WO2010109544A1 - Composition contenant un acide nucléique comme principe actif destinée à une application externe - Google Patents

Composition contenant un acide nucléique comme principe actif destinée à une application externe Download PDF

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WO2010109544A1
WO2010109544A1 PCT/JP2009/001419 JP2009001419W WO2010109544A1 WO 2010109544 A1 WO2010109544 A1 WO 2010109544A1 JP 2009001419 W JP2009001419 W JP 2009001419W WO 2010109544 A1 WO2010109544 A1 WO 2010109544A1
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acid
ionic liquid
external preparation
nucleic acid
fatty acid
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PCT/JP2009/001419
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English (en)
Japanese (ja)
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小林勝則
濱本英利
中野達朗
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株式会社メドレックス
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Priority to PCT/JP2009/001419 priority Critical patent/WO2010109544A1/fr
Priority to JP2011505673A priority patent/JP5681883B2/ja
Publication of WO2010109544A1 publication Critical patent/WO2010109544A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to a composition for an external preparation containing a fatty acid ionic liquid in which a nucleic acid is dissolved as an essential component.
  • nucleic acid transdermal preparations have been published. For example, one using a complex of nucleic acid and cationic aminoglycoside as an active ingredient (Patent Document 1), one using a mixture of nucleic acid and polypeptide (Patent Document 2), one using a mixture of nucleic acid and alginic acid (Patent Document 1) 3, 4) are known.
  • Patent Document 1 a complex of nucleic acid and cationic aminoglycoside as an active ingredient
  • Patent Document 2 one using a mixture of nucleic acid and polypeptide
  • Patent Document 1 3 one using a mixture of nucleic acid and alginic acid
  • nucleic acids have a large molecular weight, usually about 10,000 or more, greatly exceeding the range of molecular weights that can be absorbed through the skin. That is, in the skin, the barrier function that separates the external environment from the living body's internal environment is very well developed, so that the permeation of substances having a molecular weight exceeding 1,000 is remarkably suppressed. Therefore, it was extremely difficult to absorb the nucleic acid transdermally.
  • nucleic acids are adsorbed and supported on nanoparticles, and the nucleic acids are percutaneously absorbed as the nanoparticles penetrate into the skin and cells (Patent Document 5). Furthermore, it has been reported that a protonic ionic liquid is effective for dissolving and transdermally absorbing nucleic acids (Patent Document 6). Thus, various attempts have been made. Transdermal absorbability has not been obtained yet.
  • An object of the present invention is to provide a non-aqueous external preparation composition in which nucleic acid is dissolved and transdermal absorbability is improved.
  • the present inventors have been able to enhance the solubility of nucleic acids in external preparations by using a fatty acid ionic liquid having 2 to 20 carbon atoms as a solvent, and also percutaneously absorb nucleic acids. It was found that the property can be improved.
  • the present inventors have found that the solubility of the nucleic acid can be controlled by mixing a plurality of fatty acid ionic liquids or by diluting the fatty acid ionic liquid with an organic solvent. As a result, it was found that the transdermal absorbability of nucleic acid can be set to the most optimal state by controlling the solubility of the nucleic acid in the ionic liquid close to saturation.
  • the solubility of the nucleic acid can be controlled by diluting the nucleic acid in an ionic liquid (dissolving ionic liquid) that dissolves the nucleic acid well with a solution (organic solvent or ionic liquid for dilution) that does not dissolve the nucleic acid. It was also found that the percutaneous absorbability of nucleic acid tends to be improved as the nucleic acid concentration in the preparation increases. The present inventors have completed the present invention based on these findings.
  • the gist of the present invention is as follows.
  • a non-aqueous external preparation composition containing a nucleic acid other than a transcription factor decoy dissolved in a fatty acid-based mixed ionic liquid wherein the composition of the fatty acid-based mixed ionic liquid is: a) one or more lower fatty acid-based ionic liquids that are triethanolamine, diethanolamine, and triethanolamine salts of lower fatty acids having 2 to 7 carbon atoms; b) a fatty acid-based ionic liquid having 2 to 20 carbon atoms having a nucleic acid solubility of 1 w / w% or less, and / or an organic solvent having a nucleic acid solubility of 1 w / w% or less,
  • An external preparation composition characterized in that the mixed ionic liquid is mixed and dispersed in an external preparation base.
