US20090075860A1 - Transdermal absorption enhancer - Google Patents

Transdermal absorption enhancer Download PDF

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US20090075860A1
US20090075860A1 US11/912,964 US91296406A US2009075860A1 US 20090075860 A1 US20090075860 A1 US 20090075860A1 US 91296406 A US91296406 A US 91296406A US 2009075860 A1 US2009075860 A1 US 2009075860A1
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liquid crystal
weight
transdermal absorption
lyotropic liquid
compounded
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Yoko Yamaguchi
Rie Igarashi
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Japan Science and Technology Agency
Nanoegg Research Laboratories Inc
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Japan Science and Technology Agency
Nanoegg Research Laboratories Inc
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a transdermal absorption enhancer by which various active ingredients are transdermally absorbed.
  • Transdermal administration is easy and convenient as compared with oral administration and administration by injection, and may also be advantageous in terms of duration of the effect and reduction of expression of the side effects, whereby that is an excellent administration method.
  • the active ingredient in order to permeate the active ingredient into the body by transdermal administration, the active ingredient is to be penetrated through the skin which constitutes the primary barrier of the living body and, therefore, its bioavailability (amount of the drug absorbed with a blood flow) is inherently low.
  • dipropylene glycol, hexylene glycol, isoparaffin, sodium laurylsulfate, an ethylene oxide adduct of lauryl alcohol, polyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, propyl carbonate, sodium pyrrolidonecarboxylate, urea, lactic acid, sodium lactate, lecithin, dimethyl sulfoxide, pyrrolidonecarboxylate, nicotinate, N-methylproline ester, cholesteryl oleate, amine oxide or the like is compounded with preparations for external application as a transdermal absorption enhancer.
  • Non-Patent Document 1 and Non-Patent Document 2 are examples of retinoic acid having an action of enhancing regeneration of the skin by enhancing differentiation and growth of keratinocytes.
  • Non-Patent Document 1 Yoko Yamaguchi, “Novel Nano-Technology for Transdermal Delivery”, Bio Venture, vol. 4, no. 6, pages 62 to 64, 2004
  • Non-Patent Document 2 Y. Yamaguchi, T. Nagasawa, N. Nakamura, M. Takenaga, M. Mizoguchi, S. Kawai, Y. Mizushima and R. Igarashi, “Successful Treatment of Photo-Damaged Skin of Nano-Scale atRA Particles Using a Novel Transdermal Delivery”, 104, 29 to 40, 2005.
  • nano-particle including retinoic acid therein is expected for its clinical application as a method for transdermal absorption of retinoic acid with little irritation of retinoic acid to the skin, investigation of methods for transdermal absorption of various active ingredients is still meaningful.
  • an object of the present invention is to provide a transdermal absorption enhancer by which various active ingredients are transdermally absorbed.
  • lyotropic liquid crystal (refer, for example, to Japanese Patent Nos. 2,547,151 and 3,459,253) which has been already known as a basic material for pharmaceutical preparations for external application and for cosmetics has an action of enhancing the transdermal absorption of various active ingredients.
  • transdermal absorption enhancer of the present invention achieved on the basis of the above finding is characterized in that lyotropic liquid crystal is an effective ingredient as mentioned in claim 1 .
  • the transdermal absorption enhancer mentioned in claim 2 is characterized in that, in the transdermal absorption enhancer according to claim 1 , the lyotropic liquid crystal contains 5% by weight to 80% by weight of a surfactant and 5% by weight to 80% by weight of water.
  • the transdermal absorption enhancer mentioned in claim 3 is characterized in that, in the transdermal absorption enhancer according to claim 2 , the surfactant is a nonionic surfactant and/or lecithin.
  • the transdermal absorption enhancer mentioned in claim 4 is characterized in that, in the transdermal absorption enhancer according to claim 3 , the nonionic surfactant is at least one member selected from the group consisting of polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene hydrogenated castor oil.
  • the transdermal absorption enhancer mentioned in claim 5 is characterized in that, in the transdermal absorption enhancer according to claim 2 , the lyotropic liquid crystal further contains 1% by weight to 80% by weight of oil.
  • the transdermal absorption enhancer mentioned in claim 6 is characterized in that, in the transdermal absorption enhancer according to claim 5 , the oil is squalane.
