WO2005088299A1 - Méthode de test de la perméabilité dermique d'un médicament transdermique convoyé par un transporteur dermique - Google Patents

Méthode de test de la perméabilité dermique d'un médicament transdermique convoyé par un transporteur dermique Download PDF

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Publication number
WO2005088299A1
WO2005088299A1 PCT/JP2004/013219 JP2004013219W WO2005088299A1 WO 2005088299 A1 WO2005088299 A1 WO 2005088299A1 JP 2004013219 W JP2004013219 W JP 2004013219W WO 2005088299 A1 WO2005088299 A1 WO 2005088299A1
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transdermal
drug
candidate
transdermal drug
skin
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PCT/JP2004/013219
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English (en)
Japanese (ja)
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Akira Tsuji
Masao Kato
Yoshimichi Sai
Qing Li
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Hisamitsu Medical Co., Ltd.
Kanazawa University Technology Licensing Organization Inc.
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Priority to JP2006510873A priority Critical patent/JP4714807B2/ja
Publication of WO2005088299A1 publication Critical patent/WO2005088299A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility

Definitions

  • the present invention relates to a method for assaying skin permeability of a transdermal drug or a candidate transdermal drug, and more particularly, to a method for transdermal drug or transdermal drug delivery using a chamber sectioned on the skin section into a subcutaneous tissue side and an epidermal side.
  • the present invention relates to a method for measuring skin permeability of a transdermal drug or a transdermal candidate drug, which measures and evaluates the degree of skin permeability of a skin candidate drug through a skin transporter (a transporter provided in skin tissue).
  • Transdermal drug delivery is often used as a route of administration for potent low molecular weight therapeutic agents, and avoids first-pass metabolism, reduces pain, reduces drug delivery, and reduces the likelihood of conventional dosage forms such as tablets and injections. It has excellent effects, including the possibility of sustained release.
  • transdermal administration of nonsteroidal anti-inflammatory drugs has been introduced to avoid disadvantages of the oral route, such as gastrointestinal inflammation and ulceration (e.g., J. Pharm.Sci.
  • transdermal delivery has limited applications due to low skin penetration.
  • the skin is a physical and biochemical, both-sided barrier.
  • the outermost layer of skin, the stratum corneum (SC) has been described as the largest barrier to the penetration of various substances due to its physical structure.
  • xenobiotic metabolizing enzymes in the skin are the second biochemical noria.
  • GST daltathione S-transferase
  • MRPs multidrug metabolism-related proteins
  • OATP organic-one transport polypeptide family members
  • indomethacin which is an NSAID
  • indomethacin is transdermally administered and used as a hydrophobic model conjugate for investigating a novel enzyme in transdermal delivery
  • J. Pharm. Sci. 84: 482-488, 1995; J. Control Release 90: 335-343, 2003; J. Control Release 88: 243-252, 2003 a novel enzyme in transdermal delivery
  • several approaches have been taken to promote its efficient transdermal penetration (J. Control Release 75: 155-166, 2001; Biol. Pharm. Bull. 25: 779-782, 2002)
  • Manthol has also been used as a paracellular marker.
  • An object of the present invention is to clarify that carrier-mediated transport is involved in transdermal permeation of a therapeutic agent, and then through a skin transporter of a transdermal drug or a transdermal candidate drug.
  • An object of the present invention is to provide a method for assaying the skin permeability of a transdermal drug or a candidate transdermal drug, which measures and evaluates the degree of skin permeability in all cases.
  • indomethacin an NSAID transdermally delivered, as a hydrophobic model drug in order to investigate the characteristics of the mechanism of transdermal delivery.
  • the present invention provides (1) a solution in which a transdermal drug or a candidate transdermal drug is dissolved is injected into one of the chambers divided into a subcutaneous tissue side and an epidermis side by a skin section, On the other hand, a predetermined solution is injected, and the degree of skin permeability of the transdermal drug or the candidate transdermal drug through the skin transporter is measured and evaluated after a predetermined time under the survival condition of the skin section.
  • the measurement of the degree of skin permeability "evaluation is one or more measurements of saturation, inhibition effect, directionality and energy dependence of skin penetration".