  • the lower fatty acid-based ionic liquid is levulinic acid diethanolamine salt and / or levulinic acid triethanolamine salt.
  • a fatty acid-based ionic liquid having 2 to 20 carbon atoms and having a nucleic acid solubility of 1 w / w% or less is selected from among isopropanolamine salts, diisopropanolamine salts and triisopropanolamine salts of fatty acids having 2 to 20 carbon atoms.
  • the non-aqueous external preparation composition according to any one of the above (1) to (3), wherein one or more are selected.
  • the fatty acid having 2 to 20 carbon atoms is one selected from glycolic acid, methoxyacetic acid, levulinic acid, decanoic acid, oleic acid, and isostearic acid, as described in (4) above Non-aqueous external preparation composition.
  • a non-aqueous external preparation composition containing a nucleic acid other than a transcription factor decoy dissolved in a fatty acid-based mixed ionic liquid wherein the composition of the fatty acid-based mixed ionic liquid is: a) one or more ionic liquids that are diethanolamine or triethanolamine salts of levulinic acid or glycolic acid; b) one or more ionic liquids that are glycolic acid, methoxyacetic acid, levulinic acid, decanoic acid, oleic acid or isostearic acid diisopropanolamine salt, triisopropanolamine salt, and the mixed ionic liquid is The non-aqueous external preparation composition according to (1) above, wherein the composition is dispersed in an ointment base or a patch base.
  • a non-aqueous external preparation composition containing a nucleic acid other than a transcription factor decoy dissolved in a fatty acid-based mixed ionic liquid wherein the composition of the fatty acid-based mixed ionic liquid is: a) an ionic liquid which is a levulinic acid diethanolamine salt and / or a levulinic acid triethanolamine salt; b) one or more ionic liquids which are diisopropanolamine salt or triisopropanolamine salt of levulinic acid, decanoic acid, oleic acid or isostearic acid, and the mixed ionic liquid is an ointment base or patch
  • the non-aqueous external preparation composition according to (1) wherein the non-aqueous external preparation composition is mixed and dispersed in a base.
  • a fatty acid-based ionic liquid having 2 to 20 carbon atoms is used in combination, the nucleic acid of an appropriate therapeutic concentration is dissolved by controlling the solubility of the nucleic acid in the ionic liquid, and the transdermal absorbability is optimized.
  • the nucleic acid of an appropriate therapeutic concentration is dissolved by controlling the solubility of the nucleic acid in the ionic liquid, and the transdermal absorbability is optimized.
  • the solubility of the nucleic acid in the ionic liquid can be controlled and the transdermal absorbability of the nucleic acid can be improved, so that the ionic liquid for dissolution and the organic solvent for dilution, dilution Optimizing transdermal absorbability by combining ionic liquids for use, various external preparations containing nucleic acids, such as solutions, ointments, patches, etc., can be provided according to the purpose and application. It was.
  • the present invention relates to a non-aqueous external preparation composition containing a nucleic acid other than a transcription factor decoy and a fatty acid mixed ionic liquid having 2 to 20 carbon atoms as essential components.
  • nucleic acid is a generic term for DNA and RNA, which are medicinal ingredients.
  • the DNA is not particularly limited as long as it is DNA used for gene therapy. For example, DNA vaccine, antisense, ribozyme, aptamer, siRNA and the like can be mentioned.
  • the content of the nucleic acid in the external preparation composition is not particularly limited as long as it is percutaneously absorbed and becomes a therapeutically effective amount.
  • the “fatty acid-based mixed ionic liquid” is a mixed ionic liquid having the following composition (weight ratio), a) one or more lower fatty acid ionic liquids which are triethanolamine salts, diethanolamine salts, triethanolamine salts of lower fatty acids having 2 to 7 carbon atoms; b) a fatty acid-based ionic liquid having 2 to 20 carbon atoms having a nucleic acid solubility of 1 w / w% or less, and / or an organic solvent having a nucleic acid solubility of 1 w / w% or less, which is dissolved in the fatty acid-based ionic liquid.
