl acetate was added to the resulting reaction solution for extraction. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / hexane mixture) to give 17.9 g (38% yield) of the title compound as a light brown, transparent liquid.

[0127] This compound was further purified by silica gel column chromatography (ethyl acetate / hexane mixture) and separated into 2-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide and 5-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide in a 60:40 ratio (by weight). 1 The results of H-NMR measurement are as follows:

[0128] 2-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.7-0.9(m,12H),0.9-1.7(m,22H),1.85-2.0(m,2H),2.2-2.4(m,4H),2.56(d,J=7.2Hz,OH),3.55(dd,J= 6.0,9.5Hz,1H),3.87(dd,J=6.0,9.5Hz,1H),3.99(m,2H),4.29(m,1H),4.44(d,J=4.3Hz,1H),4.60(t,J=4.9Hz,1H),5.04(m,1H),5.21(s,1H)

[0129] 5-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.7-0.9(m,12H),0.9-1.7(m,22H),1.83(brs,OH),1.85-2.0(m,2H),2.2-2.4(m,4H),2.2-2.4(m,4H) ,3.74(ddd,J=2.1.5.2,9.8Hz,1H),3.82-3.93(m,3H),4.31(s,1H),4.38(d,J=4.6Hz,1H),4.83(t,J=5.0Hz,1H),5.07(m,1H),5.13(m,1H)

[0130] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) isosorbide is also called C22 isosorbide ester.

[0131] (6) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide

[0132] [ka]

[0133] Under a nitrogen atmosphere, 0.56 g of 5% palladium on carbon was added to a solution of 4.66 g (10.0 mmol) of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide in 14 mL of ethyl acetate. After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature under atmospheric pressure and a hydrogen atmosphere for 2 days. After replacing the hydrogen in the system with nitrogen, the 5% palladium on carbon was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 4.65 g (99% yield) of the title compound as a colorless, transparent liquid.

[0134] Mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide is also referred to as saturated C22 isosorbide ester.

[0135] (7) Synthesis of mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol

[0136] [ka]

[0137] To a solution of 0.65 g (7.1 mmol) of glycerol and 0.59 g (4.3 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) was slowly added dropwise 1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate (methyl tetrahydrofarnesyl acetate) at 80°C. After stirring at 100°C for 18 hours, 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 (mobile phase: ethyl acetate / hexane mixture) to obtain the title compound as a colorless, transparent liquid. The compound obtained was as follows: 1 The results of H-NMR measurement and viscosity measurement are as follows:

[0138] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.90(m,9H),1.00-1.70(m,15H),1.97(td,J=7.8,17.0Hz,2H),2.13(t,J=6. 1Hz,1H,OH),2.25-2.45(m,4H),2.55(d,J=5.2Hz,1H,OH),3.50-4.00(m,3H),4.10-4.25(m,2H),5.08(t,J=6.7Hz,1H) Viscosity: 0.48 Pa·s (shear rate 92 1 / s)

[0139] Mono-O-(5,9,13-trimethyltetradec-4-enoyl)glycerol is also referred to as C17 glycerol ester.

[0140] (8) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol

[0141] [ka]

[0142] Under a vacuum of 60-70 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 dry N,N-dimethylformamide (48 mL) at 80°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 200 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-30:70) to obtain 13.3 g (40% yield) of the title compound as a pale yellow, transparent liquid. The resulting compound was 1 The results of H-NMR measurement are as follows:

[0143] 1 H-NMR spectrum (300MHz, CDCl3, 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=6.9Hz,J=6.9Hz,1H)

[0144] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol is also referred to as C22 glycerol ester.

[0145] (9) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol

[0146] [ka]

[0147] 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 ethyl acetate (62 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature under atmospheric pressure and a hydrogen atmosphere for 42 hours. After replacing the hydrogen in the system with nitrogen, the 5% palladium on carbon was filtered off. The filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain 20.2 g (yield 98%) of the title compound as a colorless, transparent liquid. Regarding the compound obtained, 1 The results of H-NMR measurement are as follows:

[0148] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.7-0.9(m,15H),0.95-1.75(m,26H),2.13(t,J=6.0Hz,OH),2.34(t,J=7.7Hz,2 H),2.56(d,J=5.1Hz,OH),3.55-3.75(m,2H),3.94(m,1H),4.15(dd,J=6.0,11.7Hz,1H),4.20(dd,J=4.7,11.7Hz,1H)

[0149] Mono-O-(5,9,13,17-tetramethyloctadecanoyl)glycerol is also referred to as saturated C22 glycerol ester.

[0150] (10) Synthesis of mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol

[0151] [ka]

[0152] Under a nitrogen atmosphere, a solution of 58.1 g (200 mmol) of 3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol (geranylinalool) and 19 mL (0.15 mol) of trimethyl orthoacetate was added dropwise at 135 °C over 8 hours. After stirring at the same temperature for 6 hours, a solution of 5.3 mL (42 mmol) of trimethyl orthoacetate and 0.5 mL (4 mmol) of n-hexanoic acid was added dropwise and stirred at the same temperature for an additional 2 hours. The resulting reaction solution was diluted with a 3:1 ethyl acetate / hexane mixture (300 mL), washed twice with saturated aqueous sodium bicarbonate 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 (methyl geranylgeranylacetate) was obtained as a crude liquid product, which was used directly in the next reaction.

[0153] Under a reduced pressure of 200-250 mmHg, 13.9 g (40.0 mmol) of methyl 5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoate (methyl geranylgeranylacetate) was slowly added dropwise to a solution of 7.4 g (80 mmol) of glycerol and 5.5 g (40 mmol) of potassium carbonate in dry N,N-dimethylformamide (16 mL) at 85°C, and the mixture was stirred at the same temperature for 6 hours. During this time, the methanol produced during the reaction was distilled off. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 200 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0 to 0:100) to obtain 5.44 g (33% yield) of the title compound as a transparent liquid. Regarding the resulting compound, 1 The results of H-NMR measurement and viscosity measurement are as follows:

[0154] 1H-NMR spectrum (270MHz, CDCl3, 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=5.4,1 1.4Hz,1H),3.68(dd,J=3,11.4Hz,1H),3.92(m,1H),4.15(dd,J=6.0,11.6Hz,1H),4.21(dd,J=4.8,11.6Hz,1H),5.05-5.15(m,4H) Viscosity: 0.37 Pa·s (shear rate 92 1 / s)

[0155] Mono-O-(5,9,13,17-tetramethyloctadeca-4,8,12,16-tetraenoyl)glycerol is also called geranylgeranyl glyceryl acetate.

[0156] (11) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol

[0157] [ka]

[0158] Under a nitrogen atmosphere, 10 g of 5,9,13,17-tetramethyloctadecanoic acid and 20 ml of methylene chloride were added with one drop of pyridine, and 5.2 g of thionyl chloride was added dropwise at room temperature. After the addition was completed, the mixture was refluxed for 1 hour and concentrated under reduced pressure to obtain 10.5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride.

[0159] 2.56 g of erythritol, 2.21 g of pyridine, and 70 ml of dry DMF were mixed and heated to dissolve. After cooling to room temperature, a solution of 5 g of the 5,9,13,17-tetramethyloctadecanoic acid chloride obtained above dissolved in 10 ml of methylene chloride was added dropwise, followed by stirring at room temperature for 1 hour. 100 ml of methylene chloride was added to the resulting reaction solution, which was washed three times with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica gel column chromatography to obtain 2.83 g of the title compound as a transparent semi-solid. HPLC analysis indicated that the title compound contained 91.6% 1-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol and 8.4% 2-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol. Furthermore, the resulting compound was 1 The results of H-NMR measurement were as follows:

[0160] 1 H-NMR spectrum (270MHz, CDCl3, TMS) δ:0.8-0.9(m,15H),1.0-1.7(m,26H),2.11(br.s,1H),2 .33(t,J=7.9Hz,2H),2.66(br.s,1H),2.75(br.s,1H),3.6-3.9(m,4H),4.29-4.36(m,2H)

[0161] Mono-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol is also referred to as saturated C22 erythritol ester.

[0162] (12) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)pentaerythritol

[0163] [ka]

[0164] Under a vacuum of 60-70 mmHg and a nitrogen stream, 250 g (0.71 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 157 g (1.15 mol) of pentaerythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL) at 78-83°C. After stirring at the same temperature for 10 hours, formic acid was added at 75°C to adjust the pH to 4. The resulting solution was concentrated under reduced pressure and then diluted with t-butyl methyl ether (1.5 L). The resulting insoluble material was filtered off. The filtrate was washed twice with 10% aqueous sodium bicarbonate and then treated with activated carbon (8 g) for decolorization. The residue obtained after filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate mixture) to give the title compound.

[0165] The obtained compound 1 H-NMR measurement, infrared absorption (IR) spectrum measurement by infrared spectroscopy, and viscosity measurement were carried out. The results are as follows:

[0166] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.95(m,12H),1.00-1.70(m,22H),1 .90-2.05(m,2H),2.25-2.45(m,4H),3.64(s,6H),4.24(s,2H),5.07(brs,1H) IR spectrum (NaCl thin film method): 3387, 2926, 2866, 1739, 1461, 1378, 1267, 1139, 1051 Viscosity: 1.7Pa·s

[0167] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)pentaerythritol is also referred to as C22 pentaerythritol ester.

[0168] (13) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol

[0169] [ka]

[0170] 3.81 g of pentaerythritol, 2.21 g of pyridine, and 120 mL of dry DMF were mixed and heated to dissolve. After cooling to room temperature, a solution of 5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride (obtained in the synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol (11) dissolved in 5 mL of methylene chloride was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 1 hour. 100 mL of methylene chloride was added to the resulting reaction solution, which was washed three times with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica gel column chromatography to obtain 2.50 g of mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol with the following physical properties. The purity of this product was 99.5% or higher by HPLC analysis. The NMR analysis results were as follows:

[0171] 1 H-NMR spectrum (270MHz, CDCl3, TMS) δ:0.8-0.9(m,15H),1.0-1.7(m,26H),2.34(t,J=7.4Hz,2H),3.06(brs,3H),3.63(s,6H),4.17(s,2H)

[0172] Mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol is also referred to as saturated C22 pentaerythritol ester.

