WO2009119836A1 - 転写因子デコイを有効成分とする外用剤組成物 - Google Patents
転写因子デコイを有効成分とする外用剤組成物 Download PDFInfo
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- WO2009119836A1 WO2009119836A1 PCT/JP2009/056369 JP2009056369W WO2009119836A1 WO 2009119836 A1 WO2009119836 A1 WO 2009119836A1 JP 2009056369 W JP2009056369 W JP 2009056369W WO 2009119836 A1 WO2009119836 A1 WO 2009119836A1
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- C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/13—Decoys
Definitions
- the present invention relates to a composition for an external preparation containing a fatty acid ionic liquid in which a transcription factor decoy is dissolved as an essential component.
- Transcription factor means a protein that regulates gene transcription by binding to DNA upstream or downstream of the promoter.
- Representative examples include NF- ⁇ B, E2F, GATA-3, STAT-1, STAT-6, Ets, AP-1 etc. can be mentioned.
- decoy means “decoy” in English, and a substance having a structure resembling that which a substance should originally bind or act on is called decoy.
- the transcription factor decoy a double-stranded oligonucleotide having the same base sequence as the transcription factor binding region on the genomic DNA is mainly used (Patent Documents 1 to 3).
- a transcription factor decoy comprising such an oligonucleotide
- a part of the transcription factor binds to the transcription factor decoy without binding to the binding region on the genomic DNA to be originally bound. For this reason, the transcription factor couple
- these oligonucleotides are called transcription factor decoys because they function as a fake (bait) of a binding region on a real genomic gene and bind to a transcription factor. It is known that administration of a transcription factor decoy can reduce the activity of a target transcription factor and treat or prevent a disease caused by the transcription factor.
- Non-patent Document 1 NF- ⁇ B decoy is used as the transcription factor decoy, the contribution of NF- ⁇ B can be suppressed, so that symptoms such as allergies, asthma and rheumatism can be suppressed or reduced. Therefore, development of a new anti-inflammatory ointment using this NF- ⁇ B decoy has been promoted, and clinical application has been promoted particularly as a therapeutic agent for facial lesions of severe atopic dermatitis (Non-patent Document 1).
- the problem is that the molecular weight of the transcription factor decoy is usually about 10,000 or more, greatly exceeding the range of molecular weight that can be absorbed through the skin.
- the barrier function that separates the outside from the living body's internal environment is very well developed in the skin, so that the permeation of substances having a molecular weight of 1,000 is remarkably suppressed. Therefore, it was expected that it would be difficult to obtain a therapeutic effect by external application except for a severely lesioned site where the skin barrier function such as an erosive site is remarkably lowered. Even in actual treatment, this expected result was obtained, and how to enhance the transdermal absorbability of transcription factor decoys such as NF- ⁇ B decoy has emerged as a major problem.
- An object of the present invention is to provide an external preparation composition that stably dissolves transcription factor decoys such as NF- ⁇ B decoy and has improved transdermal absorbability.
- the present inventors have added ionic liquid to the transcription factor decoy.
- the solubility of transcription factor decoys in external preparations can be improved by using a fatty acid ionic liquid having 2 to 20 carbon atoms under non-aqueous conditions as a solvent. It was found that the transdermal absorbability of the transcription factor decoy can be improved.
- the present inventors have also found that the solubility of the transcription factor decoy in the external preparation can be controlled by mixing a plurality of fatty acid ionic liquids.
- the transdermal absorbability of the transcription factor decoy can be promoted by controlling the solubility. That is, since the formulation of the present invention has improved transdermal absorbability by controlling the solubility of the transcription factor decoy, the decoy has a very low concentration (0.0001 to 1 w / w%), which has not been reported in the past. It was found that even in this preparation, decoy was absorbed through the skin and the effect could be expressed. The present inventors have completed the present invention based on these findings.
- the gist of the present invention is as follows.
- [1] A non-aqueous external preparation composition containing a transcription factor decoy dissolved in a fatty acid ionic liquid obtained from a fatty acid having 2 to 20 carbon atoms and an organic amine compound having 4 to 12 carbon atoms.
- [2] The external preparation composition according to [1], wherein the fatty acid having 2 to 20 carbon atoms is one or more selected from the group consisting of glycolic acid, methoxyacetic acid, levulinic acid, capric acid and isostearic acid. .
- the organic amine compound having 4 to 12 carbon atoms is one or more selected from the group consisting of diethanolamine, triethanolamine, diisopropanolamine and triisopropanolamine, according to the above [1] or [2] Topical preparation composition.
- the mixed ionic liquid is an ionic liquid (I) which is a diethanolamine salt or triethanolamine salt of a fatty acid having 2 to 5 carbon atoms, and a diisopropanolamine salt or triisopropanolamine salt of a fatty acid having 2 to 20 carbon atoms.
- the nonaqueous external preparation composition according to [4] above which is a mixture with a certain ionic liquid (II).
- the nonaqueous external preparation composition described in [5] above, wherein the fatty acid having 2 to 5 carbon atoms of the ionic liquid (I) is selected from the group consisting of glycolic acid, methoxyacetic acid and levulinic acid.
- a non-aqueous external preparation composition according to claim 1. [24] The nonaqueous external preparation composition described in [22] or [23] above, which contains a mixed ionic liquid of a plurality of fatty acid ionic liquids and the concentration of the mixed ionic liquid is 0.008 to 30 w / w% object. [25] The nonaqueous external preparation composition described in any one of [1] to [24] above, to which an organic solvent is added.
- the transcription factor according to any one of [1] to [30], wherein the transcription factor is selected from the group consisting of NF- ⁇ B, E2F, GATA-3, STAT-1, STAT-6, Ets, and AP-1.
- a non-aqueous external preparation composition [32] The above NF- ⁇ B decoy, wherein the transcription factor decoy comprises the sequence GGRHTYYHC (wherein R represents A or G, Y represents C or T, and H represents A, C, or T, respectively) [31] The nonaqueous external preparation composition described in [31].
- the E2F decoy comprises the sequence TTTCCCGC.
- the ionic liquid is an ionic liquid (I) which is a diethanolamine salt or a triethanolamine salt of a fatty acid having 2 to 5 carbon atoms, and a diisopropanolamine salt or a triisopropanolamine salt of a fatty acid having 2 to 20 carbon atoms.
- I ionic liquid
- the transcription factor decoy To stabilize the transcription factor decoy and improve the transdermal absorbability of the transcription factor decoy by preparing a composition for external use comprising a transcription factor decoy and a fatty acid ionic liquid having 2 to 20 carbon atoms as essential components. Can do. Further, by using a plurality of fatty acid ionic liquids, the transdermal absorbability can be further improved by controlling the solubility of the transcription factor decoy. In particular, the stability of the transcription factor decoy can be improved by preparing a non-aqueous external preparation composition. As described above, the present invention can be used to provide various external preparation products such as solutions, ointments and patches containing a transcription factor decoy.
- the present invention provides a composition for external use containing a transcription factor decoy and a fatty acid ionic liquid having 2 to 20 carbon atoms as essential components.
- the transcription factor targeted by the decoy in the present invention is not particularly limited as long as it is a factor that regulates gene transcription and is a protein other than RNA polymerase.
- NF- ⁇ B, E2F, GATA-3, STAT- Preferred are those that are being developed as drug targets, such as 1, STAT-6, Ets, AP-1, and the like.
- the “transcription factor decoy” is not particularly limited as long as it is a nucleic acid capable of binding to a transcription factor competitively with a region on genomic DNA to which the transcription factor originally binds or acts, but typically Which contains the same or substantially the same base sequence as the transcription factor binding region on the genomic DNA, usually 14 to 35 base pairs, more preferably 15 to 30 base pairs, still more preferably 17 to 25 base pairs, most preferably Is a double-stranded oligonucleotide consisting of 18-22 base pairs.
- the “substantially identical base sequence” is a base sequence in which 1, 2, or 3 bases are replaced with other bases in the consensus sequence of the transcription factor binding region, and is equal to or more than the consensus sequence.
- the double-stranded oligonucleotide may be any of double-stranded DNA, double-stranded RNA, and DNA: RNA hybrid, but is preferably double-stranded DNA.
- the base sequence (consensus sequence) commonly found in transcription factor binding regions (cis elements) is well known for each transcription factor, and usually consists of about 5 to 15 base pairs.
- Examples of consensus sequences to which typical transcription factors bind include the following.
- Transcription factor NF- ⁇ B sequence GGRHTYYHC (wherein R represents A or G, Y represents C or T, and H represents A, C, or T)
- Transcription factor E2F sequence TTTSSCGS (wherein S means G or C)
- Transcription factor GATA-3 WGATAR (wherein W represents A or T, and R represents A or G, respectively)
- Transcription factor STAT-1 sequence TTCNNNGAA (where N means A, G, T or C)
- Transcription factor STAT-6 sequence TTCNNNNGAA (where N represents A, G, T or C)
- Transcription factor Ets sequence MGGAW (wherein M represents A or C, and W represents A or T, respectively)
- Transcription factor AP-1 Sequence TGASTMA (wherein S represents G or C, and M represents A or C, respectively)
- dumbbell-type decoy oligonucleotides dumbbell-type decoy oligonucleotides having intra
- sequences homologous to cis elements contained in the decoy for each transcription factor include the following.
- E2F decoy: sequence TTTCCCGC (3a) GATA-3 decoy: array AGATAG
- Ets decoy sequence CCGAA (7a)
- a cis element sequence to which a transcription factor binds usually consists of about 5 to 15 base pairs. Therefore, generally used transcription factor decoys are 1 to 30 in total at one end or both ends, preferably 1 to 25 base pairs, more preferably 2 to 20, and particularly preferably 3 to 17 base pairs are added.
- the added base (sequence) may be any as long as it does not adversely affect the physical properties of the transcription factor decoy.
- NF- ⁇ B decoy for example, 5′-CCTTGAAG GGATTTCCC TCC-3 ′ (SEQ ID NO: 1), 5'-AGTTGAGG GGACTTTCC CAGGC-3 '(SEQ ID NO: 2), 5'-AGTTGA GGACTTTCC AGGC-3 '(SEQ ID NO: 3), etc.
- E2F decoy for example, 5'-CTAGA TTTCCCGC G-3 '(SEQ ID NO: 4), 5'-CTAGA TTTCCCGC GGATC-3 '(SEQ ID NO: 5), etc.
- As a STAT-6 decoy for example, 5′-GATCAAGACCTT TTCCCAAGAA ATCTAT-3 ′ (SEQ ID NO: 9), etc.
- Ets decoy for example, 5'-AATTCAC CGGAA GTATTCGA-3 '(SEQ ID NO: 10), etc.
- AP-1 decoy for example, examples thereof include double-stranded oligonucleotides each consisting of a base sequence such as 5′-AGCTTG TGAGTCA GAAGCT-3 ′ (SEQ ID NO: 11) (target sequence of transcription factor is underlined).
- stability chemical and / or enzyme
- specific activity affinity with transcription factor
- Transcription factor decoy is, for example, using a commercially available DNA / RNA automatic synthesizer (Applied Biosystems, Beckman, etc.) to sense a single-stranded oligonucleotide having a base sequence designed as described above. It can be produced by synthesizing each of the strand and the antisense strand and annealing them, but other methods known in the art may be used.
- a commercially available DNA / RNA automatic synthesizer Applied Biosystems, Beckman, etc.
- the content of the transcription factor decoy dissolved in the composition for external use of the present invention is not particularly limited as long as the amount finally blended in the external preparation is percutaneously absorbed to reach a therapeutically effective amount. .
- the content of the transcription factor decoy blended in the external preparation composition may be 0.0001 to 1 w / w%, for example. More preferably, 0.0001 to 0.2 w / w% can be mentioned. Most preferably, 0.0001 to 0.1 w / w% can be mentioned.