  • the transdermal absorption enhancer mentioned in claim 7 is characterized in that, in the transdermal absorption enhancer according to claim 2 , the lyotropic liquid crystal further contains 1% by weight to 55% by weight of a polyhydric alcohol.
  • the transdermal absorption enhancer mentioned in claim 8 is characterized in that, in the transdermal absorption enhancer according to claim 7 , the polyhydric alcohol is glycerol.
  • the transdermal absorption enhancer mentioned in claim 9 is characterized in that, in the transdermal absorption enhancer according to claim 2 , the lyotropic liquid crystal further contains 0.01% by weight to 10% by weight of an auxiliary surfactant.
  • the transdermal absorption enhancer mentioned in claim 10 is characterized in that, in the transdermal absorption enhancer according to claim 9 , the auxiliary surfactant is cholesterol.
  • a transdermal absorption composition of the present invention is characterized in that, lyotropic liquid crystal is compounded with an active ingredient as mentioned in claim 11 .
  • the transdermal absorption composition mentioned in claim 12 is characterized in that, in the transdermal absorption composition according to claim 11 , the active ingredient is at least one member selected from the group consisting of organic compound, peptide, protein, oligonucleotide, DNA and RNA.
  • the transdermal absorption composition mentioned in claim 13 is characterized in that, in the transdermal absorption composition according to claim 11 , the active ingredient is a macromolecular substance where molecular weight is not less than 1,000 or a water-soluble substance.
  • the transdermal absorption composition mentioned in claim 14 is characterized in that, in the transdermal absorption composition according to claim 11 , the active ingredient is compounded in a form of being included in the inside of fine particles of inorganic acid salt with divalent metal.
  • the transdermal absorption composition mentioned in claim 15 is characterized in that, in the transdermal absorption composition according to claim 11 , the active ingredient is compounded in an amount of 0.01% by weight to 50% by weight to the lyotropic liquid crystal.
  • transdermal absorption enhancer as a novel pharmaceutical use of lyotropic liquid crystal which has been utilized as a basic material for pharmaceutical preparations for external application and for cosmetics and, in the transdermal absorption enhancer of the present invention, various active ingredients are able to be transdermally absorbed.
  • FIG. 1 is a graph which shows the changes in concentration of retinoic acid in blood in Example 1.
  • FIG. 2 is a graph which shows the changes in production amount of HB-EGF when each of the four kinds of samples is applied in Example 2.
  • FIG. 3 is a graph which shows the changes in production amount of HB-EGF when each of the four kinds of samples is applied and production amount of HB-EGF of the skin to which nothing is applied in Example 3.
  • FIG. 4 is a cross-sectional picture of the skin when each of the five kinds of samples is applied and a cross-sectional picture of the skin to which nothing is applied in Example 5.
  • FIG. 5 is a graph which shows the changes in concentration of insulin in blood in Example 5.
  • FIG. 6 is a graph which shows the changes in rate of niacinamide in total blood to the administered dose with the passage of time in Example 6.
  • FIG. 7 is a graph which shows the changes in residual rate of retinoic acid in the five kinds of samples with the passage of time in Example 7.
  • FIG. 8 is a graph which shows the changes in residual rate of retinol palmitate in the four kinds of samples with the passage of time in Example 8.
  • FIG. 9 is a cross-sectional picture of the skin to which lyotropic liquid crystal compounded with SOD is applied in Example 9.
  • FIG. 10 is a cross-sectional picture of the skin to which a dispersion solution where SOD is dispersed in water is applied in the same.
  • FIG. 11 is a cross-sectional picture of the skin to which only water is applied in the same.
  • FIG. 12 is a cross-sectional picture of the skin to which each of the six kinds of samples is applied in Example 10.
  • FIG. 13 is a fluorescent cross-sectional picture of the skin to which lyotropic liquid crystal compounded with oligo-DNA fluorescently labeled with FITC is applied in Example 11.
  • FIG. 14 is a fluorescent cross-sectional picture of the skin to which a dispersion solution where oligo-DNA fluorescently labeled with FITC is dispersed in water is applied in the same.
  • FIG. 15 is a fluorescent cross-sectional picture of the skin to which lyotropic liquid crystal compounded with fluorescently labeled dextran (molecular weight: 4,000) with FITC is applied in Example 12.
  • FIG. 16 is a fluorescent cross-sectional picture of the skin to which lyotropic liquid crystal compounded with fluorescently labeled dextran (molecular weight: 70,000) with FITC is applied and a fluorescent cross-sectional picture of the skin to which a dispersion solution where fluorescently labeled dextran (the same as above) is dispersed in water is applied in Example 13.