[0173] (14) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)diglycerol

[0174] [ka]

[0175] Under a vacuum of 60-70 mmHg and a nitrogen stream, 199 g (0.564 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 259 g (1.56 mol) of diglycerol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL) at 78-83 °C. After stirring at the same temperature for 10 h, formic acid was added at 75 °C to adjust the pH to 4. The resulting solution was concentrated under reduced pressure and then diluted with t-butyl methyl ether (1.5 L). The resulting insoluble material was filtered off. The filtrate was washed twice with 10% aqueous sodium bicarbonate and then treated with activated carbon (8 g) for decolorization. The residue obtained after filtration and concentration was dissolved in ethanol and filtered through cellulose powder. The residue obtained after concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate mixture) to obtain the title compound as a clear viscous liquid. The obtained compound 1 The results of H-NMR measurement are as follows:

[0176] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.90(m,12H),1.00-1.70(m,22H),1.97(ddd,J=6.9,7.8 ,17.4Hz,2H),2.20-2.45(m,4H),3.50-4.10(m,8H),4.10-4.25(m,2H),5.08(dd,J=6.6,6.6Hz,1H)

[0177] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)diglycerol is also referred to as C22 diglycerol ester.

[0178] (15) Synthesis of mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)glycerol

[0179] [ka]

[0180] To a solution of 0.57 g (6.2 mmol) of glycerol and 0.85 g (6.2 mmol) of potassium carbonate in dry N,N-dimethylformamide (3 mL) was slowly added dropwise 1.0 g (3.1 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate at 80°C. After stirring at 100°C for 12 hours, 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 (mobile phase: ethyl acetate / hexane mixture) to give 459 mg (yield 35%) of the title compound as a colorless viscous substance. Regarding the resulting compound, 1 The results of H-NMR measurement are as follows:

[0181] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.80-0.95 (m, 12H), 1.00-1.80 (m, 19H), 1.90-2.20 (m, 5H), 3.50-4.00 (m, 3H), 4.10-4.30 (m, 2H), 5.71 (brs, 1H)

[0182] Mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)glycerol is also called C20 glycerin ester or glyceryl phytenate.

[0183] (16) Synthesis of mono-O-(3,7,11,15-tetramethylhexadecanoyl)glycerol

[0184] [ka]

[0185] Under a nitrogen atmosphere, 0.26 g of 5% palladium carbon was added to a solution of 2.52 g (6.10 mmol) of C20 glycerin ester in ethyl acetate (15 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature for 1 day under a hydrogen atmosphere at normal pressure. After replacing the hydrogen in the system with nitrogen, the 5% palladium carbon was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 2.50 g (yield 99%) of the title compound as a colorless, transparent liquid. Regarding the obtained compound, 1 The results of H-NMR measurement are as follows:

[0186] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.8-0.9(m,12H),0.9-1.0(m,3H),1.0-2.0(m,22H),2.1-2.4(m,2H),3.4-4.0(m,3H),4.05-4.25(m,2H)

[0187] Mono-O-(3,7,11,15-tetramethylhexadecanoyl)glycerol is also known as saturated C20 glycerol ester, or glyceryl phytanate.

[0188] [Example 2] Preparation of precursor formulation, gel formation test, and analysis of liquid crystal structure (1) According to the formulation ratios shown in Table 1 below, a self-assembling lipid (hereinafter also referred to as SOL; abbreviated as SOL in the table) was synthesized in Example 1 as an amphiphilic compound having an isoprenoid fatty chain with 22 carbon atoms (isoprenoid lipid), a phospholipid (SPC) soybean phosphatidylcholine (LIPOID S100, Lipoid Corporation; abbreviated as SPC in the table and below), oil, and alcohol were mixed. The self-assembling lipid (SOL) is a lipid that can form a gel when mixed with water alone. In the table, "EtOH" stands for ethanol, and "PG" stands for propylene glycol (the same applies to Tables 1 to 5 and 8 to 12). Some formulations further contained the surfactant P80 (polyoxyethylene sorbitan monooleate (20E.O.), NIKKOL TO-10MV, Nikko Chemicals Co., Ltd.) and the water-soluble polymer HPC (hydroxypropyl cellulose, HPC-SSL, Nippon Soda Co., Ltd.). The resulting mixture was dissolved in a water bath at 40°C or less to prepare precursor formulations Nos. 1 to 61 shown in Table 1.

[0189] Furthermore, precursor formulations Nos. 62 to 64 were prepared in the same manner as above, using EPC (phosphatidylcholine, egg yolk-derived, 163-21181, Fujifilm Wako Pure Chemical Industries, Ltd.), DMPC (dimyristoyl phosphatidylcholine, COATSOME MC-4040, NOF Corporation), or DPPC (dipalmitoyl phosphatidylcholine, COATSOME MC-6060, NOF Corporation) instead of SPC as the phospholipid, according to the formulation ratios shown in Table 2.

[0190] Furthermore, instead of the amphiphilic compound having an isoprenoid fatty chain with a carbon number of 22, the amphiphilic compound having an isoprenoid fatty chain with a carbon number of 17 synthesized in Example 1, or glyceryl monooleate having linear oleic acid as the fatty chain (Rikemal XO-100, NOF Corporation) was used, or no amphiphilic compound having an isoprenoid fatty chain was used, according to the blending ratios shown in Table 3, in the same manner as above to prepare precursor formulations No. 65 to 75.

[0191] A gel formation test was conducted on the precursor formulations Nos. 1 to 75 obtained in this manner. A portion of each precursor formulation (approximately 100 to 300 mg) was added to excess aqueous medium in a vial (water for injection for Nos. 1 to 61 and 64 to 75, and approximately 0.5 to 2 mL of phosphate-buffered saline (PBS) at pH 7.4 for Nos. 62 and 63), and the mixture was mixed at room temperature (25°C) using a spoon and / or a vortex mixer. As a result, for all precursor formulations Nos. 1 to 75, a gel composition that separated into the excess aqueous medium and was colorless, transparent, or opaque in appearance was obtained.

[0192] The gel compositions obtained from precursor preparations No. 1 to 70 were embedded directly into a pinhole slit, and the non-lamellar liquid crystal structure was analyzed by small-angle X-ray scattering diffraction measurement using a small-angle X-ray scattering (SAXS) device (Rigaku Corporation, Nano-Viewer).

[0193] The obtained liquid crystal phases and the scattering vector value q1 [nm-1] of the peak located on the smallest angle side are shown in Tables 1 to 3. Note that HII means inverted hexagonal liquid crystal, Pn3m means inverted cubic liquid crystal belonging to the crystallographic space group Pn3m, Im3m means inverted cubic liquid crystal belonging to the crystallographic space group Im3m, and Fd3m means inverted cubic liquid crystal belonging to the crystallographic space group Fd3m. Some gel compositions had two magnitudes (scattering vector value q1) of the same liquid crystal phase, and some had two different types of liquid crystal phases.

[0194] As shown in Tables 1 and 2, when an amphiphilic compound having a 22-carbon isoprenoid fatty chain, i.e., SOL synthesized in Example 1, was used, SOL-containing precursor formulations were able to form nonlamellar liquid crystals over a wide range of SOL:phospholipid ratios (weight ratio) from 100:0 to at least 30:70, regardless of the type of amphiphilic compound, phospholipid, and oil. Furthermore, SOL-containing precursor formulations were able to form nonlamellar liquid crystals over a wide range of SOL + phospholipid (total amount of SOL and phospholipid):oil ratios (weight ratio) from 100:0 to at least 20:80. Furthermore, SOL-containing precursor formulations successfully formed liquid crystalline gels even when certain amounts of P80 or HPC were added as additives. Various liquid crystal structures, such as reversed cubic and reversed hexagonal liquid crystals belonging to the crystallographic space groups Pn3m, Im3m, and Fd3m, were obtained by varying the combination of amphiphilic compound, phospholipid, and oil. The q1 value, which is determined by the lattice constant, varied over a wide range of values.

[0195] When SPC was used as the phospholipid and sesame oil (triglyceride) as the oil, no liquid crystalline gel was formed at a phospholipid:oil ratio of 85:15 or 75:25 (weight ratio) without SOL (not shown in the table). Therefore, when sesame oil (triglyceride) is used at these ratios, the addition of SOL or an amphiphilic compound with an isoprenoid fatty chain (isoprenoid lipid) appears to be necessary to form a liquid crystalline gel by blending phospholipids.

[0196] [Table 1] TIFF2026001219000032.tif226156TIFF2026001219000033.tif22670

[0197] [Table 2]

[0198] [Table 3]

[0199] [Example 3] Preparation of emulsion (dispersant) and analysis of liquid crystal structure (1) According to the blending ratios shown in Table 4 below, an amphiphilic compound having an isoprenoid-type fatty chain with 22 carbon atoms synthesized in Example 1, which is a self-assembling lipid (abbreviated as SOL in the table), soybean phosphatidylcholine (LIPOID S100, Lipoid Corporation; abbreviated as SPC in the table) as a phospholipid, oil, and alcohol were mixed to obtain an oily solution. Meanwhile, Pluronic F127 (Unilube) was used as a surfactant. (R) Pluronic aqueous solution was prepared by mixing the oily solution (70DP-950B, NOF Corporation) with water for injection (Otsuka Distilled Water). In some formulations, the surfactant P80 was added to the oily solution, or the antioxidants ascorbic acid and sodium sulfite were added to the Pluronic aqueous solution. The oily solution and Pluronic aqueous solution thus prepared were completely dissolved in a water bath below 30°C, then mixed together at room temperature and stirred with a spoon or stirrer tip to form a suspension. This suspension was then dispersed using a high-pressure homogenizer (Starbust Minimo, Sugino Machine) to prepare white emulsions containing fine particles (Formulations No. 76-105). These emulsions were prepared in amounts of 7-30 g each.

[0200] Furthermore, instead of the amphiphilic compound having an isoprenoid fatty chain with a carbon number of 22, the amphiphilic compound having an isoprenoid fatty chain with a carbon number of 17 or 20 synthesized in Example 1, sorbitan monooleate having linear oleic acid as the fatty chain (NIKKOL SO-10V, Nikko Chemicals Co., Ltd.), or purified sorbitan monooleate (NIKKOL SO-10V from which low-polarity components such as oleic acid and sorbitan dioleate have been removed by silica gel column purification), or without using SOL, emulsions of Formulations No. 106 to 116 were prepared in the same manner as above, according to the blending ratios shown in Table 5.