- the transcription factor decoy is dissolved in a fatty acid ionic liquid having 2 to 20 carbon atoms.
- the “fatty acid ionic liquid having 2 to 20 carbon atoms” represents an equimolar molten salt or an equimolar equilibrium mixture of a fatty acid having 2 to 20 carbon atoms and an organic amine compound.
- an excessive amount of fatty acid or organic amine can be added to the external preparation composition. The excess amount is preferably within 0.2 times the molar amount.
- the organic amine compound is preferably an organic amine compound having 4 to 12 carbon atoms.
- the “fatty acid having 2 to 20 carbon atoms” includes, for example, intermediate fatty acids having 2 to 10 carbon atoms such as glycolic acid, levulinic acid, caproic acid, octanoic acid and capric acid, such as lauric acid, myristic acid, Saturated or unsaturated higher fatty acids having 11 to 20 carbon atoms such as palmitic acid, stearic acid, isostearic acid and oleic acid can be used.
- Preferable examples include fatty acids having 5 to 20 carbon atoms such as levulinic acid, capric acid, myristic acid, isostearic acid and oleic acid.
- the solubility of the transcription factor decoy can be controlled, and an appropriate mixed ionic liquid can be prepared and used.
- Particularly preferred fatty acids include levulinic acid and isostearic acid.
- the “organic amine compound having 4 to 12 carbon atoms” refers to an organic amine compound having 4 to 12 carbon atoms.
- Preferable examples include linear or branched alkylamine compounds substituted with a hydroxyl group. More preferable examples include diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine and the like.
- the fatty acid-based ionic liquid used in the present invention may be a single ionic liquid or a mixed ionic liquid.
- the “mixed ionic liquid” means a mixture of a plurality of fatty acid ionic liquids having 2 to 20 carbon atoms, wherein the fatty acid is common but the organic amine compounds are different.
- an appropriate combination can be used as appropriate in order to control the solubility and transdermal absorbability of the transcription factor decoy.
- the composition ratio of the mixed ionic liquid can be determined in consideration of the role of the ionic liquid.
- a mixture of an ionic liquid having a high solubility and an ionic liquid having a low solubility is used.
- examples of the ionic liquid for dissolution (ionic liquid (I)) having high solubility of the transcription factor decoy include diethanolamine salts or triethanolamine salts of fatty acids having 2 to 5 carbon atoms.
- examples of the fatty acid having 2 to 5 carbon atoms include glycolic acid, methoxyacetic acid, and levulinic acid. More preferably, levulinic acid can be mentioned. Therefore, ionic liquids for dissolving transcription factor decoys include, for example, levulinic acid diethanolamine salt, levulinic acid triethanolamine salt, glycolic acid diethanolamine salt, glycolic acid triethanolamine salt, methoxyacetic acid diethanolamine salt, methoxyacetic acid triethanolamine salt Etc.
- the ionic liquid having low solubility of the transcription factor decoy ionic liquid (II)
- a decoy having a solubility of 1 w / w% or less can be exemplified. More preferable examples include those having a decoy solubility of 0.5 w / w% or less. Particularly preferred are those having a decoy solubility of 0.2% or less. More specifically, examples of the diluting ionic liquid (ionic liquid (II)) having low solubility of the transcription factor decoy include diisopropanolamine salts or triisopropanolamine salts of fatty acids having 2 to 20 carbon atoms.
- Preferred examples include diisopropanolamine salts or triisopropanolamine salts of fatty acids having 5 to 20 carbon atoms.
- fatty acids having 5 to 20 carbon atoms include levulinic acid, capric acid, myristic acid, isostearic acid, oleic acid and the like. More preferably, levulinic acid and isostearic acid can be mentioned.
- ionic liquids with low solubility of transcription factor decoys include, for example, levulinic acid diisopropanolamine salt, levulinic acid triisopropanolamine salt, capric acid diisopropanolamine salt, capric acid triisopropanolamine salt, isostearic acid diisopropanolamine salt. And isostearic acid triisopropanolamine salt.
- Preferred examples include levulinic acid diisopropanolamine salt, levulinic acid triisopropanolamine salt, isostearic acid diisopropanolamine salt, and isostearic acid triisopropanolamine salt.
- the fatty acid-based ionic liquid of the present invention contains, for example, a fatty acid having 2 to 20 carbon atoms and an organic amine compound, preferably an organic amine compound having 4 to 12 carbon atoms, either in an equimolar amount or, if necessary, an excess amount. And can be prepared by mixing at room temperature or under heating. The excess amount is preferably within 0.2 times the molar amount.
- the mixed ionic liquid can be obtained, for example, by mixing the ionic liquids prepared as described above at an appropriate composition ratio.
- the amount of the ionic liquid for dissolving the transcription factor decoy since it is necessary to first dissolve the transcription factor decoy, it is necessary to use an ionic liquid having high solubility. After the decoy is dissolved, it is important to dilute with a diluting ionic liquid to bring the solubility in the mixed ionic liquid closer to saturation. Therefore, it is necessary to set the amount of the ionic liquid for dissolving the decoy to 3 to 3000 times the amount of the transcription factor decoy.
- the amount of the appropriate ionic liquid used is more preferably 3 to 1000 times, particularly preferably 3 to 800 times the amount of decoy.
- the concentration of the fatty acid-based ionic liquid in the external preparation composition of the present invention is greatly influenced by the shape of the external preparation, but for example, 10 to 50 w / w% as a liquid, for example, about 0.008 to 30 w as an ointment / w% is preferred.
- a more preferable concentration in the ointment preparation is 0.01 to 20 w / w%, and a most preferable concentration is 0.01 to 10 w / w%.
- the concentration of the ionic liquid in the external preparation composition is also related to the amount of transcription factor decoy used, and if the amount of transcription factor decoy used is small, the amount of fatty acid-based ionic liquid used may be relatively small. become.
- levulinic acid triethanolamine salt or levulinic acid diethanolamine salt it is desirable to add a concentration of about 3 to 3000 times the decoy concentration.
- a preferable concentration of the single ionic liquid is 3 to 200 times the decoy concentration.
- a particularly preferred concentration of the single ionic liquid is 3 to 100 times the decoy concentration.
- a mixed ionic liquid obtained by mixing a plurality of ionic liquids can be used.
- one or more ionic liquids that are diethanolamine salts or triethanolamine salts of fatty acids having 2 to 5 carbon atoms can be used as the ionic liquid for dissolution (ionic liquid (I)).
- the ionic liquid for dilution (ionic liquid (II)) one or more ionic liquids which are diisopropanolamine salts or triisopropanolamine salts of fatty acids having 2 to 20 carbon atoms can be used.
- the composition ratio of the mixed ionic liquid is the type of fatty acid in the ionic liquid for dilution (specifically, the fatty acid in the ionic liquid for dilution is (1) a fatty acid having 2 to 5 carbon atoms, and (2) a fatty acid having 14 to 20 carbon atoms. , (3) the case of a fatty acid having 6 to 13 carbon atoms), the preferred range varies.
- examples of the “fatty acid having 2 to 5 carbon atoms” include glycolic acid, methoxyacetic acid, ethoxyacetic acid, levulinic acid, and lactic acid.
- Preferred examples include glycolic acid, methoxyacetic acid, and levulinic acid. . Particularly preferred is levulinic acid.
- examples of the “fatty acid having 6 to 13 carbon atoms” include 2-ethylhexanoic acid, capric acid and the like, with capric acid being preferred.
- examples of the “fatty acid having 14 to 20 carbon atoms” include myristic acid, isostearic acid, oleic acid and the like, and preferred examples include isostearic acid and oleic acid.
- ionic liquid (I)) which is a diethanolamine salt or triethanolamine salt of a fatty acid having 2 to 5 carbon atoms, and a triisopropanolamine salt or diisopropanolamine salt of a fatty acid having 2 to 5 carbon atoms
- ionic liquid (I): ionic liquid (II) can be in a range of 1: 1 to 1: 5.
- ionic liquid (I) levulinic acid triethanolamine salt
- levulinic acid triisopropanolamine salt levulinic acid triisopropanolamine salt
- ionic liquid (II) levulinic acid triisopropanolamine salt
- ionic liquid (I) levulinic acid diethanolamine salt
- levulinic acid triisopropanolamine salt levulinic acid triisopropanolamine salt
- the weight ratio of liquid (I): ionic liquid (II) is preferably in the range of 1: 1 to 1: 8, more preferably 1: 1 to 1: 4.
- An ionic liquid that is a diethanolamine salt or triethanolamine salt of a fatty acid having 2 to 5 carbon atoms is used as the ionic liquid for dissolution (ionic liquid (I)), and the ionic liquid for dilution (ionic liquid (II))
- ionic liquid (I): ionic liquid (II) 1: 1
- Mixed ionic liquids with a composition ratio of ⁇ 1: 50 can be used.
- ionic liquid (I) levulinic acid triethanolamine salt
- diisopropanolamine salt of isostearic acid is used as the ionic liquid for dilution (ionic liquid (II)
- an ionic liquid that is a diethanolamine salt or triethanolamine salt of a fatty acid having 2 to 5 carbon atoms is used, and the ionic liquid for dilution (ionic liquid (II))
- ionic liquid (II) weight in the range of 40: 1 to 2: 1
- a ratio of mixed ionic liquids can be used.
- ionic liquid (I) levulinic acid triethanolamine salt
- diisopropanolamine salt of capric acid ionic liquid for dilution
- an ionic liquid that is a diethanolamine salt or triethanolamine salt of a fatty acid having 2 to 5 carbon atoms as an ionic liquid for dissolution (ionic liquid (I))
- An ionic liquid (IIa) which is an amine salt can be used.
- levulinic acid triisopropanolamine salt ionic liquid (II)
- isostearic acid diisopropanolamine salt ionic liquid (IIa)
- the decoy concentration in the ionic liquid should be set as much as possible in consideration of the transcription factor decoy content (concentration) in the preparation. It is adjusted to approach. For example, when the concentration of the transcription factor decoy is 0.0001 to 0.5 w / w%, the composition ratio of the ionic liquid for dissolution and the ionic liquid for dilution is adjusted with reference to the decoy solubility shown in Example 2 it can.
- the concentration of the transcription factor decoy in the preparation is 0.02%
- levulinic acid triethanolamine salt is used as the ionic liquid for dissolution (ionic liquid (I))
- the weight ratio of the mixed ionic liquid is preferably in the range of 1: 0 to 1:30, with the levulinic acid triethanolamine salt being 1.
- the weight ratio is more preferably in the range of 1: 2 to 1:20, and still more preferably in the range of 1: 2 to 1:13.
- the “external preparation composition” is used as a concept including both a non-aqueous external preparation composition and a hydrous external preparation composition.
- the “non-aqueous external preparation composition” is an external preparation composition that does not contain water as a component. In the non-aqueous external preparation composition, the occluded / adsorbed moisture contained in the reagent is not considered.
- the “hydrated external preparation composition” contains water as a constituent element. The amount of water contained varies depending on the shape of the preparation, but it is desirable that the amount of water be sufficiently mixed with the base and uniformly dispersed. The water concentration in the preparation is preferably about 10% or less.
- the non-aqueous external preparation composition of this invention can contain an organic solvent further.
- organic solvent refers to a solvent that functions to dilute and solvate a transcription factor decoy in a fatty acid-based ionic liquid. Furthermore, what works to improve transdermal absorbability with respect to the skin surface is desirable.