  • the transdermal absorption enhancer of the present invention is characterized in that lyotropic liquid crystal is an effective ingredient.
  • the lyotropic liquid crystal in accordance with the present invention means such a thing that, in a system where surfactant (amphipathic molecule having a hydrophilic part and a hydrophobic (lipophilic) part in a molecule) and water are coexisting, a liquid crystal state (a state where a predetermined regularity in molecular orientation is maintained as if in the case of crystal while fluidity is still available as if in the case of liquid) is formed depending upon the mixing ratio of both parts and upon temperature.
  • surfactant amphipathic molecule having a hydrophilic part and a hydrophobic (lipophilic) part in a molecule
  • a liquid crystal state a state where a predetermined regularity in molecular orientation is maintained as if in the case of crystal while fluidity is still available as if in the case of liquid
  • the surfactant which is a constituting component of the lyotropic liquid crystal there is no particular limitation so far as it is able to form a liquid crystal state (a periodical structure where the interplanar spacing is 10 nm to 800 nm is particularly preferred) in a system coexisting with water depending upon the mixing ratio with water and upon temperature.
  • it may be a surfactant of any of the types of nonionic type, anionic type, cationic type and amphoteric type and may also be a surfactant derived from nature such as lecithin (for example, egg yolk lecithin and soybean lecithin) and saponin.
  • a single surfactant may be used solely or plural kinds thereof may be mixed and used.
  • nonionic surfactant examples include polyoxyethylene alkyl ether, polyoxyethylene alkyl phenol ether, alkyl glucoside, polyoxyethylene fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid alkanolamide and polyoxyethylene hydrogenated castor oil.
  • anionic surfactant examples include soap (sodium salt, potassium salt, etc.
  • alkylbenzenesulfonate such as sodium salt
  • higher alcohol sulfate salt such as sodium salt
  • polyoxyethylene alkyl ether sulfate such as sodium salt
  • ⁇ -sulfofatty acid ester such as sodium salt
  • ⁇ -olefin sulfonate such as sodium salt
  • monoalkylphosphate salt such as sodium salt
  • alkanesulfonate such as sodium salt
  • the cationic surfactant are alkyl trimethylammonium salt (such as chloride), dialkyl dimethylammonium salt (such as chloride), alkyl dimethylbenzylammonium salt (such as chloride) and amine salt (such as acetate salt and hydrochloride salt).
  • amphoteric surfactant examples include alkylamino fatty acid salt (such as sodium salt), alkylbetaine and alkylamine oxide.
  • Rate of the surfactant in the lyotropic liquid crystal is preferably 5% by weight to 80% by weight, more preferably 7% by weight to 70% by weight and, still more preferably, 10% by weight to 65% by weight.
  • HLB value of the surfactant is preferably not less than 8, more preferably not less than 10 and, still more preferably, not less than 12.
  • Water which is a constituting component of the lyotropic liquid crystal distilled water or the like may be used.
  • Water used therefor may contain organic solvent which is miscible with water such as ethanol and isopropanol.
  • Rate of water in the lyotropic liquid crystal is preferably 5% by weight to 80% by weight, more preferably 10% by weight to 60% by weight and, still more preferably, 13% by weight to 50% by weight.
  • the lyotropic liquid crystal may further contain oil besides the surfactant and water.
  • oil When oil is contained therein, the liquid crystal structure becomes similar to a lamella structure formed by the intercellular lipid in a horny layer and, upon application to the skin surface, a phase transfer of the intercellular lipid structure is apt to happen and, as a result, an excellent enhancing action of transdermal absorption is achieved for the active ingredient.
  • oils examples include vegetable oil such as wheat germ oil, corn oil, sunflower oil and castor oil; silicone oil; ester oil such as isopropyl myristate, glyceryl trioctanoate, diethylene glycol monopropylene pentaerythritol ether and pentaerythrityl tetraoctanoate; squalane; squalene; liquid paraffin; and polybutene.
  • a single oil may be used solely or plural kinds thereof may be mixed and used.
  • Rate of the oil in the lyotropic liquid crystal is preferably 1% by weight to 80% by weight, more preferably 5% by weight to 70% by weight and, still more preferably, 10% by weight to 65% by weight.