[0201] The emulsions of formulations No. 76–116 obtained in this manner were subjected to small-angle X-ray scattering (SAXS) structural analysis using a NANO Viewer nanoscale X-ray structural analysis system (Rigaku). Each emulsion was introduced into a capillary tube at atmospheric pressure and measured in a vacuum chamber (the sample itself was at atmospheric pressure). The scattering intensity distributions obtained for formulations No. 76, 77, 81–86, 88, 89, 92–103, 105–109, and 115 showed at least two scattering peaks. The peak ratio was 1:√3:2, which is characteristic of reversed hexagonal liquid crystals, indicating that these emulsions were liquid crystal emulsions (hexasomes) in which reversed hexagonal liquid crystal particles were dispersed in an aqueous phase. The scattering intensity distributions obtained from emulsions Nos. 77, 83-86, 88, 89, 92, 103, and 105 showed a broad scattering peak along with a scattering peak characteristic of reversed hexagonal liquid crystals, and these emulsions were considered to be liquid crystal emulsions containing a sponge phase (L3 phase).The scattering intensity distributions obtained from emulsions Nos. 79, 87, 90, 91, 104, and 110-114 showed a broad scattering peak, and these emulsions were considered to be liquid crystal emulsions in which sponge phase (L3 phase) particles were dispersed in an aqueous phase. The scattering intensity distribution obtained from the emulsion of formulation No. 78 showed at least three scattering peaks, with a peak ratio of √2:√4:√6, characteristic of cubic liquid crystals belonging to the Im3m crystallographic space group. This indicates that the emulsion is a liquid crystal emulsion in which cubic liquid crystal particles belonging to the Im3m crystallographic space group are dispersed in an aqueous phase. Furthermore, the scattering intensity distribution obtained from the emulsions of formulations No. 80 and No. 116 showed at least six scattering peaks, with a peak ratio of √3:√8:√11:√12:√16:√19, characteristic of cubic liquid crystals belonging to the Fd3m crystallographic space group. This indicates that the emulsion is a liquid crystal emulsion in which cubic liquid crystal particles belonging to the Fd3m crystallographic space group are dispersed in an aqueous phase.

[0202] When using the amphiphilic compound having an isoprenoid-type fatty chain with 22 carbon atoms synthesized in Example 1 as SOL, liquid crystal emulsions having non-lamellar liquid crystals could be prepared over a wide range of SOL:phospholipid ratios and SOL+phospholipid:oil ratios shown in Table 4, similar to the liquid crystal gels and fluids obtained from the precursor formulations shown in Example 2. Furthermore, liquid crystal emulsions could be prepared satisfactorily even when a certain amount of P80 or an antioxidant was added as an additive.

[0203] [Table 4]

[0204] [Table 5]

[0205] [Example 4] Safety evaluation in the body (1) The precursor formulations of formulations Nos. 1 to 6, 8 to 10, 12 to 16, 19, 21 to 24, 27, 31, 34, 38, 50, 52 to 54, 57, 59, 61, 65 to 67, 69, and 71 prepared in Example 2, and the emulsions of formulations Nos. 76 to 85, 88, 89, 91 to 93, 102, 103, 106, 108, and 109 prepared in Example 3 were intraperitoneally administered to evaluate their safety in the body as follows. Eight to ten week old female Wistar rats were used for the evaluation.

[0206] Furthermore, since the precursor formulation forms non-lamellar liquid crystals and becomes a bulk gel after administration, if a foreign body reaction is induced, phenomena related to the foreign body reaction (such as abscesses, which are white pus) can be observed at a level that is directly visible. The abscesses that occur in the present invention are cystic tissues containing leukocytes and other particles due to a non-infectious, aseptic foreign body reaction. On the other hand, since the emulsion is in a solution state containing non-lamellar liquid crystal particles, it can spread throughout the peritoneal cavity. Therefore, if tissue damage is induced, tissue damage throughout the peritoneal cavity can be observed. Furthermore, because the emulsion is in the form of particles, absorption and transfer into the bloodstream through the peritoneum, etc., is faster than in a bulk gel state, making it easier to clearly observe systemic toxicity (mainly hepatotoxicity).

[0207] (1) Safety evaluation of precursor formulations First, the rats were anesthetized with pentobarbital and placed in the supine position. An approximately 30 mm abdominal midline incision was made. An approximately 20 mm incision was made in the parietal peritoneum of the upper abdominal cavity, and complete hemostasis was achieved. The peritoneal incision was closed with six continuous sutures using 5-0 silk suture. Approximately 23 mg of the precursor formulation (using a pipetter set to 30 μL) was dripped and spread along the sutured incision. After spraying the sample application site with water for injection (Otsuka distilled water) using a simple manual spray bottle (Spray Vial No. 2, Maruemu Co., Ltd.) (5 pumps, approximately 180 mg), the abdominal wall was immediately sutured closed in two layers to complete the surgery.

[0208] Seven days after surgery, general anesthesia was administered again and laparotomy was performed. The safety of the applied precursor formulation was evaluated by observing the intraperitoneal findings.

[0209] Regardless of the carbon number or whether the fatty acid chain was isoprenoid or linear, the precursor formulations Nos. 1, 2, 9, 13, 14, 22, 52, 53, 65, 66, and 71, which contained no or only low amounts of phospholipids, exhibited abscesses surrounding the gel. These abscesses were due to leukocyte infiltration unrelated to infection and were white pus resulting from a foreign body reaction to the administered precursor formulation. Examples of abscesses are shown in Figure 1 (Figures 1A-C: with the precursor formulation of No. 1; Figure 1D: with the precursor formulation of No. 71). The arrows in Figures 1A-D indicate the abscesses.

[0210] On the other hand, in the precursor preparations Nos. 3 to 6, 8, 10, 12, 15, 16, 19, 21, 23, 24, 27, 31, 34, 38, 50, 54, 57, 59, 61, 67, and 69, which contain a certain amount or more of phospholipids, no intraperitoneal findings related to side effects, including abscesses, were observed.

[0211] In the precursor preparation No. 65, which contained C17 glycerol ester but no phospholipid, not only the abscesses described above but also slight enlargement of the liver and adhesion between the liver and the omentum were observed.

[0212] From the above results, it was revealed that the precursor formulation prepared in Example 2, regardless of the presence or absence of oil, surfactant, and water-soluble polymer, did not cause foreign body reactions or side effects associated therewith as long as it contained a certain amount or more of phospholipid. In particular, when C22 sorbitan ester or saturated C22 sorbitan ester was used, no side effects, including foreign body reactions, occurred in formulations containing phospholipids at a SOL:phospholipid ratio of at least 30%.

[0213] Thus, it was confirmed that the safety of the precursor formulation was improved by adding a phospholipid to the amphiphilic compound having an isoprenoid fatty chain with 17 or 22 carbon atoms synthesized in Example 1. Furthermore, it was thought that formulations using an amphiphilic compound having an isoprenoid fatty chain with 22 carbon atoms were less likely to cause side effects even at higher doses.

[0214] (2) Safety assessment of emulsions First, the rats were given general anesthesia using pentobarbital and placed in the supine position. A certain amount of the emulsion prepared in Example 3 was administered intraperitoneally using a syringe equipped with a 26G needle (1 mL Terumo syringe). In addition, in the case of emulsions that were too viscous to pass through a 26G needle, a certain amount of emulsion was administered intraperitoneally using a syringe without a needle (1 mL Terumo syringe) through an approximately 1 cm midline abdominal incision. After administration, the abdominal wall was sutured closed in two layers to complete the surgery.

[0215] Seven days after surgery, general anesthesia was administered again and laparotomy was performed. The safety of the applied emulsion was evaluated by observing the findings in the abdominal cavity.

[0216] As a result, findings related to side effects were observed in emulsions of formulations No. 76, 78, 80, and 81, which contained an amphiphilic compound having a 22-carbon isoprenoid fatty acid chain and contained no or a low amount of phospholipid. For example, in emulsion of formulation No. 76, which contained a C22 glycerin ester and no phospholipid, slight ascites was observed in one of three cases at a dose of 360 μL, and one of three cases at a dose of 720 μL died after three days, and the remaining two cases showed slight liver enlargement. Furthermore, emulsions of formulations No. 78, 80, and 81, which contained a C22 pentaerythritol ester or a C22 sorbitan ester as an amphiphilic lipid having a 22-carbon isoprenoid fatty acid chain and contained no or a low amount of phospholipid, also showed slight liver enlargement and / or adhesions around the liver, similar to those observed in emulsion No. 76, which used a C22 glycerin ester.

[0217] Emulsions containing C20 glycerin esters or saturated C20 glycerin esters with a 20-carbon isoprenoid fatty chain and no phospholipids, formulations No. 108 and No. 109, also showed adverse drug reactions. For example, in the emulsion containing C20 glycerin esters and no phospholipids, three of three patients died one day after administration of formulation No. 108, which contained a C20 glycerin ester but no phospholipids. In the emulsion containing saturated C20 glycerin esters and no phospholipids, formulation No. 109, which contained a 220 μL dose, one of three patients died three days after administration, and the remaining two patients showed multiple adverse drug reactions, including ascites, liver enlargement, adhesions around the liver, and whitening of the liver surface. These results demonstrate that the safety of emulsions containing C20 glycerin esters or saturated C20 glycerin esters is clearly low, even when phospholipids are added. On the other hand, in the emulsions of formulations Nos. 77, 79, 82-85, 88, 89, 91-93, 102, and 103, which contain an amphiphilic compound with a 22-carbon isoprenoid fatty acid chain and a certain amount of phospholipid, no side effects were observed throughout the abdominal cavity, even at a dose of at least 720 μL. For example, the SOL:phospholipid ratio in the emulsions of formulations Nos. 82 and 102 was 70:30. The total weight of lipids (SOL and phospholipids) and oil contained in 720 μL of emulsion was 0.18 g for formulations No. 77, 82-85, 93, and 103, 0.15 g for formulations No. 88, 89, 91, and 92, and 0.14 g for formulations No. 79 and 102, which corresponds to a human dose of 60 g, 50 g, and 48 g, respectively (assuming a rat weight of 150 g and a human weight of 50 kg).