- ethers such as THF, butyl ether, polyethylene glycol methyl ether, ketones such as methyl isobutyl ketone, lower alkyl carboxylic acid esters such as ethyl acetate, propyl acetate, and ethyl butyrate such as diethyl sebacate and isopropyl myristate , Fatty acid esters such as diisopropyl adipate, myristyl palmitate, stearyl stearate, myristyl myristate, oleic acid triglyceride, lignocerate, ceryl cellophosphate, lacseryl lactolate, carbonate esters such as propylene carbonate, for example olive oil, And vegetable oils such as palm oil.
- ethers such as THF, butyl ether, polyethylene glycol methyl ether, ketones such as methyl isobutyl ketone, lower alkyl carboxylic acid esters such as eth
- Preferable examples include fatty acid esters such as isopropyl myristate and diethyl sebacate, and vegetable oils such as coconut oil and olive oil.
- higher alcohols such as benzyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, 2-octyldodecanol, such as ethanol, propanol, isopropanol, n-butanol, pentanol, octanol,
- Examples thereof include lower alcohols having 1 to 12 carbon atoms such as dodecanol, and polyhydric alcohols such as ethylene glycol, glycerin, propylene glycol, and 1,3-butylene alcohol.
- Preferable examples include ethanol, isopropanol, ethylene glycol, and propylene glycol.
- the presence / absence and addition amount of these organic solvents can be appropriately selected as necessary.
- a range of 0.5 to 10 w / w% is preferable.
- the non-aqueous external preparation composition of the present invention can further contain a chelating agent.
- the “chelating agent” refers to a chelating agent used for removing divalent metal ions such as Zn in order to suppress the activity of a DNA-degrading enzyme present on the skin surface. Specific examples include those that can be used for this purpose and have less skin irritation.
- edetic acid disodium salt EDTA ⁇ 2Na
- acetyl acetate ester such as acetyl acetate methyl ester, acetyl acetate ethyl ester, etc.
- EDTA * 2Na can be mentioned.
- the “external preparation” in the present specification can be used in various dosage forms depending on the target disease and intended use. For example, liquids, gels, ointments, creams, lotions, patches and the like can be mentioned. Moreover, the manufacturing method can be performed by adopting pharmacologically widely used means. Furthermore, as other additives, known antioxidants, preservatives, thickeners, and preservatives that are generally used can be appropriately used. Examples of the antioxidant include ascorbic acid, sodium bisulfite, sodium sulfite, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, tocopherol, sodium pyrosulfite, butylhydroxyanisole, propyl gallate and the like.
- preservatives include benzoic acid, sodium benzoate, sorbic acid, sodium sorbate, sodium dehydroacetate, paraoxybenzoic acid, sodium paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate (propylparaben), paraoxybenzoic acid
- examples thereof include butyl, isopropyl paraoxybenzoate, isobutyl paraoxybenzoate, propionic acid, sodium propionate, benzalkonium chloride, salicylic acid or a mixture thereof.
- Preferable examples include methylparaben, propylparaben, benzalkonium chloride and salicylic acid or a mixture thereof.
- the thickener is a substance that is solid at room temperature and hardly soluble in water.
- examples of the inorganic material include amorphous silicon dioxide, kaolin (gypsum), diatomaceous earth, talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium silicate, calcium silicate, calcium phosphate, barium sulfate and the like. Can do.
- examples of the organic material include crystalline cellulose. Preferable examples include light anhydrous silicic acid.
- the external preparation composition of the present invention can be prepared by dissolving or suspending a medicinal component in a constituent component serving as a base of a preparation.
- a base of the external preparation composition for example, in an ointment, white petrolatum, liquid paraffin, gelled hydrocarbon and the like can be used as a base.
- Gelled hydrocarbons are gels of hydrocarbons such as liquid paraffin, paraffin, isoparaffin, squalane, squalene, and polybutene. In particular, liquid paraffin gelled with polyethylene resin and oil / fat gelled with rubber / elastomer are preferred.
- plastibase obtained by gelling liquid paraffin (JP) with 5 to 10% by weight polyethylene resin, poroid (trade name), and hydrophilicity obtained by adding glycerin fatty acid ester to gelled hydrocarbon
- examples thereof include gelled hydrocarbons (Plastic base hydrophilic (trade name)).
- oils such as squalane, liquid paraffin, petrolatum, lanolin, solid paraffin, beeswax and the like, emulsified by adding water, a surfactant, a moisturizer and the like. It is done.
- liquid preparation examples include, for example, a mixed solution of alcohols such as isopropanol, ethanol, propylene glycol, and glycerin, and oils and fats such as olive oil and soybean oil, and water.
- an adhesive is used as a base.
- the pressure-sensitive adhesive mentioned here mainly comprises an elastomer, a tackifier, a softener, a filler, an antioxidant and the like.
- softeners, fillers, and antioxidants can be appropriately increased or decreased as necessary.
- elastomer examples include styrene-isoprene-styrene block (hereinafter referred to as SIS) copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butadiene rubber-styrene block copolymer, styrene-butadiene rubber, examples thereof include synthetic rubbers such as polyisoprene, polyisobutylene, polybutene, butyl rubber, and silicon rubber, for example, acrylic resins such as polymethyl acrylate and polymethyl methacrylate, and natural rubber.
- SIS styrene-isoprene-styrene block
- SIS styrene-butadiene-styrene block copolymer
- styrene-ethylene-butadiene rubber-styrene block copolymer examples include synthetic rubbers such as polyisoprene
- Preferred examples include those based on rubber polymers such as styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, polybutene, polyisoprene, butyl rubber, and natural rubber. These may be used alone or in combination of two or more. Moreover, the said resin film may be used independently and 2 or more types may be laminated
- rubber polymers such as styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, polybutene, polyisoprene, butyl rubber, and natural rubber. These may be used alone or in combination of two or more. Moreover, the said resin film may be used independently and 2 or more types may be laminated
- the tackifier includes alicyclic hydrocarbon resin, polyterpene resin, aliphatic hydrocarbon resin, polystyrene resin, rosin, hydrogenated rosin and the like.
- Preferable examples include alicyclic hydrocarbon resins.
- the softener include petroleum softeners such as process oil and low molecular weight polybutene, fatty oil softeners such as castor oil and coconut oil, and purified lanolin.
- Examples of the filler include zinc oxide, titanium oxide, calcium carbonate, silicic acid and the like.
- NF- ⁇ B induces the expression of many inflammation-related genes, so NF- ⁇ B decoy exerts a multifaceted anti-inflammatory effect by suppressing the expression of those genes, and also because of its action specificity, steroids It is expected to have fewer side effects than Currently, clinical application of this decoy for atopic dermatitis is being investigated.
- the external preparation composition of the present invention produced as described above has low toxicity and needs to suppress gene transcription control by a transcription factor that binds to the transcription factor decoy contained in the external preparation composition.
- Suffering from diseases that are expected to improve the pathological condition by suppressing the transcriptional regulation such as humans or other mammals (eg, mice, rats, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) It can be administered transdermally to a treated animal.
- the administration protocol of the external preparation composition of the present invention varies depending on the administration subject, target disease, symptom, etc., but for example, when used for the treatment of adult atopic dermatitis, NF- Appropriate amount of ⁇ B decoy (usually about 0.1 mg to 1 g, preferably about 1 to 500 mg) is administered transdermally about 1 to 5 times a day, preferably about 1 to 3 times a day. Can do. If symptoms are particularly severe, the dose may be increased according to the symptoms.
- the extract was filtered, and the solvent was distilled off with an evaporator until the remaining amount was 0.15 ml. 100 ⁇ l of the obtained concentrated solution was collected, and the amount of decoy collected by HPLC was measured. The amount of decoy detected from the tape of the third skin layer was used as a scale (ng / layer) representing skin permeability.
- OVA-induced mouse DTH model (delayed allergic reaction model)
- OVA ovalbumin
- D-PBS Dulbecco's Phosphate-buffered Salines
- Freund's incomplete adjuvant was added to the OVA 10 mg / mL solution, and the mixture was shaken with a vortex (trade name) mixer for 5 minutes to form an emulsion to prepare an OVA / emulsion.
- OVA / emulsion was administered at 100 ⁇ L / site at two intradermal sites in the upper and lower abdomen of BALB / c mice (female 7 weeks old).
- Decoy administration For single administration, apply 20 mg of each preparation to the right foot 24 hours before secondary sensitization, and for secondary sensitization 1, 2 and 3 days for repeated administration. The drug was removed with wet cotton wool.
- OVA 2 mg / mL was administered subcutaneously at the center of the sole of the sensitized foot of the mouse at 50 ⁇ L / site.
- D-PBS (-) was administered to the non-sensitized foot at 50 ⁇ L / site.
- DTH reaction measurement 24 hours after the secondary sensitization the center of both feet was measured with a thickness gauge (Mitutoyo). The measurement was performed three times, and the average value was used as the foot thickness.
- Percutaneous absorption (inhibition of delayed allergic reaction) was evaluated using the inhibition rate (%) of foot thickness increase in the test drug administration group as an index relative to the increase in foot thickness in the decoy-free drug administration group (0% group). . Comparison between groups was performed by t-test.
- Non-aqueous liquid composition of NF- ⁇ B decoy is an easily soluble compound in water, and it was difficult to produce a non-aqueous external preparation. However, it could be dissolved in the following fatty acid-based ionic liquid, and NF- ⁇ B decoy could be made into a liquid.
- Nonaqueous external preparation composition (single ionic liquid) with levulinic acid-based ionic liquid Levulinic acid, equimolar amounts of diethanolamine and triethanolamine were weighed and mixed, and heated at 80 ° C. for 20 minutes to prepare two types of levulinic acid-based ionic liquids.
- NF- ⁇ B decoy represented by SEQ ID NO: 1 was weighed and added to about 1.0 g of two levulinic acid-based ionic liquids and heated at 80 ° C. for about 30 minutes. After cooling to room temperature, the decoy dissolution status was confirmed. As a result, the NF- ⁇ B decoy was dissolved in a levulinic acid ionic liquid of diethanolamine salt or triethanolamine salt, and a non-aqueous liquid preparation could be prepared. Furthermore, when the solubility of the NF- ⁇ B decoy in the above two types of ionic liquids was determined, it was found that the following Table 1 was obtained.
- Nonaqueous external preparation composition using glycolic acid ionic liquid Glycolic acid and equimolar amounts of diethanolamine and triethanolamine were weighed and mixed, and heated at 80 ° C. for 20 minutes to prepare two types of glycolic acid-based ionic liquids. 10 mg of the NF- ⁇ B decoy represented by SEQ ID NO: 1 was weighed and dissolved in about 100 mg of each ionic liquid of glycolic acid diethanolamine salt and glycolic acid triethanolamine salt. The decoy was dissolved in the ionic liquid to form a uniform solution, and a non-aqueous liquid preparation could be produced.
- Example 2 Non-aqueous liquid composition of NF- ⁇ B decoy (mixed ionic liquid) Since the transdermal absorbability of external preparations is affected by the drug concentration and drug environment (whether it is close to saturation, etc.), as shown below, NF- ⁇ B in a mixed ionic liquid solution centered on levulinic acid A decoy solution was prepared. In addition, the solubility of the NF- ⁇ B decoy in the mixed ionic liquid was determined.
- Solubility of NF- ⁇ B decoy in levulinic acid mixed ionic liquid (i): A mixed ionic liquid was prepared by adding levulinic acid triethanolamine salt to 1 and adding levulinic acid triisopropanolamine salt in a weight ratio of 1 to 9. The solubility of NF- ⁇ B decoy in these mixed ionic liquids was measured according to the method of Example 1. The results are shown in Tables 3-1 and 3-2 below.