  • the lyotropic liquid crystal may further contain a polyhydric alcohol.
  • a polyhydric alcohol When a polyhydric alcohol is contained therein, it is possible to attempt for making the formation of liquid crystal structure easy (expansion of phase region) and for making it stable.
  • the polyhydric alcohol are polyalkylene glycol (such as polyethylene glycol and polyalkylene glycol), glycerol, propylene glycol, 1,3-propanediol, 2-butene-1,4-diol, pentane-1,5-diol, 2,2-dimethylpropane-1,3-diol, 3-methylpentane-1,5-diol, pentane-1,2-diol, 2,2,4-trimethylpentane-1,3-diol, 2-methylpropane-1,3-diol, hexylene glycol, 1,3-butylene glycol, dipropylene glycol, diethylene glycol and triethylene glycol.
  • Rate of the polyhydric alcohol in the lyotropic liquid crystal is preferably 1% by weight to 55% by weight, more preferably 3% by weight to 52% by weight and, still more preferably, 5% by weight to 50% by weight.
  • the lyotropic liquid crystal may further contain an auxiliary surfactant such as cholesterol.
  • an auxiliary surfactant such as cholesterol.
  • Rate of the auxiliary surfactant in the lyotropic liquid crystal is preferably 0.01% by weight to 10% by weight.
  • the lyotropic liquid crystal is able to be prepared by mixing of the surfactant and water which are constituting components thereof in a predetermined ratio at predetermined temperature. If necessary, an operation where the constituting component is temporarily warmed before or after mixing may be carried out.
  • active ingredient means that which is able to act as a drug for attempting prevention and treatment of various diseases and maintenance and improvement of health and beauty for mammals including human being and, to be more specific, its examples are vitamins, prostaglandins, anti-cancer drug, growth hormones, various growth factors, vaccine antigen, gene encoding useful protein and other organic compound, peptide, protein, oligonucleotide, DNA and RNA.
  • transdermal absorption enhancer of the present invention transdermal absorption of substances which have been impossible or difficult to be penetrated into the skin and permeated into the body such as macromolecular substances where molecular weight is 1,000 or more (although there is no particular limitation for the upper limit of the molecular weight, it is, for example, 500,000 to 1,000,000) and water-soluble substances such as niacinamide (nicotinamide) (the water-soluble substance may be defined, for example, as “a substance which shows a transmittance (1/absorbance) of within a range of 70% to 100% at 450 nm wavelength in a state of being dispersed in water and, when its appearance is observed, no macroscopic separation is noted”) is now made possible.
  • lyotropic liquid crystal which has been utilized as a basic material for pharmaceutical preparations for external application and for cosmetics is an effective ingredient of the transdermal absorption enhancer of the present invention, it is now possible to prepare a transdermally absorption composition when the lyotropic liquid crystal is compounded with an active ingredient.
  • Compounding amount of the active ingredient to the lyotropic liquid crystal is, for example, from 0.01% by weight to 50% by weight.
  • the lyotropic liquid crystal is compounded, for example, with a substance having an enhancing action of differentiation and growth of keratinocytes, a substance having a suppressive action to melanin pigment production or a substance having an enhancing action for the synthesis of intercellular lipid of horny layer, it is now possible to prepare a dermal regeneration enhancing composition where aging of the skin, generation of spots, etc. are effectively able to be suppressed.
  • Examples of the substances having an enhancing action of differentiation and growth of keratinocytes are retinal, 3-dehydroretinal, retinoic acid, 3-dehydroretinoic acid, substances similar to retinoic acid, retinol, retinol fatty acid ester and 3-dehydroretinol fatty acid ester.
  • Examples of the substances having a suppressive action to melanin pigment production are ascorbic acid glucoside, arbutin and superoxide dismutase (SOD).
  • Examples of the substances having an enhancing action for the synthesis of intercellular lipid of horny layer are niacinamide, etc.
  • Such a substance itself may be uniformly dispersed in the lyotropic liquid crystal followed by being incorporated among the phases of the liquid crystal structure so that it is compounded, or it may be included in the inside of fine particles of inorganic acid salt with divalent metal such as fine particles where diameter is 100 nm to 1,000 nm comprising calcium carbonate, magnesium carbonate, zinc carbonate, calcium phosphate, magnesium phosphate and zinc phosphate (with regard to a method therefor, refer, if necessary, to WO 02/096396) and the fine particles (nano-particles) into which such a substance is included are uniformly dispersed in the lyotropic liquid crystal followed by being incorporated among the phases of the liquid crystal structure so that they are compounded.