[0218] In emulsion formulation No. 106, which contained a C17 glycerin ester with a 17-carbon isoprenoid fatty acid chain and no phospholipid, side effects began to be observed at a dose of 72 μL. At a dose of 220 μL, liver enlargement and adhesions around the liver were observed in three of three cases, with one case showing slight ascites. At a dose of 720 μL, three of three cases died one day later. It was revealed that emulsions using C17 glycerin esters, when not containing phospholipids, had stronger side effects on the liver than emulsions using amphiphilic compounds with a 22-carbon isoprenoid fatty acid chain.

[0219] From the above results, it was revealed that the safety of the emulsion prepared in Example 3 was enhanced by including a certain amount of phospholipid, regardless of the presence or absence of oil, surfactant, and antioxidant. This tendency was particularly pronounced in the emulsion using an amphiphilic compound having an isoprenoid fatty chain with 22 carbon atoms, which was extremely safe even at high doses. Emulsions using amphiphilic lipids having an isoprenoid fatty chain with 20 carbon atoms were not superior in terms of safety when administered internally compared to emulsions using amphiphilic compounds having an isoprenoid fatty chain with 17 or 22 carbon atoms.

[0220] Furthermore, formulations that did not contain phospholipids but contained additives selected from the group consisting of oils, surfactants, antioxidants, and water-soluble polymers (HPCs) exemplified in this example did not show improved safety compared to formulations that did not contain these additives.

[0221] When glyceryl monooleate is used as the SOL, a surfactant known as Cytrem (e.g., manufactured by Danisco A / S, Grindsted, Denmark) is used. (R)It has been reported (e.g., Non-Patent Document 2) that the addition of Citrem LR10, BC-FS SG, and other commercially available compounds improves safety. However, when the above-mentioned safety evaluation was performed on emulsions in which the C17 glycerin ester of Formulation No. 106 containing C17 glycerin ester was replaced with a mixture of C17 glycerin ester:Citrem at a ratio of 80:20, 60:40, or 40:60, side-effect-related findings comparable to those observed with the emulsion of Formulation No. 106 were observed. Furthermore, when safety was evaluated using a precursor formulation with a C17 glycerin ester:Citrem ratio of 60:40, side-effect-related findings similar to those observed with the precursor formulation No. 65, which does not contain phospholipids, were observed. Therefore, it was demonstrated that the addition of Citrem does not improve the safety of formulations using amphipathic lipids with isoprenoid-type fatty chains according to the present invention.

[0222] From the above results, it was revealed that preparations containing amphipathic compounds with isoprenoid fatty chains that contain a certain amount or more of phospholipids are highly safe, regardless of the dosage form (e.g., precursor preparations, emulsions). In particular, preparations containing amphipathic compounds with isoprenoid fatty chains with a carbon number of 22 have a high risk of side effects if they do not contain phospholipids, but by containing a certain amount or more of phospholipids, they become extremely safe and can be used safely in the body even at high doses.

[0223] [Example 5] Evaluation of emulsion particle size and stability (1) The particle size distribution of the phospholipid-containing emulsions Nos. 77, 79, 81-105, 107, and 110-116 prepared in Example 3 was measured by dynamic light scattering using a Zetasizer Nano-ZS (Malvern Instruments). Measurement samples were prepared by diluting each emulsion 200-fold with distilled water immediately after preparation (within 2 days at room temperature) or after a certain period of time had passed at room temperature. Table 6 shows the average particle size (nm) (Z-Average) obtained from each measurement sample, the time elapsed since preparation for emulsions that had passed at room temperature, and the change in average particle size (nm) (average particle size of emulsion after a certain period of time had passed minus the average particle size of emulsion immediately after preparation).

[0224] Regarding the stability over time at room temperature, the emulsions of Preparations Nos. 83, 84, 86 to 88, 92, 94, 95, and 98 to 100, which used the amphiphilic compound having an isoprenoid fatty chain with 22 carbon atoms synthesized in Example 1, showed almost no change in average particle size over a long period of time. In addition, their appearances also showed almost no change.

[0225] In contrast, the average particle size of emulsions Nos. 110 to 114, which used sorbitan monooleate (NIKKOL SO-10V) or purified sorbitan monooleate, which have linear oleic acid as the fatty chain, increased significantly. Furthermore, the appearance of these emulsions became more white, and some samples clearly showed the formation of aggregates. Thus, formulations containing sorbitan monooleate were unstable regardless of the purity of sorbitan monooleate.

[0226] Therefore, it was revealed that emulsions containing an amphiphilic compound with a 22-carbon isoprenoid-type fatty chain and a phospholipid have significantly superior stability over time than emulsions using an amphiphilic compound with a linear oleic acid fatty chain and a phospholipid.

[0227] [Table 6]

[0228] [Example 6] Confirmation of spray performance Pump sprays were prepared by filling 1 to 5 mL of each emulsion of formulations Nos. 77, 79, 81 to 84, 87 to 90, 92 to 99, and 101 to 105, which contain an amphiphilic compound with an isoprenoid-type fatty chain having 22 carbon atoms and a phospholipid, prepared in Example 3, into a simple manual spray bottle (Spray Vial No. 2, manufactured by Maruemu).

[0229] The emulsions of all the above preparations could be sprayed in mist or bar form, and when sprayed once from a distance of about 2 cm to the test surface, the area where the emulsion adhered formed an approximately circular shape in all cases.

[0230] [Example 7] Evaluation of effectiveness regarding adhesion prevention effect The anti-adhesion effects of precursor preparations No. 31 and 72-75, and emulsions No. 83-97, 99-101, 104, 105, 115, and 116 were evaluated using 10-week-old female Wistar rats.

[0231] First, rats were anesthetized with pentobarbital and placed in the supine position. A 30 mm midline abdominal incision was made. Approximately 20 mm incisions were made in the left and right parietal peritoneum of the upper abdomen, and complete hemostasis was achieved. The left and right peritoneal incisions were closed with six continuous sutures using 5-0 silk sutures.

[0232] Next, approximately 23 mg of the precursor formulation (using a pipettor set to 30 μL) or approximately 72 mg of the emulsion was dripped and spread over the incision and suture on the right side of the peritoneum to cover the suture (sample application side). In the case of the precursor formulation, to induce liquid crystal formation, water for injection (Otsuka distilled water) was sprayed (5 pumps, approximately 180 mg) onto the sample application site using a simple manual spray bottle (Spray Vial No. 2, Maruemu). Nothing was applied to the incision and suture on the left side of the peritoneum (non-application side / control). After applying the sample to the incision and suture on the right side of the peritoneum, the abdominal wall was immediately sutured closed in two layers (abdominal closure) to complete the surgery.

[0233] Seven days after surgery, general anesthesia was administered again and the abdomen was opened. Adhesion at the incision suture site on the sample application side and non-application side was evaluated according to the adhesion strength scoring and adhesion extent percentage definitions below. In this evaluation, no findings related to side effects were observed for any of the above preparations.

[0234] Adhesion strength: Grade 0: No adhesion Grade 1: Adhesion that can be separated with light traction (no tissue damage) Grade 2: Adhesion that can be separated with strong traction (without tissue damage) Grade 3: Adhesion with tissue damage due to strong traction separation Adhesion coverage rate: The percentage of adhesion length relative to the approximately 20mm incision suture area (%) judgement: The percentage of adhesion area in the sample-applied incision compared to the non-applied incision (adhesion area rate on the sample-applied side / adhesion area rate on the non-applied side x 100) is 40% or less: A, 41-60%: B+, 61-80%: B-, and 81% or more: C

[0235] The evaluation results of the adhesion prevention effect are shown in Table 7.

[0236] The precursor formulation No. 31 and emulsions Nos. 83-97, 99-101, 104, and 105, which contained both sorbitan ester and phospholipid as SOL, all showed a high adhesion prevention (reduction) effect on the sample-applied side compared to the non-applied side. On the other hand, the precursor formulations Nos. 72-75 and emulsions Nos. 115 and 116, which did not contain SOL, showed a low adhesion prevention (reduction) effect.

[0237] Therefore, it was revealed that the precursor formulation and emulsion containing both SOL and phospholipids have no visible side effects in the abdominal cavity and have the effect of preventing (reducing) adhesions.

[0238] [Table 7]

[0239] Furthermore, we evaluated the anti-adhesion effect of the non-lamellar liquid crystal formulation containing SOL and phospholipids in New Zealand White rabbits (female, 13 weeks old at the time of surgery) instead of Wistar rats. Under anesthesia, the rabbits' abdomens were incised, and an approximately 4 × 5 cm area of ​​the peritoneum and right internal oblique muscle on the right abdominal wall was resected (side-wall resection site). The 6th segment of the cecal distension was abraded with gauze and dried under an incandescent lamp for approximately 60 minutes (cecal abrasion site) to create a cecal-peritoneal adhesion model. In the test group, 800 μL of the non-lamellar liquid crystal formulation was applied to the side-wall resection site and the abraded cecum, and the abdomen was then closed. In the control group, 5 mL of saline was applied to the side-wall resection site and the abraded cecum, and the abdomen was then closed. During the experimental period, each rabbit's general condition was observed once daily (before and after surgery on the day of surgery), and their body weight was measured on the days of surgery and dissection. Seven days after surgery, the rabbits were euthanized, and the abdominal cavity and intraperitoneal organs were examined macroscopically. Adhesion at the application site was also evaluated. Similar to the rat study, the anti-adhesion effects were observed. For example, formulation No. 88 demonstrated a higher anti-adhesion effect than the control saline group. Regardless of the formulation administered, no obvious abnormalities were observed in the weight changes of individual animals, and no systemic toxicity was observed. Furthermore, no abnormal findings (inflammation, hypertrophy, organ adhesions, etc.) were observed at the application site or in the intraperitoneal organs (liver, spleen, etc.), and no accumulation of ascites or pleural effusion was observed.