- the solubility of NF- ⁇ B decoy increases the addition amount of ionic liquid (levulinic acid triisopropanolamine salt) with low decoy solubility to ionic liquid (levulinic acid triethanolamine salt) with high decoy solubility. It was shown that it is greatly reduced by this. That is, as shown in Tables 3-1 and 3-2, when there are more ionic liquids with low decoy solubility than about 1: 2 with respect to ionic liquids with high decoy solubility, the decoy solubility drastically decreases. Became clear.
- levulinic acid diisopropanol salt decreased decoy solubility more rapidly than the addition of levulinic acid triisopropanolamine salt.
- the levulinic acid diethanol salt has a high decoy solubility, but when the levulinic acid triisopropanolamine salt is added in an amount of 2 to 3 times, the solubility greatly decreases.
- capric acid diisopropanol salt drastically decreases the decoy solubility only by adding a small amount.
- Example 3 NF- ⁇ B decoy ointment preparation An ionic liquid solution in which decoy was dissolved was mixed with a base for external preparations, and the preparation of various external preparation compositions was examined. First, a decoy ointment preparation was prepared by mixing with an ointment base, and the effect of the ionic liquid on the skin permeability of the decoy was confirmed. (1) Effect of levulinic acid ionic liquid in ointment formulation: Levulinic acid and triethanolamine were weighed out and mixed. An appropriate amount of propyl gallate was added thereto and heated at 80 ° C. for 20 minutes.
- the obtained viscous solution is weighed at room temperature, and the NF- ⁇ B decoy represented by SEQ ID NO: 1 is added to it and dissolved by heating at 40 ° C. for 2 days to dissolve the NF- ⁇ B decoy.
- An ionic liquid solution of triethanolamine levulinate was prepared. Gelled hydrocarbons, light anhydrous silicic acid, methyl paraoxybenzoate, and disodium edetate were weighed and mixed with the ionic liquid solution. Further, a solution in which isostearic acid and diisopropanolamine were heated and mixed at 80 ° C. for 20 minutes and an appropriate amount of propylene carbonate were added to prepare a total of 50.00 g of decoy ointment preparation.
- the ointment preparation using the levulinic acid-based mixed ionic liquid has better skin permeation than the ointment preparation using the single ionic liquid of levulinic acid trieta. It turns out that it gives sex. That is, from the results in Table 9, it was shown that the ointment preparation having a composition in which the decoy concentration in the ionic liquid is closer to saturation has better skin permeability.
- the ionic liquid for dissolution levulinic acid triethanolamine salt
- the ionic liquid for dilution diisopropanolamine salt of isostearic acid
- the ionic liquid for dissolution 1: 0 with the ionic liquid for dissolution as 1. It was revealed that it can be used at a composition ratio in the range of ⁇ 1: 22.
- the addition of an ionic liquid for dilution with low decoy solubility to lower the decoy solubility of the ionic liquid further improves the transdermal absorbability of the decoy. . Therefore, by using a combination of the dissolving ionic liquid and the diluting ionic liquid, it becomes possible to select an ionic liquid having an appropriate solubility for the amount of decoy used.
- Example 4 Effect of Decoy Concentration in Ointment Formulation on Skin Permeability
- the influence of the decoy concentration in the ointment formulation on the skin permeability of NF- ⁇ B decoy was examined. Reagents were weighed out according to the composition (w / w%) shown in Table 11 below to prepare a total of 50.00 g of decoy ointment preparation. The skin permeability (peeling test) and transdermal absorbability (single administration) of these ointment preparations were evaluated, and the results are also shown in Table 11.
- Example 5 Effect of Decoy Concentration in Ionic Liquid on Skin Permeability
- the skin permeability of NF- ⁇ B decoy is affected by the decoy concentration in the ointment formulation as shown in Example 4, and Example 3
- the decoy concentration in the ionic liquid (whether or not it is close to the saturation concentration) has a great influence. Therefore, the effect of the ionic liquid decoy concentration in the preparation on skin permeability was examined.
- Reagents were weighed out according to the composition (w / w%) shown in Table 12 below to prepare a total of 50.00 g of decoy ointment preparation.
- the skin permeability (peeling test) of these ointment formulations was evaluated, and the results are also shown in Table 12.
- the ionic liquid concentration required to dissolve the decoy and enhance skin permeability is, for example, in the range of about 3 to less than 16 times the decoy concentration in the case of levulinic acid triethanolamine salt. I thought it would be nice. Further, since the saturation solubility in the case of levulinic acid triethanolamine salt is 28.3 w / w% (Table 1), the saturation in Production Example 1 and Production Example 6 is 44% and 21%. Therefore, it was shown that when the degree of saturation in the ionic liquid is about 40% or more, the skin permeability becomes remarkable, and when it becomes about 21% or less, the skin permeability is lost. This result is considered to be applicable to other ionic liquids and mixed ionic liquids as well.
- Example 6 Effect of Decoy Concentration in Mixed Ionic Liquid on Skin Permeability
- the higher the concentration of a drug dissolved in the base the more osmotic pressure due to the concentration works, and the skin permeability improves.
- the change in the decoy concentration in a single ionic liquid was examined, and it was found that the decoy concentration greatly affects the skin permeability. Therefore, it was examined whether the same applies to the mixed ionic liquid.
- NF- ⁇ B decoy represented by SEQ ID NO: 1, according to the composition (w / w%) in Table 13 below
- a decoy ointment preparation was prepared so that the total amount was 50 g in the same manner as in Example 3. did.
- the transdermal absorbability (single administration) of NF- ⁇ B decoy in these ointment formulations was evaluated, and the results are shown in Tables 13 and 14 and FIG.
- Example 7 Effect of decoy concentration in mixed ionic liquid-based ointment formulations
- concentration of mixed ionic liquid was made constant, and how changes in decoy concentration in the formulation affected skin permeability was examined.
- Reagents were weighed out according to the composition (w / w%) shown in Table 15 below, and a total of 50.00 g of decoy ointment preparation was prepared according to Example 3.
- the skin permeability (peeling test) and transdermal absorbability (single administration) of these ointment preparations were evaluated. The results are also shown in Table 15.
- the skin permeation amount of the decoy increased as the decoy concentration increased. Also, correspondingly, the effect was also manifested in the transdermal absorbability test (delayed allergic reaction inhibition rate) of mice.
- Example 8 Concentration effect of mixed ionic liquid in low concentration decoy ointment formulation When the decoy concentration in the formulation was low, it was examined how the change in the concentration of the mixed ionic liquid affects skin permeability. Reagents were weighed out according to the composition (w / w%) shown in Table 16 below, and a total of 50.00 g of decoy ointment preparation was prepared according to Example 3. The skin permeability (peeling test) and transdermal absorbability (single administration) of these ointment preparations were evaluated. The results are also shown in Table 16.
- the decoy concentration in the ionic liquid when the decoy concentration in the ionic liquid is kept constant and the decoy concentration in the preparation is decreased, the decoy concentration in the preparation can be reduced to 1/5 as shown in Production Example 17 and Production Example 18.
- skin permeability was found to be reduced to about 1/10.
- the transdermal absorbability test delayed allergic reaction inhibition rate
- Example 9 Effect of composition change of mixed ionic liquid (change in composition of ionic liquid for dissolution and ionic liquid for dilution) on skin permeability of decoy How change of composition of mixed ionic liquid affects skin permeability
- the composition of Production Example 14 was fixed, and only the ionic liquid for dilution (isostearic acid diisopropanolamine salt) and plastibase (trade name) in the preparation were varied, so that the ionic liquid for dissolution and for dilution were used.
- the transdermal absorbability (single administration) of these ointment preparations was evaluated. The results are also shown in Table 17 below.
- Example 10 Effect of combination of various ionic liquids on skin permeability of decoy Mixed ionic liquids were prepared using various ionic liquids, and how changes in the composition affect skin permeability. investigated. Reagents were weighed out according to the composition (w / w%) shown in Table 18 below, and a total of 50.00 g of decoy ointment preparation was prepared according to Example 3. These ointment formulations were evaluated for skin permeability (peeling test) and mouse transdermal absorbability (single administration). The results are also shown in Table 18.
- the composition of the mixed ionic liquid in Table 18 was set to a value close to the saturation solubility from the decoy concentration used and the solubility of the decoy in the various mixed ionic liquids described in Example 2.
- skin permeability of the decoy was shown in the skin permeability test (peeling test layer 3) and the mouse transdermal absorbability test.
- the decoy can be appropriately absorbed percutaneously by designing the composition of the ionic liquid in consideration of the decoy solubility and the decoy concentration of the ionic liquid.
- Example 11 Decrease effect of repeated administration of formulation and decoy concentration in formulation
- Example 8 Even as a decoy concentration in the formulation of 0.001% The result was that it penetrated the skin and had a delayed-type allergic reaction inhibitory effect. Therefore, if repeated administration is performed, it is expected that the decoy concentration can be further reduced. Therefore, the reagents were weighed out according to the composition (w / w%) shown in Table 19 below, and a total of 50.00 g of decoy ointment preparation was prepared according to Example 3. The mouse transdermal absorbability of decoy in these ointment formulations was evaluated according to the above repeated administration protocol. The results are also shown in Table 19.
- the external preparation composition of the present invention exhibits excellent solubility and transdermal absorbability of the transcription factor decoy, it can be a simple and effective DDS preparation of the transcription factor decoy.
- the use of the mixed ionic liquid shows extremely excellent transdermal absorbability even at a decoy concentration of about 1/10000 that is currently in clinical trials (2%). Therefore, the external preparation composition of the present invention is a decoy-type nucleic acid pharmaceutical. Can greatly reduce the cost of medical care and contribute to the medical economy.