  • the skin permeation test method of the transdermal drug or transdermal candidate drug described in (1) or (2) above, or (4) radioactive isotope or fluorescent substance as the transdermal drug or transdermal candidate drug The method for assaying skin permeability of a transdermal drug or a transdermal candidate drug described in any of (1) to (3) above, wherein a labeled transdermal drug or a transdermal candidate drug is used, (5) Transdermal drug As a solution in which a drug or a transdermal candidate drug is dissolved, a solution containing an energy source in which the subcutaneous tissue or a transdermal drug candidate is dissolved in the subcutaneous tissue side, and a transdermal drug or a transdermal drug candidate in the epidermis side (1)-(4), wherein the method for assaying the skin permeability of a
  • a transdermal drug or a candidate transdermal drug according to any one of the above (5) to (7), which is a Hanks solution;
  • the drug or transdermal candidate drug is used for both the subcutaneous tissue side and the epidermis side, and the transcutaneous drug labeled with a radioisotope or a fluorescent substance or the transdermal drug candidate is examined for saturated transdermal penetration.
  • the penetration of the transdermal drug or the transdermal candidate drug according to any one of the above (1)-(8), characterized in that it is examined whether the penetration of the transdermal drug or the transdermal candidate drug is energy-dependent. It relates to a method for testing sex.
  • the present invention relates to (12) a solution in which a transdermal drug or a transdermal candidate drug is dissolved, and a solution in which a transdermal drug or a transdermal candidate drug is dissolved in a test substance, and a subcutaneous tissue side of the skin slice.
  • the percutaneous drug or the percutaneous candidate drug is injected into the subcutaneous tissue side in one chamber partitioned into the epidermis side and a predetermined solution is injected into the other, and after a predetermined time under the conditions for survival of the skin section, Skin permeability of a transdermal drug or a transdermal candidate drug characterized by measuring the degree of skin permeability of the agent via the skin transporter and comparing and evaluating the degree of skin permeability (13) maintaining the solution on the subcutaneous tissue side at body temperature and the solution on the epidermis side at room temperature, and after a predetermined time, permeation of the transdermal drug or the candidate transdermal drug through the skin transporter
  • the present invention relates to the method for screening a substance for promoting or suppressing skin permeability of a transdermal drug or a transdermal candidate drug according to the above (12), wherein the degree of sex is measured.
  • the present invention is also characterized in that (14) the measurement of the degree of skin permeability 'evaluation is one or more measurements of the saturation, inhibition effect, directionality and energy dependence of skin penetration' evaluation. And (15) a radioactive isotope as a transdermal drug or a transdermal candidate drug as described in (12) or (13) above, or a (15) transdermal drug or a transdermal candidate drug. Skin permeability of transdermal drug or transdermal candidate drug as described in (12)-(14) above, characterized in that a transdermal drug or transdermal candidate drug labeled with a body or a fluorescent substance is used.
  • the solution obtained by dissolving is a solution containing an energy source obtained by dissolving a transdermal drug or a candidate transdermal drug on both the subcutaneous tissue side and the epidermis side.
  • the solution containing an energy source is a Hanks solution.
  • Transdermal drugs labeled with radioactive isotopes or fluorescent substances using unlabeled transdermal drugs or transdermal candidate drugs on both the subcutaneous tissue side and epidermis side Saturated transdermal penetration of transdermal candidate drugs
  • the present invention relates to a method for screening an inhibitor.
  • FIG. 1 is a diagram showing an outline of a transdermal permeation test of indomethacin by a Ussing-type Chamber method using hairless mouse skin.
  • FIG. 2 is a diagram showing the results of percutaneous penetration of [ 14 C] indomethacin (A) and [] mantol (B) into hairless mouse skin.
  • FIG. 3 is a graph showing the effect of unlabeled indomethacin on the transdermal penetration of [ 14 C] indomethacin (A) and [ ⁇ ⁇ ] mantol (B).
  • FIG. 4 is a graph showing the effects of NaN and NaF on percutaneous penetration of [ 14 C] indomethacin (A) and [3 ⁇ 4] mantol (B) in the secretion direction.
  • Fig. 6 is a view showing non-linear percutaneous permeability of [ 14 C] indomethacin in the absorption direction.
  • FIG. 7 shows the results of transdermal penetration of Fluo-3 into hairless mouse skin.
  • FIG. 8 shows the results of expression of transporter mRNA in hairless mouse skin and normal human skin.
  • a solution in which the transdermal drug or the transdermal candidate drug is dissolved is applied to the skin section on the subcutaneous tissue side and the epidermal side. Parcel Inject into one of the chambers, and inject the prescribed solution into the other, and after a predetermined period of time under the conditions for survival of the skin section, through the skin transporter of the transdermal drug or the candidate transdermal drug.