[0240] [Example 8] In vitro release test of leuprolide acetate (1) As in Example 2, the C17 glycerin ester having an isoprenoid fatty chain with 17 carbon atoms synthesized in Example 1, which is a self-assembling lipid (abbreviated as SOL in the table), surfactant P80 (polyoxyethylene sorbitan monooleate (20 E.O.)), and ethanol were mixed in the formulation shown in Table 8 below, and the mixture was stirred at 60°C for 5 minutes. To the resulting solution, DMPC (dimyristoylphosphatidylcholine, COATSOME MC-4040, NOF Corporation), DOPC (dioleylphosphatidylcholine, COATSOME MC-8181, NOF Corporation), DOPE (dioleylphosphatidylethanolamine, COATSOME ME-8181, NOF Corporation), or DOPG-Na (dioleylphosphatidylglycerin sodium, COATSOME MG-8181LS, NOF Corporation) was added as a phospholipid, and the mixture was stirred at 60°C for 1 hour to prepare precursor formulations Nos. 117 to 120.

[0241] When precursor preparations No. 117 to No. 120 were added to a large excess of PBS at pH 7.4, gel compositions were obtained. Small-angle X-ray scattering diffraction measurements were performed on each gel composition in the same manner as in Example 2, confirming that all gel compositions had a non-lamellar liquid crystal structure. The resulting liquid crystal phases and the scattering vector values ​​q1 [nm-1] of the peaks located at the smallest angles are shown in Table 8.

[0242] [Table 8]

[0243] Next, precursor preparations Nos. 121 to 124 containing leuprolide acetate (prepared from Nos. 117 to 120, respectively) were prepared as follows. First, a dialysis tube (Pur-A-Lyzer TM3.75 mg of leuprolide acetate (L0249, Tokyo Chemical Industry Co., Ltd.) was added to a dialysis tube (MINI 12000, Sigma-Aldrich) and dissolved in 5 mg of dimethyl sulfoxide. 91.25 mg of precursor formulations No. 117-120 were then added. Each resulting mixture was stirred for 2 minutes with a pellet pestle to obtain 100 mg of precursor formulations No. 121-124 containing leuprolide acetate. For comparison, 3.75 mg of leuprolide acetate was added to a dialysis tube and dissolved in 96.25 mg of PBS (pH 7.4) to obtain 100 mg of aqueous solution No. 125 containing leuprolide acetate.

[0244] In vitro release tests were conducted on precursor formulations Nos. 121-124 (100 mg) containing leuprolide acetate and aqueous solution No. 125 (100 mg). A dialysis tube with a floating rack attached to the top was placed in a 25 mL vial containing 20 mL of PBS solution (pH 7.4) containing 0.02% P80, ensuring that the precursor formulation was fully submerged in the PBS solution. The vial was then left to stand at room temperature (25 °C). Subsequently, 500 μL of the PBS solution in the vial was sampled at 0, 1, 3, 6, 12, 24, 48, 72, 120, and 168 hours after the start of the test over a 7-day period. It was visually observed that all of the precursor formulations Nos. 121-124 added to the PBS solution formed gel-like compositions.

[0245] The quantification of leuprolide acetate in the sample collected from the PBS solution was carried out by LC / MS / MS analysis using a previously prepared calibration curve under the following analytical conditions:

[0246] Analytical column: Shodex ODP2HP-2B 2.0mm I.D. x 50mm (Showa Denko K.K.) Mobile phase: water (containing 0.1% formic acid):acetonitrile = 70:30 Flow rate: 0.1 mL, column temperature: 40°C, injection volume: 10 μL Precursor ion: 605.3 m / z, Product ion: 249.0 m / z

[0247] Figure 2 shows in vitro release data from precursor formulations Nos. 121-124 and aqueous solution No. 125 containing leuprolide acetate. In Figure 2, the horizontal axis represents time (days), and the vertical axis represents the release rate (%) of leuprolide acetate into PBS solution at each time point relative to the amount of leuprolide acetate contained in the precursor formulation at the start of the test (mean value of n = 3-6). In aqueous solution No. 125, all leuprolide acetate was rapidly released within 1 or 2 days, whereas in precursor formulations Nos. 121-124, there was no initial burst release, demonstrating sustained release of leuprolide acetate. Among these, precursor formulation No. 122 exhibited a slightly faster release rate, while precursor formulation No. 124 exhibited a slightly slower release rate. This indicates that the release rate of leuprolide acetate can be controlled by changing the type of phospholipid. These results demonstrate that the formulations of the present invention, including precursor formulations Nos. 121-124, are useful as depot preparations.

[0248] [Example 9] Subcutaneous implantation test (1) Seven to eight-week-old male Wistar rats were given general anesthesia using a triple-analgesic mixture (medetomidine hydrochloride + midazolam + butorphanol tartrate), and after shaving their backs, 100 μL each of precursor formulations No. 117 and 118 (containing C17 glycerol ester and DMPC or DOPC as a phospholipid), prepared in the same manner as in Example 8, was administered subcutaneously to the back using a syringe equipped with a 23G needle (Terumo syringe 1 mL).

[0249] Two days after administration, the animals were again given general anesthesia, and the skin containing the subcutaneous injection site was removed. After simple removal of subcutaneous fat, the injection site was macroscopically observed.

[0250] Figure 3 shows photographs of the observed formulation administration sites (Figure 3A: precursor formulation No. 117, Figure 3B: precursor formulation No. 118). In both cases, the administered formulation was present as a gel composition at the administration site without discoloration. Furthermore, in rats administered either formulation, no findings attributable to formulation-related inflammation were observed in the tissues surrounding the administration site, and no abnormal findings such as bleeding, encapsulation, or discoloration were observed.

[0251] [Example 10] Synthesis of amphiphilic compound (2) (1) Synthesis of mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol

[0252] [ka]

[0253] Under a reduced pressure of 60-70 mmHg and a nitrogen stream, 28.2 g (100 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate was slowly added dropwise to a solution of 24.3 g (317 mmol) of propylene glycol and 0.30 g (2.2 mmol) of potassium carbonate in dry N,N-dimethylformamide (70 mL) at 85°C, followed by stirring at the same temperature for 5 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 160 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to obtain 26.1 g (80% yield) of the title compound as a pale yellow, transparent liquid. The resulting compound was characterized by the following characteristics: 1 The results of H-NMR measurement are as follows:

[0254] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.75-0.90(m,9H),0.95-1.70(m,18H),1.97(td,J=7.6,18Hz,2H),2.07(b rs,OH),2.25-2.42(m,4H),3.55-3.70(m,0.7H),3.85-4.15(m,1.95H),4.98(m,0.35H),5.08(t,J=6.2Hz,1H)

[0255] Mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol is also referred to as C17 propylene glycol ester.

[0256] (2) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol

[0257] [ka]

[0258] Under a vacuum of 60-70 mmHg and a nitrogen stream, 30.0 g (85.0 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 20.6 g (271 mmol) of propylene glycol and 0.211 g (1.53 mmol) of potassium carbonate in dry N,N-dimethylformamide (60 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 120 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to obtain 21.6 g (63% yield) of the title compound as a pale yellow, transparent liquid. The resulting compound was characterized by the following: 1 The results of H-NMR measurement are as follows:

[0259] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.95(m,12H),0.95-1.70(m,25H),1.96(td,J=7.5,18Hz,2H),2.1(b rs,OH),2.25-2.42(m,4H),3.55-3.70(m,0.7H),3.85-4.15(m,1.95H),4.98(m,0.35H),5.08(t,J=6.8Hz,1H)

[0260] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol is also referred to as C22 propylene glycol ester.

[0261] (3) Synthesis of mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol

[0262] [ka]

[0263] Under a nitrogen atmosphere, 0.48 g of 5% palladium carbon was added to a solution of 3.96 g (10.0 mmol) of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol in ethyl acetate (12 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature under atmospheric pressure and a hydrogen atmosphere for 48 hours. After replacing the hydrogen in the system with nitrogen, the 5% palladium carbon was filtered off. The filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain 3.94 g (yield 99%) of the title compound as a colorless, transparent liquid. Regarding the obtained compound, 1 The results of H-NMR measurement are as follows:

[0264] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.75-0.9 (m, 15H), 0.95-1.7 (m, 29H), 2.28 (brs, OH), 2.30 (m, 2H), 3.54-3.67 (m, 0.62H), 3.88-4.1 (m, 2.07H), 4.97 (m, 0.31H)

[0265] Mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol is also referred to as saturated C22 propylene glycol ester.

[0266] [Example 11] Preparation of precursor formulation, gel formation test, and analysis of liquid crystal structure (2) According to the blending ratios shown in Table 9 below, the amphiphilic compound, which is an isoprenoid lipid synthesized in Example 1 or 10, phospholipids SPC, DMPC, DPPC, DOPC, DOPE, DOPG-Na (all the same products as those used in Examples 2 or 8) or EPC (purified egg yolk lecithin, PL-100M, Kewpie Corporation), oil, and, optionally, alcohol were mixed. The resulting mixture was dissolved in a water bath at 40°C or below to prepare precursor formulations Nos. 126 to 152 shown in Table 9. Of the isoprenoid lipids used, C17 propylene glycol ester and C22 propylene glycol ester were low-viscosity liquids, and precursor formulations could be prepared without adding alcohol (e.g., formulation No. 147).

[0267] It should be noted that C17 propylene glycol ester, C22 propylene glycol ester, and saturated C22 propylene glycol ester do not form gels by themselves when mixed with water, and therefore are not self-assembling lipids (SOLs), but are isoprenoid lipids.

[0268] A gel formation test was conducted on precursor formulations No. 126 to 152. A portion of each precursor formulation (approximately 100 to 300 mg) was added to an excess amount of water for injection (approximately 0.5 to 2 mL) in a vial, and the mixture was mixed at room temperature (25°C) using a spoon and / or a vortex mixer. As a result, for all precursor formulations No. 126 to 152, a gel composition that was colorless, transparent, or cloudy in appearance was obtained, which separated into the excess water for injection (aqueous medium).