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Abstract
Description
以上のような背景から、転写因子デコイの非水系の新たな皮膚外用剤の開発が望まれている状況であった。
また、本発明者らは、複数の脂肪酸系イオン液体を混合することによって、転写因子デコイの外用剤中の溶解度をコントロールできることを見出した。そして、溶解度をコントロールすることにより、転写因子デコイの経皮吸収性を促進できることを見出した。即ち、本発明の製剤は、転写因子デコイの溶解度コントロールにより、経皮吸収性が向上しているため、従来の報告にはない、デコイが非常に低濃度(0.0001~1w/w%)の製剤であっても、デコイが経皮吸収され、効果が発現できることを見出した。
本発明者らは、これらの知見により本発明を完成した。
[1]炭素数2~20の脂肪酸と炭素数4~12の有機アミン化合物とから得られる脂肪酸系イオン液体に、転写因子デコイを溶解して含有する、非水系外用剤組成物。
[2]炭素数2~20の脂肪酸が、グリコール酸、メトキシ酢酸、レブリン酸、カプリン酸およびイソステアリン酸からなる群より選択される1つ以上である、上記[1]に記載の外用剤組成物。
[3]炭素数4~12の有機アミン化合物が、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミンおよびトリイソプロパノールアミンからなる群より選択される1つ以上である、上記[1]または[2]に記載の外用剤組成物。
[4]脂肪酸系イオン液体が複数の脂肪酸系イオン液体の混合イオン液体である、上記[1]~[3]のいずれかに記載の非水系外用剤組成物。
[5]混合イオン液体が、炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体(I)と、炭素数2~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(II)との混合物である、上記[4]に記載の非水系外用剤組成物。
[6]イオン液体(I)の炭素数2~5の脂肪酸がグリコール酸、メトキシ酢酸およびレブリン酸からなる群より選択される、上記[5]に記載の非水系外用剤組成物。
[7]イオン液体(I)の炭素数2~5の脂肪酸がレブリン酸である、上記[6]に記載の非水系外用剤組成物。
[8]イオン液体(II)が、炭素数2~5の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、上記[5]~[7]のいずれかに記載の非水系外用剤組成物。
[9]イオン液体(II)の炭素数2~5の脂肪酸がレブリン酸である、上記[8]に記載の非水系外用剤組成物。
[10]イオン液体(I)とイオン液体(II)と重量比が、2:1~1:10の範囲である、上記[8]または[9]に記載の非水系外用剤組成物。
(10a)イオン液体(I)とイオン液体(II)と重量比が、1:1~1:5の範囲である、上記[8]または[9]に記載の非水系外用剤組成物。
[11]イオン液体(II)が、炭素数6~13の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、上記[5]~[7]のいずれかに記載の非水系外用剤組成物。
[12]イオン液体(II)の炭素数6~13の脂肪酸がカプリン酸である、上記[11]に記載の非水系外用剤組成物。
[13]イオン液体(I)とイオン液体(II)と重量比が、40:1~2:1の範囲である、上記[11]または[12]に記載の非水系外用剤組成物。
(13a)イオン液体(I)とイオン液体(II)と重量比が、10:1~2:1の範囲である、上記[11]または[12]に記載の非水系外用剤組成物。
[14]イオン液体(II)が、炭素数14~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、上記[5]~[7]のいずれかに記載の非水系外用剤組成物。
[15]イオン液体(II)の炭素数14~20の脂肪酸がイソステアリン酸である、上記[14]に記載の非水系外用剤組成物。
[16]イオン液体(I)とイオン液体(II)と重量比が、1:1~1:50の範囲である、上記[14]または[15]に記載の非水系外用剤組成物。
(16a)イオン液体(I)とイオン液体(II)と重量比が、1:2~1:30の範囲である、上記[14]または[15]に記載の非水系外用剤組成物。
[17]炭素数14~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(IIa)をさらに含有する、上記[8]に記載の非水系外用剤組成物。
[18]イオン液体(IIa)の炭素数14~20の脂肪酸がイソステアリン酸である、上記[17]に記載の非水系外用剤組成物。
[19]イオン液体(I)とイオン液体(II)および(IIa)と重量比が、1:1~1:50の範囲である、上記[17]または[18]に記載の非水系外用剤組成物。
(19a)イオン液体(I)とイオン液体(II)および(IIa)と重量比が、1:2~1:30の範囲である、上記[17]または[18]に記載の非水系外用剤組成物。
[20]転写因子デコイの濃度が0.0001~1w/w%である、上記[1]~[19]のいずれかに記載の非水系外用剤組成物。
[21]転写因子デコイの濃度が0.0001~0.2w/w%である、上記[1]~[19]のいずれかに記載の非水系外用剤組成物。
[22]炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体が、転写因子デコイ濃度の3~3000倍の濃度で含有される、上記[1]~[21]のいずれかに記載の非水系外用剤組成物。
[23]炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体が、転写因子デコイ濃度の3~1000倍の濃度で含有される、上記[1]~[21]のいずれかに記載の非水系外用剤組成物。
[24]複数の脂肪酸系イオン液体の混合イオン液体を含有し、混合イオン液体の濃度が0.008~30w/w%である、上記[22]または[23]に記載の非水系外用剤組成物。
[25]有機溶媒が添加されている、上記[1]~[24]のいずれかに記載の非水系外用剤組成物。
[26]有機溶媒が、セバシン酸ジエチル、ミリスチン酸イソプロピルおよび炭酸プロピレンからなる群より選択される1つ以上である、上記[25]に記載の非水系外用剤組成物。
[27]キレート剤が添加されている、上記[1]~[26]のいずれかに記載の非水系外用剤組成物。
[28]キレート剤がエデト酸2ナトリウム塩である、上記[27]に記載の非水系外用剤組成物。
[29]軟膏基剤が添加されて軟膏製剤になっている、上記[1]~[28]のいずれかに記載の非水系外用剤組成物。
[30]軟膏基剤がゲル化炭化水素または白色ワセリンである、上記[29]記載の非水系外用剤組成物。
[31]転写因子がNF-κB、E2F、GATA-3、STAT-1、STAT-6、EtsおよびAP-1からなる群より選択される、上記[1]~[30]のいずれかに記載の非水系外用剤組成物。
[32]転写因子デコイが配列GGRHTYYHC(式中、RはAまたはGを、YはCまたはTを、HはA、CまたはTをそれぞれ意味する。)を含むNF-κBデコイである、上記[31]記載の非水系外用剤組成物。
[33]NF-κBデコイが配列GGATTTCCCまたはGGACTTTCCを含む、上記[32]記載の非水系外用剤組成物。
[34]転写因子デコイが配列TTTSSCGS(式中、SはGまたはCを意味する。)を含むE2Fデコイである、上記[31]記載の非水系外用剤組成物。
[35]E2Fデコイが配列TTTCCCGCを含む、上記[34]に記載の非水系外用剤組成物。
[36]転写因子デコイが配列WGATAR(式中、WはAまたはTを、RはAまたはGをそれぞれ意味する)を含むGATA-3デコイである、上記[31]記載の非水系外用剤組成物。
[37]GATA-3デコイが配列AGATAGを含む、上記[36]に記載の非水系外用剤組成物。
[38]転写因子デコイが配列TTCNNNGAA(式中、NはA、G、TまたはCを意味する)を含むSTAT-1デコイである、上記[31]記載の非水系外用剤組成物。
[39]STAT-1デコイが配列TTCCGGGAAを含む、上記[38]記載の非水系外用剤組成物。
[40]転写因子デコイが配列TTCNNNNGAA(式中、NはA、G、TまたはCを意味する)を含むSTAT-6デコイである、上記[31]記載の非水系外用剤組成物。
[41]STAT-6デコイが配列TTCCCAAGAAを含む、上記[40]記載の非水系外用剤組成物。
[42]転写因子デコイが配列MGGAW(式中、MはAまたはCを、WはAまたはTをそれぞれ意味する)を含むEtsデコイである、上記[31]記載の非水系外用剤組成物。
[43]Etsデコイが配列CGGAAを含む、上記[42]記載の非水系外用剤組成物。
[44]転写因子デコイが配列TGASTMA(式中、SはGまたはCを、MはAまたはCをそれぞれ意味する)を含むAP-1デコイである、上記[31]記載の非水系外用剤組成物。
[45]AP-1デコイが配列TGAGTCAを含む、上記[44]記載の非水系外用剤組成物。
[46]上記[1]~[45]のいずれかに記載の非水系外用剤組成物中に含有される転写因子デコイに結合する転写因子による遺伝子転写制御を抑制することを必要とする哺乳動物に、該非水系外用剤組成物を経皮投与することを含む、該遺伝子転写制御の抑制方法。
[47]非水系外用剤組成物の製造のための、転写因子デコイ、および炭素数2~20の脂肪酸と炭素数4~12の有機アミン化合物とから得られる脂肪酸系イオン液体の使用。
[48]イオン液体が、炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体(I)と、炭素数2~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(II)との混合イオン液体である、上記[47]に記載の使用。
本発明におけるデコイが標的とする転写因子は、遺伝子の転写を調節している因子であってRNAポリメラーゼ以外の蛋白質であれば特に限定されないが、例えばNF-κB、E2F、GATA-3、STAT-1、STAT-6、Ets、AP-1等のような、創薬標的として開発が進められているものが好ましく挙げられる。
本明細書において「転写因子デコイ」とは、転写因子が本来結合するもしくは作用するゲノムDNA上の領域と競合的に転写因子と結合し得る核酸であれば特に制限はないが、典型的には、ゲノムDNA上の転写因子結合領域と同一もしくは実質的に同一の塩基配列を含み、通常は14~35塩基対、より好ましくは15~30塩基対、さらに好ましくは17~25塩基対、最も好ましくは18~22塩基対からなる二本鎖オリゴヌクレオチドである。「実質的に同一の塩基配列」とは、転写因子結合領域のコンセンサス配列において、1、2もしくは3個の塩基が他の塩基に置換された塩基配列であって、かつ該コンセンサス配列と同等以上(例えば、90%以上)の転写因子に対する結合性を有する配列をいう。目的の転写因子が実際に結合するゲノムDNA上の塩基配列は多種多様であり、コンセンサス配列と類似するが完全同一でないシスエレメント配列は数多く知られているので、当業者は公知のシスエレメントの配列情報に基づいて、容易に実質的に同一の塩基配列を設計することができる。尚、二本鎖オリゴヌクレオチドは二本鎖DNA、二本鎖RNA、DNA:RNAハイブリッドのいずれであってもよいが、好ましくは二本鎖DNAである。
(1)転写因子NF-κB:配列GGRHTYYHC(式中、RはAまたはGを、YはCまたはTを、HはA、CまたはTをそれぞれ意味する。)
(2)転写因子E2F:配列TTTSSCGS(式中、SはGまたはCを意味する。)
(3)転写因子GATA-3:WGATAR(式中、WはAまたはTを、RはAまたはGをそれぞれ意味する。)
(4)転写因子STAT-1:配列TTCNNNGAA(式中、NはA、G、TまたはCを意味する。)
(5)転写因子STAT-6:配列TTCNNNNGAA(式中、NはA、G、TまたはCを意味する。)
(6)転写因子Ets:配列MGGAW(式中、MはAまたはCを、WはAまたはTをそれぞれ意味する。)
(7)転写因子AP-1:配列TGASTMA(式中、SはGまたはCを、MはAまたはCをそれぞれ意味する。)
なお、2本鎖デコイオリゴヌクレオチドの修飾型として、ダンベル型デコイオリゴヌクレオチド、分子内ニックを有するダンベル型デコイオリゴヌクレオチド、ヘアピン型デコイオリゴヌクレオチドなども存在するが、本発明にかかる転写因子デコイにはこれらも含まれる。
(1a)NF-κBデコイ:配列GGATTTCCCまたはGGACTTTCC
(2a)E2Fデコイ:配列TTTCCCGC