  • a fatty acid ionic liquid which are triethanolamine salts, diethanolamine salts, triethanolamine salts of lower fatty acids having 2 to 7 carbon atoms
  • the “lower fatty acid ionic liquid having 2 to 7 carbon atoms” means an equimolar room temperature molten salt of a fatty acid having 2 to 7 carbon atoms and three organic amine compounds such as ethanolamine, diethanolamine, and triethanolamine.
  • an equimolar equilibrium mixture is represented, an excessive amount of fatty acid or organic amine can be added in consideration of the concentration of the nucleic acid used and the influence of other additives. The excess amount is preferably within 0.2 times the molar amount.
  • the fatty acid ionic liquid having 2 to 7 carbon atoms may be a single ionic liquid or a mixed ionic liquid of a plurality of fatty acid ionic liquids (including ionic liquids when only organic amine compounds are different).
  • Preferred lower fatty acid-based ionic liquids include glycolic acid diethanolamine salt, triethanolamine salt, methoxyacetic acid diethanolamine salt, triethanolamine salt, levulinic acid diethanolamine salt, and triethanolamine salt. More preferred lower fatty acid-based ionic liquids include diethanolamine salt and triethanolamine salt of levulinic acid.
  • the amount of the “fatty acid mixed ionic liquid” obtained by diluting the lower fatty acid ionic liquid can be an amount necessary for dissolving the nucleic acid and maintaining an appropriate solubility. Therefore, although it depends on the amount of nucleic acid used in the preparation, it can be preferably 0.1 to 30 w / w%, more preferably 0.1 to 10 w / w%.
  • the “fatty acid ionic liquid having 2 to 20 carbon atoms” means an equimolar room temperature molten salt or an equimolar equilibrium mixture of a fatty acid having 2 to 20 carbon atoms and an organic amine compound having 4 to 12 carbon atoms.
  • the fatty acid or the organic amine compound can be added in an excessive amount in consideration of the concentration of the nucleic acid to be used and the influence of other additives. The excess amount is preferably within 0.2 times the molar amount.
  • Preferred fatty acids include, for example, lower fatty acids having 2 to 7 carbon atoms such as glycolic acid, methoxyacetic acid, levulinic acid and hexanoic acid, for example, 8 to 12 carbon atoms such as 2-ethylhexanoic acid, octanoic acid and decanoic acid.
  • Intermediate fatty acids such as higher fatty acids having 13 to 20 carbon atoms such as lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid and oleic acid can be mentioned.
  • Preferred organic amine compounds include ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, and triisopropanolamine.
  • an ionic liquid having a nucleic acid solubility of 1 w / w% or less is used. Therefore, when a lower fatty acid having 2 to 7 carbon atoms is used as a preferable fatty acid-based ionic liquid, a diisopropanolamine salt, triisopropanolamine is used. Mention may be made of salts. More preferable examples include diisopropanolamine salt of glycolic acid, triisopropanolamine salt, diisopropanolamine salt of levulinic acid, and triisopropanolamine salt.
  • ethanolamine salt diethanolamine salt, triethanolamine salt, isopropanolamine salt, diisopropanolamine salt, triisopropanolamine salt.
  • More preferable examples include diisopropanolamine salt and triisopropanolamine salt of decanoic acid.
  • an organic amine compound similar to the intermediate fatty acid can be used, and more preferably, a diisopropanolamine salt of isostearic acid, Mention may be made of triisopropanolamine salts.
  • the “organic solvent” refers to a solvent that functions to dilute and solvate a nucleic acid in a fatty acid-based ionic liquid. That is, in order to dilute the fatty acid-based ionic liquid for nucleic acid dissolution and reduce the solubility of the nucleic acid, the organic solvent has a nucleic acid solubility of 1 w / w% or less and is an organic solvent that is uniformly dissolved in the fatty acid-based ionic liquid. It is necessary.