[0269] The gel compositions obtained from precursor preparations Nos. 126 to 152 were analyzed for non-lamellar liquid crystal structure by small-angle X-ray scattering diffraction in the same manner as in Example 2, and the liquid crystal phase and the scattering vector value q1 [nm-1] of the peak located at the smallest angle were determined. As shown in Table 9, it was demonstrated that precursor preparations containing a combination of an isoprenoid lipid and a phospholipid can form non-lamellar liquid crystal in the presence of water, not only when an isoprenoid lipid that is a self-assembling lipid (SOL) is used, but also when an isoprenoid lipid that is not an SOL is used.

[0270] Furthermore, when a precursor formulation similar to the above was prepared using propylene glycol monostearate (NIKKOL PMS-1CV, Nikko Chemicals Co., Ltd.), a pharmaceutical additive having linear stearic acid as the fatty chain, instead of the above isoprenoid lipid, no liquid crystalline gel was formed over the entire range of propylene glycol monostearate:phospholipid ratios (weight ratio) from 100:0 to 0:100.

[0271] [Table 9]

[0272] [Example 12] Preparation of emulsion (dispersant) and analysis of liquid crystal structure (2) White emulsions Nos. 153 and 154 (8 g each) containing fine particles were prepared in the same manner as in Example 3 using the C17 glycerin ester and C22 propylene glycol ester synthesized in Examples 1 and 10, respectively, in the blending ratios shown in Table 10 below.

[0273] The emulsions of Formulations No. 153 and 154 were subjected to structural analysis by small-angle X-ray scattering (SAXS) using the same method as in Example 3. The scattering intensity distribution obtained from the emulsion of Formulation No. 153 showed a broad scattering peak, suggesting that this emulsion was a liquid crystal emulsion in which sponge phase (L3 phase) particles were dispersed in an aqueous phase. Furthermore, the scattering intensity distribution obtained from the emulsion of Formulation No. 154 showed at least three scattering peaks (the scattering vector value q1 of the peak located at the smallest angle was 1.08 nm-1). The peak ratio was 1:√3:2, which is characteristic of reverse hexagonal liquid crystals, indicating that this emulsion was a liquid crystal emulsion (hexasome) in which reverse hexagonal liquid crystal particles were dispersed in an aqueous phase.

[0274] [Table 10]

[0275] [Example 13] Safety evaluation in the body (2) The precursor formulations of formulations Nos. 127, 128, 130, 131, 134, 136, 137, 139, 143, 145, 146, and 152 prepared in Example 11, and the emulsions of formulations Nos. 153 and 154 prepared in Example 12 were evaluated for safety in the body by intraperitoneal administration in the same manner as in Example 4.

[0276] (1) Safety evaluation results of precursor formulations In the precursor formulations Nos. 127 and 139, which contained low amounts of phospholipids, abscesses were observed surrounding the formed gel. On the other hand, in the precursor formulations Nos. 128, 130, 131, 134, 136, 137, 143, 145, 146, and 152, which contained higher amounts of phospholipids, no intraperitoneal findings related to adverse reactions, including abscesses as a foreign body reaction, were observed.

[0277] The composition of the precursor formulation of formulation No. 127, in which an abscess developed, corresponds to a composition in which 62.5% of the phospholipids contained in formulation No. 15, in which no abscess developed in Example 4, were replaced with oil (isoprenoid lipids (SOL in Table 1):phospholipids:oil = 60:15:25), and also has the same isoprenoid lipid (SOL in Table 1):phospholipid ratio of 80:20 as formulation No. 14, in which an abscess developed in Example 4. Therefore, these results reaffirm that a certain amount or more of phospholipids, rather than oils, is required relative to isoprenoid lipids to ensure safety in the body.

[0278] Even in intraperitoneal administration, which requires higher safety than subcutaneous implantation (Example 9), no foreign body reaction or other side effects occurred regardless of the type of phospholipid. Of particular importance is that the safety evaluation of Formulations Nos. 131, 134, 136, and 137, in which the SPC in Formulation No. 55 was replaced with various other phospholipids (EPC, DMPC, DOPC, or DOPE), showed no side effects.

[0279] Furthermore, it has been shown that when an isoprenoid lipid in which R in the general formula (I) is a hydrophilic group having one hydroxyl group is used, not only when an isoprenoid lipid in which R is derived from isosorbide is used, but also when an isoprenoid lipid derived from propylene glycol is used, by combining it with a certain amount or more of phospholipid, no foreign body reaction or other side effects occur (see Preparations Nos. 143, 145, 146, and 152).

[0280] In isoprenoid lipids where R is derived from propylene glycol ester, as with those derived from glycerin ester, isoprenoid lipids with a larger carbon number (22) were less likely to cause side effects than isoprenoid lipids with a carbon number of 17 (Preparation No. 139 vs. Preparation No. 145).

[0281] (2) Safety evaluation results of emulsion When Formulation No. 153, an emulsion containing C17 glycerol esters and a high phospholipid to isoprenoid lipid ratio of 60%, was administered to rats at a dose of 43 μL, no adverse effects were observed throughout the abdominal cavity. The total weight of the isoprenoid lipid, phospholipid, and oil contained in the 43 μL dose is converted to a human dose of 3.6 g, assuming a rat weight of 150 g and a human weight of 50 kg, so that the dose per body weight is equivalent. However, Formulation No. 153 caused slight liver hypertrophy at a higher dose of 360 μL (30 g), and increased liver hypertrophy at a dose of 720 μL (60 g). Therefore, it was shown that an emulsion containing an amphipathic compound having an isoprenoid-type fatty chain with a carbon number of 17 and a certain amount or more of phospholipids has a lower dose that can be safely administered intraperitoneally than an emulsion containing an amphipathic compound having an isoprenoid-type fatty chain with a carbon number of 22 and a certain amount or more of phospholipids.

[0282] In the emulsion of Formulation No. 154 using C22 propylene glycol ester, no side effects were observed throughout the abdominal cavity, even at a dose of 720 μL (equivalent to the above-mentioned human dose of 60 g), as was the case with the emulsions containing other amphiphilic compounds with isoprenoid-type fatty chains having 22 carbon atoms shown in Example 4 and containing a certain amount or more of phospholipids (e.g., Formulations No. 77, 79, 82-85, 88, 89, 91-93, 102, and 103).

[0283] [Example 14] In vitro release test of FD-4 As in Example 2, the C22 glycerin ester having an isoprenoid-type fatty chain with 22 carbon atoms synthesized in Example 1, the surfactant P80 (polyoxyethylene sorbitan monooleate (20E.O.)), and ethanol were mixed according to the blending ratios shown in Table 11 below, and then stirred at 60°C for 5 minutes. DMPC, DPPC, or DOPC (all the same products as those used in Examples 2 and 8) was added as a phospholipid to the resulting solution, and the mixture was stirred at 60°C for 1 hour to prepare precursor formulations Nos. 155 to 158.

[0284] When precursor preparations No. 155 to No. 158 were added to a large excess of PBS at pH 7.4, gel compositions were obtained. Small-angle X-ray scattering diffraction measurements were performed on each gel composition in the same manner as in Example 2, confirming that all gel compositions had a non-lamellar liquid crystal structure. The resulting liquid crystal phases and the scattering vector values ​​q1 [nm-1] of the peaks located at the smallest angles are shown in Table 11.

[0285] [Table 11]

[0286] Next, FD-4 (fluorescein isothiocyanate-dextran, average molecular weight 4,000, Sigma-Aldrich, product number 46944) was added to each of the precursor formulations No. 155 to 158 at a concentration of 15.6 mg / mL, and the mixture was stirred for 3 minutes using a pellet pestle to obtain FD-4-containing precursor formulations No. 159 to 162. For comparison, FD-4 was added to C22 glycerin ester alone at a concentration of 15.6 mg / mL, resulting in C22 glycerin ester precursor formulation No. 163, which contained FD-4 but no phospholipids.

[0287] An in vitro release test was conducted on precursor formulations No. 159 to 163 containing FD-4. TM100 μL of the formulation was added to a vial (MINI 12000, Sigma-Aldrich). One vial (25 mL) contained 20 mL of PBS solution (pH 7.4) containing 0.01% sodium azide. One dialysis tube with a floating rack attached to the top was placed in the vial so that the precursor formulation was fully immersed in the PBS solution, and the vial was left to stand at room temperature (25°C). Then, 500 μL of the PBS solution in the vial was sampled over a 48-hour period, starting immediately after the start of the test (the same amount of PBS was added each time). It was visually observed that all of the precursor formulations No. 159 to 163 added to the PBS solution formed gel compositions.

[0288] The FD-4 in the sample collected from the PBS solution was quantified using a fluorescence spectrophotometer (RF-5300PC: Shimadzu Corporation, Japan) (excitation wavelength: 490 nm, fluorescence wavelength: 515 nm).

[0289] Figure 4 shows the in vitro release profiles of precursor formulations Nos. 159 to 163 containing FD-4. In Figure 4, the horizontal axis represents time (hours), and the vertical axis represents the percentage of FD-4 released into the PBS solution at each time point (mean value of n = 3) relative to the amount of FD-4 contained in the precursor formulation at the start of the test. The FD-4 release rates after 48 hours were 1% for formulation No. 159, 35% for No. 160, 24% for No. 161, 39% for No. 162, and 1% for No. 163.

[0290] All of the precursor formulations containing FD-4 showed a gradual release of FD-4 without an initial burst release. The release rates of precursor formulation No. 163, which did not contain phospholipids, and formulation No. 159, which contained a low amount of phospholipids, were slow, while the release rates of precursor formulations Nos. 160 to 162, which contained a high amount of phospholipids, were faster.

[0291] These results demonstrated that in a precursor formulation containing various phospholipids added to a C22 glycerin ester with a 22-carbon isoprenoid fatty chain as an isoprenoid lipid, it is possible to control drug release according to the type and content of phospholipid.

[0292] [Example 15] In vitro release test of leuprolide acetate (2) As in Example 2, precursor formulations No. 164 to 169 were prepared according to the blending ratios shown in Table 12 below, using as isoprenoid lipids C17 glycerin esters having a 17-carbon isoprenoid fatty acid chain, C22 propylene glycol esters (R in general formula (I) has one hydroxyl group) having a 22-carbon isoprenoid fatty acid chain, C22 glycerin esters (R in general formula (I) has two hydroxyl groups), C22 sorbitan ester fractions (R in general formula (I) has three hydroxyl groups), or saturated C22 sorbitan ester fractions (R in general formula (I) has three hydroxyl groups), soybean phosphatidylcholine (LIPOID S100, Lipoid Corporation; abbreviated as SPC in the table) as a phospholipid, P80 (polyoxyethylene sorbitan monooleate (20E.O.)) as a surfactant, and ethanol.