(3a)GATA-3デコイ:配列AGATAG
(4a)STAT-1デコイ:配列TTCCGGGAA
(5a)STAT-6デコイ:配列TTCCCAAGAA
(6a)Etsデコイ:配列CGGAA
(7a)AP-1デコイ:配列TGAGTCA
5'-CCTTGAAGGGATTTCCCTCC-3'(配列番号1)、
5'-AGTTGAGGGGACTTTCCCAGGC-3'(配列番号2)、
5'-AGTTGAGGACTTTCCAGGC-3'(配列番号3)等、
(2b)E2Fデコイとして、例えば、
5'-CTAGATTTCCCGCG-3'(配列番号4)、
5'-CTAGATTTCCCGCGGATC-3'(配列番号5)等、
(3b)GATA-3デコイとして、例えば、
5'-AGCTTGAGATAGAGCT-3'(配列番号6)等、
(4b)STAT-1デコイとして、例えば、
5'-GATCTAGGGATTTCCGGGAAATGAAGCT-3'(配列番号7)、
5'-TGTGAATTACCGGAAGTG-3'(配列番号8)等、
(5b)STAT-6デコイとして、例えば、
5'-GATCAAGACCTTTTCCCAAGAAATCTAT-3'(配列番号9)等、
(6b)Etsデコイとして、例えば、
5'-AATTCACCGGAAGTATTCGA-3'(配列番号10)等、
(7b)AP-1デコイとして、例えば、
5'-AGCTTGTGAGTCAGAAGCT-3'(配列番号11)等
の塩基配列(転写因子の標的配列を下線で示す)からなる二本鎖オリゴヌクレオチドをそれぞれ挙げることができる。
本明細書において「炭素数2~20の脂肪酸系イオン液体」とは、炭素数2~20の脂肪酸と有機アミン化合物との等モルの溶融塩又は当モルの平衡混合物を表すが、使用する転写因子デコイの濃度や、他の添加物の影響を考慮し、脂肪酸又は有機アミンを過剰量、外用剤組成物中に添加することもできる。過剰量としては、0.2倍モル量以内が望ましい。有機アミン化合物としては、好ましくは炭素数4~12の有機アミン化合物が挙げられる。
本発明において「炭素数4~12の有機アミン化合物」とは、有機アミン化合物の内、炭素数が4~12のものを言う。好ましいものとしては、水酸基で置換された直鎖または分枝状アルキルアミン化合物を挙げることができる。より好ましいものとしては、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミン等を挙げることができる。
転写因子デコイの溶解度が高いイオン液体(溶解用イオン液体=イオン液体(I))としては、好ましくは、デコイの溶解度が10w/w%以上になるものを挙げることができる。更に好ましいものとしては、デコイの溶解度が20w/w%以上になるものを挙げることができる。特に好ましいものとしては、デコイの溶解度が28w/w%以上になるものを挙げることができる。
より具体的には、転写因子デコイの溶解度が高い溶解用イオン液体(イオン液体(I))として、炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩を挙げることができる。ここで炭素数2~5の脂肪酸としては、例えば、グリコール酸、メトキシ酢酸、レブリン酸等を挙げることができる。より好ましくは、レブリン酸を挙げることができる。したがって、転写因子デコイの溶解用イオン液体としては、例えば、レブリン酸ジエタノールアミン塩、レブリン酸トリエタノールアミン塩、グリコール酸ジエタノールアミン塩、グリコール酸トリエタノールアミン塩、メトキシ酢酸ジエタノールアミン塩、メトキシ酢酸トリエタノールアミン塩等を挙げることができる。
より具体的には、転写因子デコイの溶解度が低い希釈用イオン液体(イオン液体(II))として、炭素数2~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩を挙げることができる。好ましくは炭素数5~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩を挙げることができる。ここで炭素数5~20の脂肪酸としては、例えば、レブリン酸、カプリン酸、ミリスチン酸、イソステアリン酸、オレイン酸等を挙げることができる。より好ましくは、レブリン酸およびイソステアリン酸を挙げることができる。したがって、転写因子デコイの溶解度が低いイオン液体としては、例えば、レブリン酸ジイソプロパノールアミン塩、レブリン酸トリイソプロパノールアミン塩、カプリン酸ジイソプロパノールアミン塩、カプリン酸トリイソプロパノールアミン塩、イソステアリン酸ジイソプロパノールアミン塩、イソステアリン酸トリイソプロパノールアミン塩等を挙げることができる。好ましくはレブリン酸ジイソプロパノールアミン塩、レブリン酸トリイソプロパノールアミン塩、イソステアリン酸ジイソプロパノールアミン塩、イソステアリン酸トリイソプロパノールアミン塩等を挙げることができる。
混合イオン液体の組成比は、希釈用イオン液体の脂肪酸の種類(具体的には希釈用イオン液体の脂肪酸が、(1)炭素数2~5の脂肪酸、(2)炭素数14~20の脂肪酸、(3)炭素数6~13の脂肪酸である場合)に応じて、好ましい範囲が異なってくる。
本発明において「炭素数2~5の脂肪酸」としては、例えばグリコール酸、メトキシ酢酸、エトキシ酢酸、レブリン酸、乳酸等であり、好ましいものとしてはグリコール酸、メトキシ酢酸、レブリン酸を挙げることができる。特に好ましいものとして、レブリン酸を挙げることができる。
本発明において「炭素数6~13の脂肪酸」としては、例えば2-エチルヘキサン酸、カプリン酸等であり、好ましいものとしてカプリン酸を挙げることができる。
本発明において「炭素数14~20の脂肪酸」としては、例えばミリスチン酸、イソステアリン酸、オレイン酸等であり、好ましいものとしては、イソステアリン酸、オレイン酸を挙げることができる。
本明細書において「有機溶媒」とは、脂肪酸系イオン液体中の転写因子デコイを希釈し、溶媒和する働きを示すものを言う。更には、皮膚表面に対して経皮吸収性を向上させるために働きかけるものが望ましい。例えば、例えばTHF、ブチルエーテル、ポリエチレングリコールメチルエーテル等のエーテル類、例えばメチルイソブチルケトン等のケトン類、例えば酢酸エチル、酢酸プロピル、酪酸エチル等の低級アルキルカルボン酸エステル、例えばセバシン酸ジエチル、ミリスチン酸イソプロピル、アジピン酸ジイソプロピル、パルミチン酸ミリスチル、ステアリン酸ステアリル、ミリスチン酸ミリスチル、オレイン酸トリグリセリド、リグノセリン酸セリル、セロリン酸ラクセリル、ラクセル酸ラクセリル等の脂肪酸エステル類、例えば炭酸プロピレン等の炭酸エステル類、例えばオリーブ油、やし油等の植物油類等を挙げることができる。好ましいものとしては、ミリスチン酸イソプロピル、セバシン酸ジエチル等の脂肪酸エステル類、やし油、オリーブ油等の植物油類を挙げることができる。更には、例えば、ベンジルアルコール、ラウリルアルコール、ミリスチルアルコール、セチルアルコール、ステアリルアルコール、セトステアリルアルコール、2-オクチルドデカノール等の高級アルコール、例えばエタノール、プロパノール、イソプロパノール、n-ブタノール、ペンタノール、オクタノール、ドデカノール等の炭素数1~12の低級アルコール、又は例えばエチレングリコール、グリセリン、プロピレングリコール、1,3-ブチレンアルコール等の多価アルコール等を挙げることができる。好ましいものとしては、エタノール、イソプロパノール、エチレングリコール、プロピレングリコールを挙げることができる。
これら有機溶媒の添加の有無、添加量は、必要に応じて適宜選択することができる。好ましくは0.5~10w/w%の範囲を挙げることができる。
更に、その他の添加剤として、適宜、一般に使用される公知の抗酸化剤、防腐剤、増粘剤、保存剤を使用することができる。
抗酸化剤としてはアスコルビン酸、亜硫酸水素ナトリウム、亜硫酸ナトリウム、エリソルビン酸、酢酸トコフェロール、ジブチルヒドロキシトルエン、トコフェロール、ピロ亜硫酸ナトリウム、ブチルヒドロキシアニソール、没食子酸プロピルなどが挙げられる。
防腐剤としては、例えば安息香酸、安息香酸ナトリウム、ソルビン酸、ソルビン酸ナトリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸、パラオキシ安息香酸ナトリウム、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル(プロピルパラベン)、パラオキシ安息香酸ブチル、パラオキシ安息香酸イソプロピル、パラオキシ安息香酸イソブチル、プロピオン酸、プロピオン酸ナトリウム、塩化ベンザルコニウム、サリチル酸又はその混合物等を挙げることができる。好ましくは、メチルパラベン、プロピルパラベン、塩化ベンザルコニウムとサリチル酸又はその混合物等を挙げることができる。
増粘剤としては、常温で固体であり、水に難溶な物質のことを言う。例えば、無機材料としては、例えば非晶性二酸化ケイ素、カオリン(石膏)、珪藻土、タルク、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸マグネシウム、ケイ酸カルシウム、リン酸カルシウム、硫酸バリウム等のものを挙げることができる。有機材料としては、例えば、結晶セルロース等を挙げることができる。好ましいものとしては、軽質無水ケイ酸を挙げることができる。
クリーム剤においては、例えば、スクワラン、流動パラフィン、ワセリン、ラノリン、固形パラフィン、蜜ロウ等の油分と、水と、界面活性剤、保湿剤などを加えて乳化したものを基剤とすることが挙げられる。
液剤においては、例えば、イソプロパノール、エタノール、プロピレングリコール、グリセリン等のアルコール類と、例えばオリーブ油、ダイズ油等の油脂類と水との混合溶液を基剤とすることが挙げられる。
貼付剤においては、粘着剤が基剤とされる。ここで言う粘着剤とは、主にエラストマーと粘着付与剤、軟化剤、充填剤、抗酸化剤等からなるものである。特に、軟化剤、充填剤、抗酸化剤は必要に応じ適宜増減、削除できる。
上記エラストマーとしては、例えばスチレン-イソプレン-スチレン・ブロック(以下SISという)共重合体、スチレン-ブタジエン-スチレンブロック共重合体、スチレン-エチレン-ブタジエンゴム-スチレンブロック共重合体、スチレン-ブタジエンゴム、ポリイソプレン、ポリイソブチレン、ポリブテン、ブチルゴム、シリコンゴム等の合成ゴム、例えばポリアクリル酸メチル、ポリメタクリル酸メチル等のアクリル酸系樹脂、天然ゴムなどを挙げることができる。好ましいものとしては、スチレン-イソプレン-スチレン・ブロック共重合体、スチレン-ブタジエンゴム、ポリブテン、ポリイソプレン、ブチルゴム、天然ゴム等のゴム系重合体をベースとするものが挙げられる。これらは単独で使用されてもよく、2種以上が併用されてもよい。また、上記樹脂フィルムは単独で使用されてもよく、二種以上が積層されて使用されてもよい。
上記軟化剤としては、例えばプロセスオイル、低分子ポリブテン等の石油系軟化剤、例えばヒマシ油、ヤシ油等の脂肪油系軟化剤、精製ラノリン等を挙げることができる。
上記充填剤としては、例えば酸化亜鉛、酸化チタン、炭酸カルシウム、ケイ酸類などのものを挙げることができる。
上記のようにして製造される本発明の外用剤組成物は低毒性であり、該外用剤組成物中に含有される転写因子デコイに結合する転写因子による遺伝子転写制御を抑制することを必要とするヒトまたは他の哺乳動物(例、マウス、ラット、ウサギ、ヒツジ、ブタ、ウシ、ネコ、イヌ、サルなど)、例えば、当該転写制御を抑制することにより病態の改善が期待される疾患に罹患した動物などに対して、経皮的に投与することができる。
厚生労働省発行の「局所皮膚適用製剤の後発医薬品のための生物学的同等性試験ガイドライン」の方法に基づき、一部改変してデコイの皮膚透過性を評価した。
(a)定性評価試験:
被験者前腕部前面の半径1cmの範囲に軟膏製剤を塗布し、1時間経過後、塗布部位の軟膏製剤を丁寧に拭き取り、粘着テープにて貼付、剥離を繰り返した。
試料テープの最初の2枚は廃棄し、3枚目以降の5枚ずつを皮膚1層(試験管1本分)とし、第1層から第3層まで区分してテープを取得した。あらかじめ抽出溶媒(メタノール3mlと10mM Tris-EDTA(pH7.0)0.5ml)を試験管に入れておき、剥離したテープを直ちに抽出溶媒に浸した。ピーリング終了後、テープを裁断し超音波処理をした。抽出液をろ過し、残量0.2mlになるまでエバポレーターで溶媒を留去した。
得られた濃縮溶液を100μl採取し、HPLCによりデコイの有無を確認した。
被験者前腕部前面の半径15mmの範囲に軟膏製剤を塗布し、30min経過後、塗布部位の軟膏製剤を丁寧に拭き取り、粘着テープにて貼付、剥離を繰り返した。(1)と同様にして、皮膚第1層から第3層のテープを取得した。あらかじめ抽出溶媒(超純水2mlと10mM Tris-EDTA(pH7.0)0.5ml)を試験管に入れておき、剥離したテープを直ちに抽出溶媒に浸した。ピーリング終了後、テープを裁断し超音波処理をした。抽出液をろ過し,残量0.15mlになるまでエバポレータで溶媒を留去した。