  • organic solvents include ester solvents, ether solvents, and ketone solvents as proton acceptors as solvents for promoting solvation.
  • alcohol solvents can be used as proton donors.
  • ether solvents include THF, butyl ether, polyethylene glycol methyl ether, and the like.
  • ketone solvents include methyl isobutyl ketone.
  • ester solvents include lower alkyl carboxylic acid esters such as ethyl acetate, ethyl lactate, propyl acetate, and ethyl butyrate, fatty acid esters such as diethyl sebacate, isopropyl myristate, and diisopropyl adipate, such as carbonates such as propylene carbonate.
  • the esters include vegetable oils such as olive oil and palm oil.
  • the alcohol solvent examples include lower alcohols having 3 to 12 carbon atoms such as propanol, isopropanol, n-butanol, pentanol, octanol, and dodecanol, such as benzyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, and ceto. Examples thereof include higher alcohols such as stearyl alcohol and 2-octyldodecanol, for example, polyhydric alcohols such as glycerin.
  • Preferable examples include ester solvents and alcohol solvents, more preferable alcohol solvents include isopropanol, and more preferable ester solvents include ethyl lactate. The amount of these organic solvents added can be appropriately increased or decreased as necessary.
  • the nucleic acid solubility of the ionic liquid can be increased. Therefore, the fatty acid-based mixed ionic liquid was prepared as described above.
  • an organic solvent having a high solubility for example, a glycol-based solvent such as polyethylene glycol or propylene glycol is used as necessary. It can also be used to increase solubility.
  • an organic solvent having a nucleic acid solubility higher than 1 w / w% can be used as necessary.
  • the “non-aqueous external preparation composition” refers to an external preparation composition that does not contain water as a constituent component.
  • the non-aqueous external preparation of the present invention contains an external preparation base in addition to the aforementioned “fatty acid-based mixed ionic liquid”, and may further contain additives as added to ordinary external preparations as appropriate. it can.
  • the manufacturing method can be performed by adopting pharmacologically widely used means.
  • the “external preparation base” refers to a base used for, for example, a liquid, a gel, an ointment, a lotion, a patch and the like.
  • the additive to be contained commonly used known antioxidants, preservatives, thickeners and preservatives can be used.
  • antioxidants examples 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.
  • a chelating agent can be used as a preservative to suppress nucleic acid degradation.
  • a chelating agent used to remove divalent metal ions such as Zn in order to suppress the activity of a DNA-degrading enzyme present on the skin surface.
  • a chelating agent used to remove 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 little skin irritation, such as 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 of the present invention can be prepared by dissolving or mixing and suspending a fatty acid-based mixed ionic liquid in which a nucleic acid, which is a medicinal ingredient, is dissolved, in a constituent component serving as a base of the preparation.
  • a base for an external preparation for example, in an ointment, white petrolatum, liquid paraffin, gelled hydrocarbon and the like may be used as a base.
  • Gel-like 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)).
  • a mixed solution of alcohols such as isopropanol, ethanol, propylene glycol and glycerin and fats and oils such as olive oil and soybean oil can be used as a base.
  • 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.
  • the elastomer 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.
  • 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.
  • the non-aqueous external preparation composition of the present invention produced as described above can be percutaneously absorbed even at a low concentration of nucleic acid, and thus is suitable for the treatment of DNA vaccines and the like and protects against infectious diseases including avian influenza. Can be administered transdermally to humans or other mammals.
  • Example 1 Solubility of nucleic acid (salmon sperm DNA) in fatty acid-based ionic liquid (single ionic liquid)
  • Levulinic acid, glycolic acid, decanoic acid and isostearic acid are used as fatty acids, and ethanolamine, diethanolamine and triethanolamine as bases , Isopropanolamine, diisopropanolamine, and triisopropanolamine, each equimolarly weighed and mixed fatty acid and base, and heated at 80 ° C. for 20 minutes to produce a total of 24 fatty acid ionic liquids did.