  • divalent metal such as fine particles where diameter is 100 nm to 1,000 nm comprising calcium carbonate, magnesium carbonate, zinc carbonate, calcium phosphate, magnesium phosphate and zinc phosphate
  • a divalent metal ion and a counterion thereof are adsorbed on the surface (surface membrane) of the lyotropic liquid crystal so as to enhance the viscoelasticity of the membrane, whereby the physical and chemical stability of the substance incorporated among the phases is able to be improved. It is further possible to utilize in such a manner that the transdermal absorption enhancer of the present invention is previously applied on the skin surface and then the active ingredient is added thereto whereby transdermal absorption is conducted.
  • the transdermal absorption enhancer of the present invention may be directly applied to the skin surface as a preparation for external application or may be applied to the skin surface after dispersing in an ointment base, a cream base or a lotion base. It goes without saying that, in making into the preparations, known components such as antiseptic, moisturizer or antioxidant is appropriately added thereto.
  • Nano-particles comprising the three kinds of formulations as mentioned in Table 1 in which retinoic acid (an all-trans substance; hereinafter, it has the same meaning) as an active ingredient was included were prepared as follows.
  • Retinoic acid, ethanol and a 1N aqueous solution of sodium hydroxide were placed in a beaker so that retinoic acid was uniformly dissolved.
  • glycerol and Emulgen 2020G-HA polyoxyethylene octyl dodecyl ether which is a trade name of a nonionic surfactant manufactured by Kao were added thereto followed by stirring for about 10 minutes.
  • distilled water was added thereto and the mixture was stirred for about 10 minutes to give a mixed micelle of retinoic acid and the nonionic surfactant.
  • a 5M aqueous solution of magnesium chloride or a 5M aqueous solution of calcium chloride was added thereto followed by stirring for about 1 hour.
  • a 1M aqueous solution of sodium carbonate was added thereto and the mixture was stirred for about 1 hour to give nano-particles in which retinoic acid was included in a thin film of magnesium carbonate or in a thin film of calcium carbonate where the diameter was 10 nm to 1,000 nm.
  • lyotropic liquid crystal comprising 28.0% by weight of surfactant, 16.0% by weight of water, 25.0% by weight of oil and 31.0% by weight of polyhydric alcohol.
  • the nano-particles prepared in the step 1 were compounded with the lyotropic liquid crystal so as to make the compounding amount of retinoic acid 0.1% by weight (formulation 1), 0.2% by weight (formulation 2) or 0.4% by weight (formulation 3) to the lyotropic liquid crystal to give the lyotropic liquid crystal where the nano-particles in which retinoic acid was included were uniformly dispersed without degradation.
  • all of the above operations were carried out under shielding the light and the nonionic surfactant was used after being melted at about 60° C. (hereinafter, that is also the same).
  • each of vaseline compounded with nano-particles in which retinoic acid was included fine particles of calcium carbonate in which retinoic acid was included
  • vaseline compounded with retinoic acid itself so as to make the compounding amount retinoic acid same as that of the liquid crystal of the formulation 1 was applied and concentration of retinoic acid in blood was measured.
  • the result is shown in FIG. 1 .
  • (A) to (E) in FIG. 1 are as follows.
  • concentrations of retinoic acid in blood when the lyotropic liquid crystal compounded with fine particles of magnesium carbonate in which retinoic acid was included was applied and when the lyotropic liquid crystal compounded with fine particles of calcium carbonate in which retinoic acid was included was applied were nearly the same as the concentration of retinoic acid in blood when retinoic acid was hypodermically injected, whereupon it was found that the lyotropic liquid crystal had an enhancing action of transdermal absorption.
  • Vaseline Compounded with Fine Particles of Magnesium carbonate in which retinoic acid was included so as to make the compounding amount of retinoic acid same as that of the liquid crystal of the formulation 1 of Example 1 (Mg-Atra/Vaseline)
  • Lyotropic liquid crystal compounded with 0.5%, 1% and 3% (by weight) of insulin (the lyotropic liquid crystal itself was a product prepared by the step 2 of Example 1) was prepared and concentration of insulin in blood was measured by the same manner as in Example 1.
  • concentration of insulin in blood was measured by the same manner as in Example 1.