得られた濃縮溶液を100μl採取し、HPLCにより採取されたデコイ量を測定した。皮膚第3層のテープから検出されたデコイ量を皮膚透過性を表す尺度(ng/層)とした。
(1) OVAの調製および1次感作
ovalbumin(OVA)を所定量秤量し、D-PBS [Dulbecco's Phosphate-buffered Salines](-)にてOVA溶液 5mg/mLを調製した。OVA 10mg/mL溶液に等量のフロイント不完全アジュバントを添加し、ボルテックス(商品名)ミキサーで5分間振蘯してエマルジョンを形成させ、OVA/エマルジョンを調製した。
BALB/cマウス(雌7週齢)の腹部の上部と下部の皮内2ヶ所にOVA/エマルジョンを100μL/siteで投与した。
(2) デコイ投与
単回投与の場合は2次感作24時間前、反復投与の場合は2次感作1、2および3日前に、右足に各製剤20mgを塗布し、24時間後にぬるま湯を湿らせた脱脂綿にて薬剤を除去した。
(3) 2次感作
1次感作より9日後に2次感作を行った。OVAを所定量秤量し、D-PBS(-)でOVA 2mg/mL溶液を調製した。マウスの右足を感作足、左足を非感作足とした。マウス感作足裏中央部の皮下にOVA 2mg/mLを50μL/siteで投与した。また、非感作足にはD-PBS(-)を50μL/siteで投与した。
(4) DTH反応測定
2次感作より24時間後に、両足中央部をシックネスゲージ(Mitutoyo製)で測定した。測定は3回行い、その平均値を足厚とした。
評価は以下の式により、足厚の増加幅を算出した。
(感作足 足厚)-(非感作足 足厚)=(足厚増加幅)
なお、2次感作時の投与の影響により、足部に内出血が認められた個体は除外した。
デコイ非含有製剤投与群(0%群)における足厚増加幅に対する、試験製剤投与群における足厚増加の抑制率(%)を指標として、経皮吸収性(遅延型アレルギー反応抑制)を評価した。
群間比較はt-検定で行った。
NF-κBデコイは水に易溶の化合物であり、非水系の外用剤の作製は困難であった。しかし、以下の脂肪酸系イオン液体に溶解させることができ、NF-κBデコイの液剤化を図ることができた。
(1)レブリン酸系イオン液体による非水系外用剤組成物(単一イオン液体):
レブリン酸と等モルのジエタノールアミン、トリエタノールアミンをそれぞれ秤取して混合し、80℃で20分間加温して、2種のレブリン酸系イオン液体を作製した。
配列番号1で示されるNF-κBデコイを約10mg秤取し、約1.0gの2種のレブリン酸系イオン液体に加えて、80℃、約30分間加温した。室温に放冷後、デコイの溶解状況を確認した。その結果、ジエタノールアミン塩、トリエタノールアミン塩のレブリン酸系イオン液体に、該NF-κBデコイが溶解し、非水系の液剤を作製できた。
更に、上記2種のイオン液体への該NF-κBデコイの溶解度を求めたところ、以下の表1のようになることが明らかとなった。
グリコール酸と等モルのジエタノールアミン、トリエタノールアミンをそれぞれ秤取して混合し、80℃で20分間加温して、2種のグリコール酸系イオン液体を作製した。
配列番号1で示されるNF-κBデコイを10mg秤取し、約100mgのグリコール酸ジエタノールアミン塩、グリコール酸トリエタノールアミン塩の各イオン液体に溶解した。デコイは該イオン液体にそれぞれ溶解して均一溶液となり、非水系の液剤を作製できた。
外用剤の経皮吸収性は、薬剤濃度と薬物環境(飽和に近いか否か等)に影響されるため、以下に示すように、レブリン酸系を中心とする混合イオン液体溶液のNF-κBデコイ液剤を作製した。また、併せて、混合イオン液体へのNF-κBデコイの溶解度を求めた。
(1)レブリン酸系混合イオン液体におけるNF-κBデコイの溶解度(i):
レブリン酸トリエタノールアミン塩を1として、レブリン酸トリイソプロパノールアミン塩が1~9の重量比で添加された混合イオン液体を作製した。これらの混合イオン液体におけるNF-κBデコイの溶解度を、実施例1の方法に従って測定した。その結果を以下の表3-1および3-2に示す。
レブリン酸トリエタノールアミン塩を1として、レブリン酸ジイソプロパノールアミン塩が1~20の重量比で添加された混合イオン液体を作製し、これらの混合イオン液体におけるNF-κBデコイの溶解度を、実施例1の方法に従って測定した。その結果を以下の表4に示す。
レブリン酸ジエタノールアミン塩を1として、レブリン酸トリイソプロパノールアミン塩が1~4の重量比で添加された混合イオン液体を作製し、これらの混合イオン液体におけるNF-κBデコイの溶解度を、実施例1の方法に従って測定した。その結果を以下の表5に示す。
レブリン酸トリエタノールアミン塩を1として、カプリン酸ジイソプロパノールアミン塩が0.025~1の重量比で添加された混合イオン液体を作製し、これらの混合イオン液体におけるNF-κBデコイの溶解度を、実施例1の方法に従って測定した。その結果を以下の表6に示す。
グリコール酸トリエタノールアミン塩を1として、グリコール酸トリイソプロパノールアミン塩が1~8の重量比で添加された混合イオン液体を作製し、これらの混合イオン液体におけるNF-κBデコイの溶解度を、実施例1の方法に従って測定した。その結果を以下の表7に示す。
デコイが溶解したイオン液体溶液を外用剤用の基剤と混合し、各種の外用剤組成物の作製を検討した。まず、軟膏基剤と混合して、デコイの軟膏製剤を作製し、デコイの皮膚透過性に及ぼすイオン液体の効果を確認した。
(1)軟膏製剤におけるレブリン酸系イオン液体の効果:
レブリン酸とトリエタノールアミンを等モル秤取し混合した。そこに没食子酸プロピルを適量加え、80℃で20分加温した。得られた粘稠溶液を室温下に秤取し、その中に配列番号1で示されるNF-κBデコイを加えて40℃の条件下に2日間おいて加熱溶解させ、NF-κBデコイが溶解したレブリン酸トリエタノールアミン系のイオン液体溶液を作製した。
該イオン液体溶液に、ゲル化炭化水素、軽質無水ケイ酸、パラオキシ安息香酸メチル、エデト酸二ナトリウムをそれぞれ秤取し混合した。更にイソステアリン酸とジイソプロパノールアミンとを80℃で20分加温して混合した溶液と、炭酸プロピレン適量とを加え、合計50.00gのデコイ軟膏製剤を作製した。
なお、比較例としてイオン液体を使用しない軟膏製剤を作製するため、該NF-κBデコイ250mgに、炭酸プロピレン、軽質無水ケイ酸、プラスチベース(商品名)等をそれぞれ以下の表8の組成(w/w%)となるように添加し、NF-κBデコイ含有軟膏製剤を作製した。これらの軟膏製剤について皮膚透過性およびマウス経皮吸収性(反復投与)を評価し、結果を表8に示した。
a)レブリン酸系混合イオン液体(塩基の混合系)の効果:
レブリン酸トリエタノールアミン塩とレブリン酸トリイソプロパノールアミン塩の混合イオン液体を用いて、イオン液体のデコイ溶解度を調整した。配列番号1で示されるNF-κBデコイ25mgを使用し、実施例3(1)に準じて以下の表9の組成(w/w%)で示される軟膏製剤を作製した。これらの軟膏製剤について皮膚透過性およびマウス経皮吸収性(単回投与)を評価し、結果を表9に示した。
即ち、表9の結果から、イオン液体中のデコイ濃度が飽和により近い組成の軟膏製剤の方が、皮膚透過性が良好であることが示された。
イオン液体に対するNF-κBデコイの溶解度を調整するため、以下の表10の組成比(w/w%)の混合イオン液体系の軟膏製剤を作製した。
これら軟膏製剤の皮膚透過性(peeling試験)、及びマウス経皮吸収性(単回投与)を併せて表10に示した。
NF-κBデコイの皮膚透過性に対する、軟膏製剤中のデコイ濃度の影響を検討した。以下の表11の組成(w/w%)で試薬を秤取し、合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤の皮膚透過性(peeling試験)、及びマウス経皮吸収性(単回投与)を評価し、その結果を併せて表11に示した。
NF-κBデコイの皮膚透過性には、実施例4に示されるように軟膏製剤中のデコイ濃度が影響すると共に、実施例3(2)に示されるようにイオン液体中のデコイ濃度(飽和濃度に近いか否か)も大きな影響を与えている。そこで、製剤中のイオン液体のデコイ濃度が皮膚透過性に及ぼす影響を検討した。以下の表12の組成(w/w%)で試薬を秤取し、合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤の皮膚透過性(peeling試験)を評価し、その結果を併せて表12に示した。
更に、レブリン酸トリエタノールアミン塩の場合の飽和溶解度は28.3w/w%(表1)であるので、製造例1と製造例6の飽和度は、44%と21%になる。従って、イオン液体中の飽和度が約40%以上であれば、皮膚透過性が顕著になり、約21%以下になれば皮膚透過性がなくなることが示された。この結果は、他のイオン液体や混合イオン液体にも同様に適用できるものと考えられる。
外用剤では、基剤に溶解している薬物濃度が高いほど、濃度による浸透圧が働き、皮膚透過性は向上する。実施例5では、単一のイオン液体中のデコイ濃度の変化を検討し、デコイ濃度が大きく皮膚透過性に影響することを見出した。そこで、混合イオン液体の場合においても同様であるか否かを検討した。まず、配列番号1で示されるNF-κBデコイを用いて、以下の表13の組成(w/w%)に従い、実施例3と同様にして全量で50gとなるように、デコイ軟膏製剤を作製した。これら軟膏製剤におけるNF-κBデコイのマウス経皮吸収性(単回投与)を評価し、その結果を表13、14および図1に示した。
また、表12の製剤例6~8と対比すると、NF-κBデコイの皮膚透過性にはイオン液体の組成(イオン液体中のデコイ飽和度)が大きな影響を与えることが分かる。即ち、表12の製剤例6~8のように、デコイ溶解度の高いイオン液体(レブリン酸トリエタノールアミン塩)のみであれば、イオン液体中のデコイ濃度が約6%以下の場合、デコイの皮膚透過性が見出せていない。しかし、表13の混合イオン液体の場合(製剤例4、9、10)には、デコイ溶解度の低いイオン液体(イソステアリン酸ジイソプロパノールアミン塩)で希釈することにより、イオン液体中のデコイ濃度が約6%以下の場合であっても、デコイの高い皮膚透過性が認められた。従って、混合イオン液体を使用し、製剤中のデコイ含量に応じて、溶解用イオン液体(レブリン酸トリエタノールアミン塩)と希釈用のイオン液体(イソステアリン酸ジイソプロパノールアミン塩)の比率を選択して、飽和度を適切に設定することにより、皮膚透過性を促進できることが明らかとなった。
混合イオン液体の濃度を一定にして、製剤中のデコイ濃度の変化が、どのように皮膚透過性に影響するかを検討した。以下の表15の組成(w/w%)で試薬を秤取し、実施例3に準じて合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤の皮膚透過性(peeling試験)、及びマウス経皮吸収性(単回投与)を評価し、その結果を併せて表15に示した。
製剤中のデコイ濃度が低濃度の場合、混合イオン液体の濃度の変化が、どのように皮膚透過性に影響するかを検討した。以下の表16の組成(w/w%)で試薬を秤取し、実施例3に準じて合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤の皮膚透過性(peeling試験)、及びマウス経皮吸収性(単回投与)を評価し、その結果を併せて表16に示した。
更に、皮膚透過性(peeling試験第3層)によれば、製造例12と製造例18に示されるように、デコイ濃度が一定の場合、使用するイオン液体の量を10分の1にして、イオン液体中のデコイ濃度を上昇させると、デコイの皮膚透過性は約8倍上昇した。このように、イオン液体中のデコイ濃度が大きく寄与している。それ故、イオン液体中のデコイ濃度を一定にして、製剤中のデコイ濃度を減少させた場合、製造例17と製造例18に示されるように、製剤中のデコイ濃度が5分の1になれば、皮膚透過性は約10分の1に低下することが分かった。同様に、マウスの経皮吸収性試験(遅延型アレルギー反応抑制率)においても効果が3分の2に低減した。
混合イオン液体の組成の変化が、どのように皮膚透過性に影響するかを検討するため、製造例14の組成を固定し、製剤中の希釈用イオン液体(イソステアリン酸ジイソプロパノールアミン塩)とプラスチベース(商品名)のみを変動させて、溶解用イオン液体と希釈用イオン液体の組成が1:0~1:30の混合イオン液体を含有する、合計50.00gのデコイ軟膏製剤(製剤例19~25)を、実施例3に準じて作製した。これら軟膏製剤のマウス経皮吸収性(単回投与)を評価した。その結果を併せて、以下の表17に示した。