  • the ionic liquid is further added and dissolved uniformly, and the DNA solubility (g / ionic liquid 100 g) is calculated from the total amount of added DNA and the total amount of added ionic liquid. .
  • the results are shown in Tables 1 and 2 below.
  • Example 2 Solubility of nucleic acid (salmon sperm DNA) in mixed ionic liquid
  • Levulinic acid-based mixed ionic liquid triethanolamine salt / triisopropanolamine salt
  • Tables 1 and 2 above triethanolamine levulinate has high nucleic acid solubility, while triisopropanolamine levulinate has low nucleic acid solubility. Therefore, a mixed ionic liquid was prepared by mixing the two in the weight ratio shown in Table 3, and changes in the solubility of nucleic acids in the mixed ionic liquid having the composition ratio were examined. According to the method of Example 1, the solubility of salmon sperm DNA was measured in the same manner. The results are shown in Table 3 below.
  • Trieta Triethanolamine
  • Triiso Triisopropanolamine
  • Levulinic acid-based mixed ionic liquid (diethanolamine salt / triisopropanolamine salt): In the same manner as in the previous item (1), a mixed ionic liquid of levulinic acid diethanolamine and levulinic acid triisopropanolamine having the composition ratio shown in Table 4 was prepared, and the solubility of the nucleic acid was examined. The results are shown in Table 4 below.
  • Trieta Triethanolamine
  • Triiso Triisopropanolamine
  • Glycolic acid mixed ionic liquid (triethanolamine salt / triisopropanolamine salt): In the same manner as in the preceding item (1), a mixed ionic liquid of glycolic acid triethanolamine and glycolic acid triisopropanolamine having the composition ratio shown in Table 5 was prepared, and the solubility of the nucleic acid was evaluated. The results are shown in Table 5 below.
  • Trieta Triethanolamine
  • Triiso Triisopropanolamine
  • Example 3 Influence of Molecular Weight of Nucleic Acid Molecules on Solubility in Ionic Liquid
  • salmon sperm (Salmonsperm) DNA 500-1000 bp
  • synthetic double-stranded DNA represented by SEQ ID NO: 1 (93 bp)
  • ionic liquid levulinic acid triethanolamine salt
  • Example 4 Solubility of synthetic double-stranded DNA in mixed ionic liquid Using synthetic double-stranded DNA (SEQ ID NO: 1), the solubility of mixed ionic liquid (levulinic acid triethanolamine salt and levulinic acid triisopropanolamine salt) was measured. investigated. Prepare a mixed ionic liquid with the composition ratio (weight ratio) in Table 7 below, weigh the DNA so that the concentration of the synthetic double-stranded DNA in the ionic liquid is 1%, and add it to the mixed ionic liquid. Stir. As a result, as shown in Table 7, the saturation limit was reached when the mixing ratio of levulinic acid triethanolamine salt to levulinic acid triisopropanolamine salt was 1: 4. The results are shown in Table 7 in comparison with the solubility of salmon sperm DNA.
  • SEQ ID NO: 1 synthetic double-stranded DNA
  • Trieta Triethanolamine
  • Triiso Triisopropanolamine
  • Example 5 Effect on transdermal absorbability of changes in nucleic acid solubility of ionic liquid
  • the solubility of nucleic acids changes when the composition of the mixed ionic liquid is changed.
  • SEQ ID NO: 1 synthetic double-stranded DNA
  • 0.05 g of each levulinic acid-based mixed ionic liquid was added and dissolved.
  • 0.95 g of gelled hydrocarbon was added to prepare ointment formulations (formulation examples 1 to 7) having the compositions (w / w%) shown in Table 8 below.
  • Trieta triethanolamine
  • triiso triisopropanolamine
  • Other additives include EDTA, preservatives, thickeners.
  • Trieta Triethanolamine
  • Triiso Triisopropanolamine
  • Example 6 Effect of addition of alcohol solvent on nucleic acid solubility of ionic liquid Triethanolamine levulinate was used as the ionic liquid, and isopropanol was used as the alcohol solvent. Isopropanol dissolves uniformly in the ionic liquid. First, 2 mg of salmon Sperm DNA was weighed into a sample container, and the solubility of salmon sperm DNA was measured in the same manner as in Example 2 using the ionic liquid and isopropanol. The results are shown in Table 10 below.