  • 0.2 mg/200 ⁇ L of insulin was hypodermically injected and concentration of insulin in blood was measured. The result is shown in FIG. 5 .
  • (A) to (D) in FIG. 5 are as follows.
  • niacinamide is a substance which is usually very difficult to be absorbed transdermically since it is a water-soluble substance, it is permeated from the skin surface due to a enhancing action of the lyotropic liquid crystal for transdermal absorption whereby it is included into blood from capillary blood vessels in dermis.
  • the sample (B) corresponds to the lyotropic liquid crystal compounded with fine particles of calcium carbonate in which retinoic acid was included according to the formulation 1 of Example 1 while the sample (D) corresponds to the lyotropic liquid crystal compounded with fine particles of magnesium carbonate in which retinoic acid was included according to the formulation 1 of Example 1.
  • the samples (A) and (C) were prepared in accordance with the method for the preparation of the samples (B) and (D).
  • FIG. 10 a cross-sectional picture of the skin (stained by a Fontana-Masson method) when 30 ⁇ L of a dispersion solution where 0.1% (by weight) of SOD was dispersed in water was applied is shown in FIG. 10 and a cross-sectional picture of the skin (stained by a Fontana-Masson method) when 30 ⁇ L of water only was applied is shown in FIG. 11 .
  • FIG. 14 Another fluorescent cross-sectional picture of the skin to which 30 ⁇ L of a dispersion solution where 2% (by weight) of oligo-DNA fluorescently labeled with FITC was dispersed in water was applied is shown in FIG. 14 .
  • the oligo-DNA was permeated into the epidermis after two hours from the application when it was compounded with the lyotropic liquid crystal and applied.
  • penetratability into the skin was checked when the lyotropic liquid crystal compounded with 5% (by weight) of dextran (molecular weight: 70,000) fluorescently labeled with FITC was applied. Also, penetratability into the skin was checked when 30 ⁇ L of a dispersion solution where 5% (by weight) of dextran (the same one as above) fluorescently labeled with FITC was dispersed in water was applied. Fluorescent cross-sectional picture of the skin for each of the above cases is shown in FIG. 16 . As will be apparent from FIG. 16 , dextran was permeated into the epidermis within 15 minutes and, with the passage of time, it was further permeated thereinto when it was compounded with the lyotropic liquid crystal and applied.
  • a lyotropic liquid crystal comprising 16.819% by weight of squalane, 8.931% by weight of soybean lecithin, 4.466% by weight of cholesterol, 15.026% by weight of POE (60) hydrogenated castor oil, 38.897% by weight of glycerol and 15.860% by weight of distilled water was prepared.
  • retinoic acid was added thereto later, transdermal absorption of retinoic acid was able to be improved.
  • a commercially available antiseptic was added to the lyotropic liquid crystal of Example 14 to prepare a product.
  • the lyotropic liquid crystal of Example 14 was compounded with a home-made lotion base (milky liquid) and then a commercially available antiseptic was added thereto to prepare a lotion.
  • the lotion base was prepared by mixing of soybean lecithin, cholesterol, PEG 4000, cyclic silicone, Carbopol (macromolecular gelling agent), Keltrol (macromolecular gelling agent) and distilled water followed by emulsifying.
  • the present invention has an industrial applicability in such a respect that there is provided a transdermal absorption enhancer as a novel pharmaceutical use of lyotropic liquid crystal which has been utilized as a basic material for pharmaceutical preparations for external application and for cosmetics.

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US20120160095A1 (en) * 2010-11-29 2012-06-28 The Regents Of The University Of Colorado, A Body Corporate Novel Nanoporous Supported Lyotropic Liquid Crystal Polymer Membranes and Methods of Preparing and Using Same
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US10195162B2 (en) * 2011-12-27 2019-02-05 Teikoku Seiyaku Co., Ltd. Tolterodine-containing adhesive patch
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US20100305215A1 (en) * 2005-04-28 2010-12-02 Japan Science And Technology Agency Dermal regeneration enhancer
US20120160095A1 (en) * 2010-11-29 2012-06-28 The Regents Of The University Of Colorado, A Body Corporate Novel Nanoporous Supported Lyotropic Liquid Crystal Polymer Membranes and Methods of Preparing and Using Same
US10195162B2 (en) * 2011-12-27 2019-02-05 Teikoku Seiyaku Co., Ltd. Tolterodine-containing adhesive patch
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