各種のイオン液体を用いて混合イオン液体を作製し、その組成の変化が、どのように皮膚透過性に影響するかを検討した。以下の表18の組成(w/w%)で試薬を秤取し、実施例3に準じて合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤の皮膚透過性(peeling試験)、及びマウス経皮吸収性(単回投与)を評価し、その結果を併せて表18に示した。
このように、イオン液体のデコイ溶解度とデコイ濃度を考慮して、イオン液体の組成を設計することにより、デコイを適切に経皮吸収させることができるようになった。
軟膏製剤の単回投与によるデコイの皮膚透過性評価では、実施例8に示されるように、製剤中のデコイ濃度として0.001%でも皮膚透過し、遅延型アレルギー反応抑制効果があるとの結果が得られた。そのため、反復投与を行なえば、更にデコイ濃度を低減できることが期待される。そこで、以下の表19の組成(w/w%)で試薬を秤取し、実施例3に準じて合計50.00gのデコイ軟膏製剤を作製した。これら軟膏製剤におけるデコイのマウス経皮吸収性を上記反復投与プロトコルに従って評価した。その結果を併せて表19に示した。
ここで述べられた特許および特許出願明細書を含む全ての刊行物に記載された内容は、ここに引用されたことによって、その全てが明示されたと同程度に本明細書に組み込まれるものである。
本出願は、日本で出願された特願2008-088801(出願日:平成20年3月28日)を基礎としており、そこに開示される内容は本明細書にすべて包含されるものである。
Claims (48)
- 炭素数2~20の脂肪酸と炭素数4~12の有機アミン化合物とから得られる脂肪酸系イオン液体に、転写因子デコイを溶解して含有する、非水系外用剤組成物。
- 炭素数2~20の脂肪酸が、グリコール酸、メトキシ酢酸、レブリン酸、カプリン酸およびイソステアリン酸からなる群より選択される1つ以上である、請求項1に記載の外用剤組成物。
- 炭素数4~12の有機アミン化合物が、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミンおよびトリイソプロパノールアミンからなる群より選択される1つ以上である、請求項1または2に記載の外用剤組成物。
- 脂肪酸系イオン液体が複数の脂肪酸系イオン液体の混合イオン液体である、請求項1~3のいずれか1項に記載の非水系外用剤組成物。
- 混合イオン液体が、炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体(I)と、炭素数2~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(II)との混合物である、請求項4に記載の非水系外用剤組成物。
- イオン液体(I)の炭素数2~5の脂肪酸がグリコール酸、メトキシ酢酸およびレブリン酸からなる群より選択される、請求項5に記載の非水系外用剤組成物。
- イオン液体(I)の炭素数2~5の脂肪酸がレブリン酸である、請求項6に記載の非水系外用剤組成物。
- イオン液体(II)が、炭素数2~5の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、請求項5~7のいずれか1項に記載の非水系外用剤組成物。
- イオン液体(II)の炭素数2~5の脂肪酸がレブリン酸である、請求項8に記載の非水系外用剤組成物。
- イオン液体(I)とイオン液体(II)と重量比が、2:1~1:10の範囲である、請求項8または9に記載の非水系外用剤組成物。
- イオン液体(II)が、炭素数6~13の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、請求項5~7のいずれか1項に記載の非水系外用剤組成物。
- イオン液体(II)の炭素数6~13の脂肪酸がカプリン酸である、請求項11に記載の非水系外用剤組成物。
- イオン液体(I)とイオン液体(II)と重量比が、40:1~2:1の範囲である、請求項11または12に記載の非水系外用剤組成物。
- イオン液体(II)が、炭素数14~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩である、請求項5~7のいずれか1項に記載の非水系外用剤組成物。
- イオン液体(II)の炭素数14~20の脂肪酸がイソステアリン酸である、請求項14に記載の非水系外用剤組成物。
- イオン液体(I)とイオン液体(II)と重量比が、1:1~1:50の範囲である、上記[14]または[15]に記載の非水系外用剤組成物。
- 炭素数14~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(IIa)をさらに含有する、請求項8に記載の非水系外用剤組成物。
- イオン液体(IIa)の炭素数14~20の脂肪酸がイソステアリン酸である、請求項17に記載の非水系外用剤組成物。
- イオン液体(I)とイオン液体(II)および(IIa)と重量比が、1:1~1:50の範囲である、上記[17]または[18]に記載の非水系外用剤組成物。
- 転写因子デコイの濃度が0.0001~1w/w%である、請求項1~19のいずれか1項に記載の非水系外用剤組成物。
- 転写因子デコイの濃度が0.0001~0.2w/w%である、請求項1~19のいずれか1項に記載の非水系外用剤組成物。
- 炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体が、転写因子デコイ濃度の3~3000倍の濃度で含有される、請求項1~21のいずれか1項に記載の非水系外用剤組成物。
- 炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体が、転写因子デコイ濃度の3~1000倍の濃度で含有される、請求項1~21のいずれか1項に記載の非水系外用剤組成物。
- 複数の脂肪酸系イオン液体の混合イオン液体を含有し、混合イオン液体の濃度が0.008~30w/w%である、請求項22または23に記載の非水系外用剤組成物。
- 有機溶媒が添加されている、請求項1~24のいずれか1項に記載の非水系外用剤組成物。
- 有機溶媒が、セバシン酸ジエチル、ミリスチン酸イソプロピルおよび炭酸プロピレンからなる群より選択される1つ以上である、請求項25に記載の非水系外用剤組成物。
- キレート剤が添加されている、請求項1~26のいずれか1項に記載の非水系外用剤組成物。
- キレート剤がエデト酸2ナトリウム塩である、請求項27に記載の非水系外用剤組成物。
- 軟膏基剤が添加されて軟膏製剤になっている、請求項1~28のいずれか1項に記載の非水系外用剤組成物。
- 軟膏基剤がゲル化炭化水素または白色ワセリンである、請求項29記載の非水系外用剤組成物。
- 転写因子がNF-κB、E2F、GATA-3、STAT-1、STAT-6、EtsおよびAP-1からなる群より選択される、請求項1~30のいずれか1項に記載の非水系外用剤組成物。
- 転写因子デコイが配列GGRHTYYHC(式中、RはAまたはGを、YはCまたはTを、HはA、CまたはTをそれぞれ意味する。)を含むNF-κBデコイである、請求項31記載の非水系外用剤組成物。
- NF-κBデコイが配列GGATTTCCCまたはGGACTTTCCを含む、請求項32記載の非水系外用剤組成物。
- 転写因子デコイが配列TTTSSCGS(式中、SはGまたはCを意味する。)を含むE2Fデコイである、請求項31記載の非水系外用剤組成物。
- E2Fデコイが配列TTTCCCGCを含む、請求項34に記載の非水系外用剤組成物。
- 転写因子デコイが配列WGATAR(式中、WはAまたはTを、RはAまたはGをそれぞれ意味する)を含むGATA-3デコイである、請求項31記載の非水系外用剤組成物。
- GATA-3デコイが配列AGATAGを含む、請求項36に記載の非水系外用剤組成物。
- 転写因子デコイが配列TTCNNNGAA(式中、NはA、G、TまたはCを意味する)を含むSTAT-1デコイである、請求項31記載の非水系外用剤組成物。
- STAT-1デコイが配列TTCCGGGAAを含む、請求項38記載の非水系外用剤組成物。
- 転写因子デコイが配列TTCNNNNGAA(式中、NはA、G、TまたはCを意味する)を含むSTAT-6デコイである、請求項31記載の非水系外用剤組成物。
- STAT-6デコイが配列TTCCCAAGAAを含む、請求項40記載の非水系外用剤組成物。
- 転写因子デコイが配列MGGAW(式中、MはAまたはCを、WはAまたはTをそれぞれ意味する)を含むEtsデコイである、請求項31記載の非水系外用剤組成物。
- Etsデコイが配列CGGAAを含む、請求項42記載の非水系外用剤組成物。
- 転写因子デコイが配列TGASTMA(式中、SはGまたはCを、MはAまたはCをそれぞれ意味する)を含むAP-1デコイである、請求項31記載の非水系外用剤組成物。
- AP-1デコイが配列TGAGTCAを含む、請求項44記載の非水系外用剤組成物。
- 請求項1~45のいずれか1項に記載の非水系外用剤組成物中に含有される転写因子デコイに結合する転写因子による遺伝子転写制御を抑制することを必要とする哺乳動物に、該非水系外用剤組成物を経皮投与することを含む、該遺伝子転写制御の抑制方法。
- 非水系外用剤組成物の製造のための、転写因子デコイ、および炭素数2~20の脂肪酸と炭素数4~12の有機アミン化合物とから得られる脂肪酸系イオン液体の使用。
- イオン液体が、炭素数2~5の脂肪酸のジエタノールアミン塩またはトリエタノールアミン塩であるイオン液体(I)と、炭素数2~20の脂肪酸のジイソプロパノールアミン塩またはトリイソプロパノールアミン塩であるイオン液体(II)との混合イオン液体である、請求項47に記載の使用。
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US8232265B2 (en) | 2005-10-07 | 2012-07-31 | Board Of Trustees Of The University Of Alabama | Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients |
US8802596B2 (en) | 2005-10-07 | 2014-08-12 | Board Of Trustees Of The University Of Alabama | Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients |
US9278134B2 (en) | 2008-12-29 | 2016-03-08 | The Board Of Trustees Of The University Of Alabama | Dual functioning ionic liquids and salts thereof |
CN102791295A (zh) * | 2010-02-12 | 2012-11-21 | 普罗卡塔生物系统有限公司 | 核酸复合物 |
JP2016500095A (ja) * | 2012-11-27 | 2016-01-07 | ホビオネ サイエンティア リミテッド | テトラサイクリン局所製剤、その調製及び使用 |
WO2021070893A1 (ja) * | 2019-10-11 | 2021-04-15 | 東レ株式会社 | 温度応答性イオン液体を含む医薬組成物 |
JPWO2021070893A1 (ja) * | 2019-10-11 | 2021-04-15 | ||
JP7322895B2 (ja) | 2019-10-11 | 2023-08-08 | 東レ株式会社 | 温度応答性イオン液体を含む医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
EP2266626A1 (en) | 2010-12-29 |
CN102046208B (zh) | 2014-07-02 |
CN102046208A (zh) | 2011-05-04 |
US20160090600A1 (en) | 2016-03-31 |
JP5674020B2 (ja) | 2015-02-18 |
US20110092438A1 (en) | 2011-04-21 |
EP2266626B1 (en) | 2014-06-18 |
JPWO2009119836A1 (ja) | 2011-07-28 |
EP2266626A4 (en) | 2012-10-17 |
KR20100127300A (ko) | 2010-12-03 |
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