  • Example 7 Effect of addition of ester solvent on nucleic acid solubility of ionic liquid Triethanolamine levulinate was used as the ionic liquid, and ethyl lactate was used as the ester solvent. Lactic acid ethyl ester is uniformly dissolved in the ionic liquid.
  • 2 mg of salmon sperm DNA was weighed into a sample container, and the solubility of salmon sperm DNA was measured in the same manner as in Example 6. The results are shown in Table 11 below.
  • esters dissolved in the ionic liquid reduce the nucleic acid solubility of the ionic liquid for dissolution (levulinic acid triethanolamine salt) in the same manner as the isopropanol of Example 6. Accordingly, it has been clarified that these esters can be used as a dilution solvent for adjusting the solubility.
  • Test example 1 Evaluation test of transdermal absorbability to skin (peeling test) The skin on the back of Wister male rats (6 weeks old) was shaved. The samples obtained in Example 5 (Formulation Examples 1 to 6) were applied to a circular area with a diameter of 1.5 cm of shaved skin. After the application, the adhesive pad was protected on the drug application surface. After 30 minutes of application, the adhesive pad was peeled off and the sample remaining on the skin was wiped off. An adhesive tape was affixed to the skin of the applied part and peeled off.
  • the adhesive tape was applied and peeled off twice, and the DNA in the sample was extracted from the tape with the extraction solvent (2 mL of ultrapure water and 0.5 mL of 10 mM Tris-EDTA (pH 7.0)), The extracted amount was quantified by HPLC. The results are shown in Table 9 and FIG.
  • the non-aqueous external preparation composition of the present invention exhibits excellent skin permeability of nucleic acid, it can be a simple and effective DDS preparation of nucleic acid. In the field of DNA vaccines and the like, the non-aqueous external preparation composition of the present invention can supply a simpler and more effective product.

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Abstract

La présente invention concerne une composition destinée à une application externe, qui contient un acide nucléique et qui présente une bonne perméabilité cutanée. Un acide nucléique est dissous dans un liquide ionique d'un sel de triéthanol amine ou d'un sel de diéthanol amine d'un acide gras de faible poids moléculaire. La solution résultante est mélangée à un solvant organique et/ou un liquide ionique d'un sel de triisopropanol amine ou d'un sel de diisopropanol amine d'acide gras afin d'ajuster la solubilité de l'acide nucléique, préparant de ce fait une solution liquide ionique mixte contenant l'acide nucléique. La solution liquide ionique est mélangée à un matériau de base et est dispersée dans celui-ci afin d'obtenir un onguent ou un patch adhésif à matrice, produisant de ce fait une composition non-aqueuse destinée à une application externe. La composition contenant un acide nucléique destinée à une application externe possède une excellente perméabilité cutanée. En variant les types d'acides nucléiques utilisés, il devient possible de fournir des compositions destinées à une application externe appropriées pour des finalités diverses.
PCT/JP2009/001419 2009-03-27 2009-03-27 Composition contenant un acide nucléique comme principe actif destinée à une application externe WO2010109544A1 (fr)

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JP2011505673A JP5681883B2 (ja) 2009-03-27 2009-03-27 核酸を有効成分とする外用剤組成物

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JP2014131975A (ja) * 2012-12-05 2014-07-17 Miyoshi Oil & Fat Co Ltd 親水性室温イオン液体とその用途
CN109789216A (zh) * 2016-08-29 2019-05-21 加利福尼亚大学董事会 基于离子物种的皮肤治疗局部制剂
US11786597B2 (en) 2013-11-03 2023-10-17 The Regents Of The University Of California Ionic liquids for transdermal drug delivery

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US11786597B2 (en) 2013-11-03 2023-10-17 The Regents Of The University Of California Ionic liquids for transdermal drug delivery
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