  • the method is not particularly limited as long as it is a method for measuring and evaluating the degree of skin permeability in all cases.
  • the temperature (solution temperature) of the solution on the subcutaneous tissue side or the epidermis side is not particularly limited.
  • the degree of skin permeability of the candidate drug through the skin transporter can be measured, it is preferable to maintain the solution on the subcutaneous tissue side at body temperature and the solution on the epidermis side at room temperature. Further, as the above-mentioned measurement of the degree of skin permeability 'evaluation, one or two or more measurements of skin saturation, inhibition effect, directional directivity and energy dependency can be preferably mentioned. However, a method for measuring and evaluating a transdermal drug or a transdermal candidate drug at a low concentration using another high-sensitivity detector is also included in the present invention.
  • transdermal drug or transdermal candidate drug is not limited to the existing transdermal drug, but may be used as an oral drug or a candidate substance to be developed as a transdermal drug in the future.
  • the transdermal drug or the transdermal candidate drug may be a chemical substance or a composition such as an extract of animals, plants and microorganisms.
  • centrally acting drugs drugs ⁇ antiepileptic drugs Bronchodilators, antibiotics and corticosteroids, antifungals, antivirals, cardiovascular drugs, drugs for parasitic skin diseases, antineoplastic drugs, local anesthetics, eye drops, nasal drops, peripheral vessels Dilators (such as whiskers), germicidal disinfectants for skin, wounds Dermatological drugs, hormonal drugs, antihistamine drugs, drugs for purulent skin diseases, topical enzyme drugs, skin ulcer drugs, cosmetics, hair restorer, hair restorer, animals and plants Extracts such as strong extracts, crude drugs, nucleic acids, polypeptides and the like can be mentioned.
  • these transdermal drugs or transdermal candidate drugs will be described.
  • Analgesics, antipruritics, astringents, and anti-inflammatory drugs include amcinod, prednisolone acetate valerate, diflucortron valerate, dexamethasone valerate, betamethasone valerate, diflorazone acetate, acetate Hydrocortisone, difluprednate, betamethasone dipropionate, dexamethasone, triamcinolone acetonide, halucino-d, full methasone pivalate, mometasone furoate, fluocinod, fluocinolone acetonide, Rudroxycortide, Prednisolone, Alclomethasone Propionate, Clobetasol Propionate, Dexamethasone Propionate, Deprodone Propionate, Metamethasone Propionate, Clobetasone Butyrate, Hydrocortisone Butyrate, Hydrocort
  • antibiotics and corticosteroid mixed preparations oxytetracycline hydrochlortisone, tetracycline hydrochloride. Hydrocortisone acetate, betamethasone valerate. Gentamicin, betamethasone valerate. Fradiomycin, triamcinolone.
  • Fradiomycin combination preparation Fradiomycin 'fluocinolone acetonide, fradiomycin sulfate' prednisolone, erythromycin, pimaricin, acyclovir, bleomycin sulfate, hydrocortisone 'Fradiomycin' combination, oxytetracycline hydrochloride 'Polymyxin B sulfate, chloramue-col. And compounding agents.
  • Antiviral agents include salicylic acid, croconazole hydrochloride, neticonazole hydrochloride, clotrimazole, ketoconazole, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, miconazole nitrate , Bifonazole, lanconazole, siccanin, ofloxacin, minosacrine hydrochloride, terbinafine hydrochloride, butenafine hydrochloride, tolnaftate, nadifloxacin, acyclovir, vidarabine and the like.
  • local anesthetics and ophthalmic agents include lidocaine, aminoethyl benzoate, atopine sulfate and naphazoline sulfate
  • vasodilators include isosorbide dinitrate and nitroglycerin
  • bronchodilators include Sulphaziazine, kanamycin sulfate, erythromycin, tetracycline hydrochloride, chloramphenicol, gentamicin sulfate, fradiomacin sulfate, colistin 'fradiomycin, nocitracin' fradiomycin sulfate, respectively.
  • bronchodilators include Sulphaziazine, kanamycin sulfate, erythromycin, tetracycline hydrochloride, chloramphenicol, gentamicin sulfate, fradiomacin sulfate, colistin 'fradiomycin, noc
  • antihistamines include diphenhydramine, diphenhydramine lauryl sulfate, Rotamiton, estradiol as a hormonal drug, popidone and iodine as germicidal disinfectants for skin, lysozyme chloride and bromelain as topical enzyme drugs, fluorouracil as an anti-neoplastic agent, skin ulcer drug As a transdermal drug or a candidate transdermal drug, chlorhexidine hydrochloride, diphenhydramine combination drug, diflucortron valerate, lidoin, Compounds containing sicon extract, tribenoside 'lid force-in, urea, lactolimus hydrate, gelatin, hydrocortisone acetate' hinokitiol, etretinate, calcipotriol, and tacalcitol can be exemplified.