[0293] When precursor preparations No. 164 to No. 169 were added to a large excess of PBS at pH 7.4, gel compositions were obtained. Small-angle X-ray scattering diffraction measurements were performed on each gel composition in the same manner as in Example 2, confirming that all gel compositions had a non-lamellar liquid crystal structure. The resulting liquid crystal phases and the scattering vector values ​​q1 [nm-1] of the peaks located at the smallest angles are shown in Table 12.

[0294] [Table 12]

[0295] Next, precursor formulations Nos. 164 to 169 were added to a dimethyl sulfoxide solution of leuprolide acetate to prepare precursor formulations Nos. 170 to 175 (100 mg) containing leuprolide acetate in the same manner as in Example 8. An in vitro release test of leuprolide acetate was conducted over a period of 7 days. It was visually observed that all of precursor formulations Nos. 170 to 175 added to a PBS solution became gel-like compositions.

[0296] Figure 5 shows the in vitro release data from precursor formulations Nos. 170 to 175 containing leuprolide acetate. In Figure 5, the horizontal axis represents time (days), and the vertical axis represents the release rate (%) of leuprolide acetate into PBS solution at each time point relative to the amount of leuprolide acetate contained in the precursor formulation at the start of the test (mean value of n = 3). Seven days after the start of the test, the release rates of leuprolide acetate were 62% for No. 170, 7% for No. 171, 64% for No. 172, 45% for No. 173, 69% for No. 174, and 16% for No. 175.

[0297] All precursor formulations containing leuprolide acetate showed a gradual release of leuprolide acetate without an initial burst release. Among precursor formulations No. 170 to 174, which had identical compositions except for the isoprenoid lipid, precursor formulation No. 171, which contained the most hydrophobic C22 propylene glycol ester, had a slow release rate, while precursor formulations No. 170 and 172 to 174, which contained C17 glycerin ester, C22 glycerin ester, C22 sorbitan ester fraction, and saturated C22 sorbitan ester fraction, respectively, with similar HLB values, had a fast release rate. Formulation No. 165, corresponding to Formulation No. 171, forms reverse hexagonal liquid crystals upon addition of PBS. Formulations No. 164 and 168, corresponding to Formulations No. 170 and 174, form Pn3m cubic liquid crystals upon addition of PBS. Formulations No. 166 and 167, corresponding to Formulations No. 172 and 173, form Pn3m cubic liquid crystals and reverse hexagonal liquid crystals upon addition of PBS. In particular, precursor Formulation No. 174, which contains a saturated C22 sorbitan ester fraction with a saturated fatty chain, showed the fastest release rate. Furthermore, the release rate of precursor Formulation No. 175, which contains a saturated C22 sorbitan ester fraction, was slower than that of precursor Formulation No. 174, which contains a high phospholipid ratio. Formulation No. 169, corresponding to Formulation No. 175, forms reverse hexagonal liquid crystals upon addition of PBS.

[0298] These results demonstrated that in a precursor formulation in which a phospholipid is added to an isoprenoid lipid represented by general formula (I), it is possible to control the release of a drug according to the type of isoprenoid lipid and the content of phospholipid.

[0299] [Example 16] Subcutaneous implantation test (2) Seven-week-old male Sprague-Dawley (SD) rats (Crl:CD(SD), SPF) were administered 72 μL of emulsion of formulation No. 87 prepared in Example 3, or 100 μL of any of the ten precursor formulations consisting of formulations Nos. 35, 129, 145, 146, 3, 126, 23, 24, 54, and 56 prepared in Examples 2 and 11, subcutaneously between the shoulder blades using a syringe equipped with a 22 G needle (n=3 for each formulation).

[0300] Seven days after administration, the rats were euthanized by exsanguination under inhalation anesthesia with sevoflurane (Mylan Pharmaceuticals), and the skin containing the subcutaneous injection site was removed. After simple removal of subcutaneous fat, the injection site was examined macroscopically.

[0301] Figures 6 and 7 show photographs of the observed formulation administration sites (Figure 6A: Emulsion No. 87, Figure 6B: Precursor formulation No. 35, Figure 6C: Precursor formulation No. 129, Figure 6D: Precursor formulation No. 145, Figure 6E: Precursor formulation No. 146, Figure 6F: Precursor formulation No. 3, Figure 7A: Precursor formulation No. 126, Figure 7B: Precursor formulation No. 23, Figure 7C: Precursor formulation No. 24, Figure 7D: Precursor formulation No. 54, Figure 7E: Precursor formulation No. 56).

[0302] In rats administered either formulation, no findings attributable to inflammation caused by the formulation were observed in the tissues surrounding the administration site, and no abnormal findings such as bleeding or discoloration were observed.

[0303] No formulation remained at the administration site of the emulsion of Formulation No. 87. Of the 10 precursor formulations mentioned above, precursor formulations No. 35, No. 145, No. 146, No. 23, No. 24, No. 54, and No. 56, which used C22 propylene glycol ester, C22 sorbitan ester fraction, or saturated C22 sorbitan ester fraction, contained gel compositions at the administration site with volumes similar to or less than the dosage of the formulation, in a state similar to the gel compositions observed during the gel formation test. On the other hand, precursor formulations No. 129, No. 3, and No. 126, which used C17 glycerin ester and C22 glycerin ester, contained larger volumes of gel compositions at the administration site compared to the gel compositions described above, indicating infiltration of biological components into the compositions.

[0304] The above results demonstrate that formulations (e.g., precursor formulations, emulsions) containing isoprenoid lipids such as C17 glycerin ester, C22 propylene glycol ester, C22 glycerin ester, C22 sorbitan ester fraction, and saturated C22 sorbitan ester fraction, and phospholipids such as SPC, can be used safely by subcutaneous administration as well as by intraperitoneal administration (Examples 4 and 13).

[0305] [Example 17] Synthesis of amphiphilic compound (3) (1) Synthesis of mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan

[0306] [ka]

[0307] 6.49 g (20 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate and 5.47 g of a 90 wt% aqueous sorbitan solution (30.0 mmol, Sorbitan M-90, Sanko Chemical Industry Co., Ltd., 90% solids with 10% water, solids content: 79-84% sorbitan, 15-18% isosorbide) were added to a reaction vessel at room temperature and stirred at 120 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.22 g (4.0 mmol) of sodium methoxide and 4 mg of sodium phosphinate monohydrate were added. The mixture was stirred at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.11 g (2.0 mmol) of sodium methoxide was added. The mixture was further stirred at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.11 g (2.0 mmol) of sodium methoxide was added again, followed by stirring at 160°C and 8 kPa for an additional 1.5 hours. After cooling to 60°C, 20 mL of ethyl acetate and 20 mL of 0.5 M hydrochloric acid were added with stirring. 60 mL of ethyl acetate was added to the resulting reaction solution for extraction. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / hexane mixture) to obtain 3.83 g (42% yield) of a fraction containing the title compound as a light brown, transparent liquid. The obtained fraction contained mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan and mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)isosorbide in a ratio of approximately 8:2 (weight ratio), as well as a small amount of a diester derived from sorbitan. 1 The results of H-NMR measurement are as follows:

[0308] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.80-0.95 (m, 12H), 1.00-1.80 (m, 19H), 1.90-2.20 (m, 5H), 3.6-4.9 (m, 6.4H), 5.1-5.3 (m, 0.6H), 5.71 (brs, 1H)

[0309] Mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan is also called C20 sorbitan ester.

[0310] The obtained fraction was used as a mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan fraction (C20 sorbitan ester fraction) in the Examples described later.

[0311] (2) Synthesis of mono-O-(3,7,11,15-tetramethylhexadecanoyl)sorbitan

[0312] [ka]

[0313] Under a nitrogen atmosphere, 0.30 g of 5% palladium carbon was added to a solution of 2.50 g (5.48 mmol) of the C20 sorbitan ester fraction in ethyl acetate (7.5 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature for 1 day under a hydrogen atmosphere at normal pressure. After replacing the hydrogen in the system with nitrogen, the 5% palladium carbon was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 2.49 g (yield 99%) of a fraction containing the title compound as a colorless, transparent liquid. The obtained fraction was analyzed as follows: 1 The results of H-NMR measurement are as follows:

[0314] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.8-0.9(m,12H),0.9-1.0(m,3H),1.0-2.0(m,22H),2.1-2.4(m,2H),3.5-4.9(m,6.4H),5.0-5.2(m,0.6H)

[0315] Mono-O-(3,7,11,15-tetramethylhexadecanoyl)sorbitan is also referred to as saturated C20 sorbitan ester.

[0316] The obtained fraction was used as a mono-O-(3,7,11,15-tetramethylhexadecanoyl)sorbitan fraction (saturated C20 sorbitan ester fraction) in the Examples described later.

[0317] (3) Synthesis of mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)propylene glycol

[0318] [ka]

[0319] Under a vacuum of 60-70 mmHg and a nitrogen stream, 10.0 g (30.8 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate was slowly added dropwise to a solution of 7.5 g (99 mmol) of propylene glycol and 60 mg (0.44 mmol) of potassium carbonate in dry N,N-dimethylformamide (22 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 50 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to afford 8.18 g (72% yield) of the title compound as a light yellow, transparent liquid with low viscosity. The resulting compound was characterized as follows: 1 The results of H-NMR measurement are as follows:

[0320] 1 H-NMR spectrum (300 MHz, CDCl3, TMS) δ: 0.80-0.95 (m, 12H), 1.00-1.80 (m, 22H), 1.90-2.20 (m, 6H), 3.6-3.70 (m, 0.72H), 3.85-4.2 (m, 1.93H), 5.0 (m, 0.36H), 5.71 (brs, 1H)

[0321] Mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)propylene glycol is also referred to as C20 propylene glycol ester.

[0322] (4) Synthesis of mono-O-(3,7,11,15-tetramethylhexadecanoyl)propylene glycol

[0323] [ka]

[0324] Under a nitrogen atmosphere, 0.36 g of 5% palladium carbon was added to a solution of 3.00 g (8.14 mmol) of mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)propylene glycol in ethyl acetate (9 mL). After replacing the nitrogen in the system with hydrogen, the mixture was stirred at room temperature under atmospheric pressure and a hydrogen atmosphere for one day. After replacing the hydrogen in the system with nitrogen, the 5% palladium carbon was filtered off. The filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain 2.96 g (yield 98%) of the title compound as a colorless, transparent liquid with low viscosity. Regarding the compound obtained, 1 The results of H-NMR measurement are as follows:

[0325] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.8-0.9(m,12H),0.9-1.0(m,3H),1.0-2.0(m, 25H),2.1-2.4(m,2H),3.55-3.70(m,0.72H),3.85-4.15(m,1.93H),4.98(m,0.36H)

[0326] Mono-O-(3,7,11,15-tetramethylhexadecanoyl)propylene glycol is also referred to as saturated C20 propylene glycol ester.

[0327] (5) Synthesis of mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan

[0328] [ka]

[0329] 3.39 g (10 mmol) of methyl 4,8,12,16-tetramethylheptadec-3-enoate and 2.74 g of a 90 wt% aqueous sorbitan solution (15.0 mmol, Sorbitan M-90, Sanko Chemical Industry Co., Ltd., 90% solids and 10% water, solids content: 79-84% sorbitan, 15-18% isosorbide) were added to a reaction vessel at room temperature and stirred at 120 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 0.11 g (2.0 mmol) of sodium methoxide and 4 mg of sodium phosphinate monohydrate were added. The mixture was stirred at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 54 mg (1.0 mmol) of sodium methoxide was added. The mixture was further stirred at 160 °C and 8 kPa for 1 hour. The vacuum was released with nitrogen, and 54 mg (1.0 mmol) of sodium methoxide was added again. The mixture was then stirred at 160°C and 8 kPa for an additional 1.5 hours. After cooling to 60°C, 10 mL of ethyl acetate and 10 mL of 0.5 M hydrochloric acid were added with stirring. 50 mL of ethyl acetate was added to the resulting reaction mixture for extraction. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / hexane mixture) to obtain 1.79 g (38% yield) of a fraction containing the title compound as a light brown, transparent liquid. The resulting fraction contained mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan and mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)isosorbide in a weight ratio of approximately 8:2, as well as a small amount of a sorbitan-derived diester. The obtained fractions were 1 The results of H-NMR measurement are as follows:

[0330] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.90(m,12H),1.00-1.60(m,19H),1.64 and 1.72(s,3H),2.00(t,J=7.4Hz,2H),3.10(d,J=7.2Hz,2H),3.5-4.9(m,6.4H),5.0-5.2(m,0.6H),5.30(t,J=7.2Hz,1H)

[0331] Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan is also called C21 sorbitan ester.

[0332] The obtained fraction was used as a mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan fraction (C21 sorbitan ester fraction) in the Examples described later.

[0333] (6) Synthesis of mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol

[0334] [ka]

[0335] Under a vacuum of 60-70 mmHg and a nitrogen stream, 3.39 g (10 mmol) of methyl 4,8,12,16-tetramethylheptadec-3-enoate was slowly added dropwise to a solution of 2.4 g (32 mmol) of propylene glycol and 19 mg (0.14 mmol) of potassium carbonate in dry N,N-dimethylformamide (7 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 30 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to afford 2.91 g (76% yield) of the title compound as a light yellow, transparent liquid with low viscosity. The resulting compound was characterized by the following characteristics: 1The results of H-NMR measurement are as follows:

[0336] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.90(m,12H),1.00-1.60(m,22H),1.62 and 1.74(s,3H),2.02(t,J=7.1Hz,2H),3.10(d,J=7.0Hz,2H),3.55-3.70(m,0.72H),3.85-4.15(m,1.92H),4.98(m,0.36H),5.31(t,J=7.0Hz,1H)

[0337] Mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol is also referred to as C21 propylene glycol ester.

[0338] (7) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol

[0339] [ka]

[0340] Under a vacuum of 60-70 mmHg and a nitrogen stream, 3.53 g (10.0 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 2.0 g (32 mmol) of ethylene glycol and 19 mg (0.14 mmol) of potassium carbonate in dry N,N-dimethylformamide (7 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 30 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to afford 2.85 g (74% yield) of the title compound as a light yellow, transparent liquid with low viscosity. The resulting compound was characterized by the following characteristics: 1 The results of H-NMR measurement are as follows:

[0341] 1 H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.95(m,12H),0.95-1.70(m,22H),1.96(td,J=7 .5,18Hz,2H),2.25-2.4(m,4H),3.68(t,J=6.4Hz,2H),4.10(t,J=6.4Hz,2H),5.08(m,1H)

[0342] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol is also called C22 ethylene glycol ester.

[0343] (8) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol

[0344] [ka]

[0345] Under a vacuum of 60-70 mmHg and a nitrogen stream, 3.53 g (10.0 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 2.9 g (32 mmol) of 1,3-butylene glycol and 19 mg (0.14 mmol) of potassium carbonate in dry N,N-dimethylformamide (7 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 30 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to afford 3.02 g (73% yield) of the title compound as a light yellow, transparent liquid with low viscosity. The resulting compound was characterized by the following characteristics: 1 The results of H-NMR measurement are as follows:

[0346] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.95(m,12H),0.95-1.80(m,25H),1.96(td,J=7.6,18.6Hz,2H),2.25-2.3 5(m,4H),3.5-3.7(m,0.5H),3.86(m,0.75H),4.12(m,0.75H),4.35(ddd,J=5.4,8.3,13.7Hz,0.75H),5.08(m,1.25H)

[0347] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl) 1,3-butylene glycol is also referred to as C22 butylene glycol ester.

[0348] (9) Synthesis of mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol

[0349] [ka]

[0350] Under a vacuum of 60-70 mmHg and a nitrogen stream, 3.53 g (10.0 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 3.3 g (32 mmol) of 3-methyl-1,3-butanediol and 19 mg (0.14 mmol) of potassium carbonate in dry N,N-dimethylformamide (7 mL) at 85°C, followed by stirring at the same temperature for 3 hours. The resulting reaction solution was diluted with an ethyl acetate / hexane mixed solvent (1:1, 30 mL), washed with water, saturated sodium bicarbonate solution, and saturated brine (twice), and then dried over magnesium sulfate. The residue obtained by filtration and concentration was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 100:0-70:30) to afford 2.94 g (69% yield) of the title compound as a light yellow, transparent liquid with low viscosity. The resulting compound was characterized by the following characteristics: 1 The results of H-NMR measurement are as follows:

[0351] 1H-NMR spectrum (300MHz, CDCl3, TMS) δ:0.80-0.95(m,12H),0.95-1.70(m,28H),1.84(t,J=6.9 Hz,2H),1.96(td,J=7.7,18.3Hz,2H),2.25-2.35(m,4H),4.25(t,J=6.9Hz,2H),5.08(m,1H)

[0352] Mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol is also called C22 isoprene glycol ester.

[0353] [Example 18] Preparation of precursor formulation, gel formation test, and analysis of liquid crystal structure (3) The amphipathic compound, which is an isoprenoid lipid synthesized in Example 17, SPC (LIPOID S100, Lipoid) as a phospholipid, and alcohol were mixed according to the blending ratios shown in Table 13. The resulting mixture was dissolved in a water bath at 40°C or less to prepare precursor formulations No. 176 to 184 shown in Table 13.

[0354] It should be noted that C20 propylene glycol ester, saturated C20 propylene glycol ester, C21 propylene glycol ester, C22 ethylene glycol ester, C22 butylene glycol ester, and C22 isoprene glycol ester do not form gels when mixed with water, and therefore are not self-assembling lipids (SOLs).

[0355] A gel formation test was conducted on precursor formulations No. 176 to 184. A portion of each precursor formulation (approximately 100 to 300 mg) was added to an excess amount of water for injection (approximately 0.5 to 2 mL) in a vial, and the mixture was mixed at room temperature (25°C) using a spoon and / or a vortex mixer. As a result, for all precursor formulations No. 176 to 184, a gel composition that was colorless, transparent, or cloudy in appearance was obtained, which separated into the excess water for injection (aqueous medium).

[0356] The gel compositions obtained from the precursor preparations Nos. 182 to 184 are considered to exhibit a liquid crystal phase of HII, similar to preparations Nos. 146 and 147.

[0357] [Table 13]

[0358] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. An amphiphilic compound represented by the following general formula (I') or a salt thereof: 【Chemistry 1】 (wherein X and Y together represent an oxygen atom or each represent a hydrogen atom; n represents 2, 1, or 0; m represents 2 or 1; 【change】 represents a single bond or a double bond, R represents a hydrophilic group obtained by removing one hydroxyl group from any one group selected from the group consisting of sorbitan, isosorbide, and glycol, 【change】 indicates that the amphiphilic compound is a geometric isomer, E (cis) or Z (trans) isomer, or a mixture thereof.

2. The compound or salt thereof according to claim 1, wherein in the general formula (I'), n=2.

3. The amphiphilic compound is selected from the group consisting of: mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)sorbitan, mono-O-(5,9,13,17-tetramethyloctadecanoyl)sorbitan, mono-O-(5,9,13-trimethyltetradec-4-enoyl)sorbitan, mono-O-(5,9,13-trimethyltetradecanoyl)sorbitan, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)isosorbide, mono-O-(5,9,13,17-tetramethyloctadecanoyl) isosorbide, mono-O-(5,9,13-trimethyltetradec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadecanoyl)propylene glycol, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)sorbitan, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)isosorbide, mono-O-(4,8,12,16-tetramethylheptadec-3-enoyl)propylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)ethylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)1,3-butylene glycol, mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)3-methyl-1,3-butanediol, mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)sorbitan, mono-O-(3,7,11,15-tetramethylhexadecanoyl)sorbitan, mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)isosorbide, mono-O-(3,7,11,15-tetramethylhexadec-2-enoyl)propylene glycol, and Mono-O-(3,7,11,15-tetramethylhexadecanoyl)propylene glycol 2. The compound of claim 1, or a salt thereof, selected from the group consisting of:

Images