  • Examples of the dosage form of the transdermal drug or the transdermal candidate drug include haptics, tapes, plasters, ointments, creams, liquids, lotions, dusting agents, mousse types, aerosol types, and the like. be able to.
  • the skin section to be used is preferably a section of hairless skin, and its origin is not particularly limited. However, skin sections of mammals such as mice, rats, dogs, dogs, and humans, and particularly those which are easy to prepare. Skin sections of hairless mice are preferred.
  • the skin section can be prepared by a conventional method such as lightly separating the subcutaneous fat of the excised skin. Further, as the skin slice, a skin slice in which the expression of a specific skin transporter is suppressed or a skin slice in which the expression of a specific skin transporter is amplified can be used as the skin slice.
  • a preferred example of the chamber sectioned into the skin section and the subcutaneous tissue side and the epidermis side is a Ussing-type Chamber to which the skin section can be attached in the vertical direction.
  • a solution in which a transdermal drug or a candidate transdermal drug is dissolved is stored in one of the subcutaneous tissue side and the epidermis side of the partitioned chamber, and a predetermined solution is stored in the other.
  • the solution is maintained at body temperature (approximately 36-37 ° C), and the solution on the epidermis side is maintained at room temperature.
  • the skin on both sides of the chamber is supplied with 95% 0/5% CO gas, for example.
  • the degree of skin permeability is measured and evaluated under the conditions of existence.
  • a transdermal drug or a transdermal candidate drug labeled with a radioisotope or a fluorescent substance can be advantageously used.
  • a transdermal drug or a transdermal drug can be used.
  • the skin candidate drug a dermal drug substance or a dermal drug substance labeled with a radioactive isotope such as 3 H, "C, 125 1 or 131 1 can be advantageously used.
  • a radioactive isotope such as 3 H, "C, 125 1 or 131 1
  • a fluorescent dye such as FM4-64 can coexist.
  • the solution on the subcutaneous tissue side in which the transdermal drug or the transdermal candidate drug is dissolved is a solution containing an energy source, that is, a solution containing glucose or other nutrients serving as an energy source.
  • an energy source that is, a solution containing glucose or other nutrients serving as an energy source.
  • Specific examples thereof include Hanks' solution, Ringer's solution, and Kleps-Henseleit solution, which are preferably similar in composition, and a solution on the epidermis side in which a transdermal drug or a candidate transdermal drug is dissolved.
  • the liquid is not particularly limited as long as it can dissolve the transdermal drug or the transdermal candidate drug.
  • the subcutaneous tissue side contains a solution containing an energy source in which the transdermal drug or transdermal candidate drug is dissolved
  • the epidermis side contains the transdermal drug or transdermal drug as a solution in which the transdermal drug or transdermal candidate drug is dissolved.
  • the solution containing the polyhydric alcohol in which the candidate skin agent was dissolved was used as a test method for the percutaneous drug or the skin permeability of the candidate candidate skin agent.
  • a method for assaying the skin permeability of a transdermal drug or a candidate transdermal drug which is a solution containing an energy source in which a transdermal drug or a transdermal candidate drug is dissolved on both the side and the epidermis, can be mentioned.
  • transdermal drug or a candidate transdermal drug When assaying the skin permeability of a transdermal drug or a candidate transdermal drug, an unlabeled transdermal drug or a candidate transdermal drug was applied to the subcutaneous tissue as described in the Examples below.
  • a solution in which a transdermal drug or a transdermal candidate drug is dissolved, and a transdermal drug a solution prepared by dissolving a transdermal candidate drug and a test substance is A predetermined solution is injected into the subcutaneous tissue side in the chamber partitioned into the epidermis side and the other side, and the skin of the transdermal drug or the transdermal candidate drug after a predetermined time under the survival condition of the skin section
  • the method is not particularly limited as long as it is a method of measuring the degree of skin permeability through a transporter and comparing and evaluating the degree of skin permeability, and the test substance may be a chemical substance.
  • the oxidation of probenecid a mitochondria that is an inhibitor of the organic acid (a-one) transport carrier present on the basal side of epithelial cells.
  • a-one organic acid
  • TEA tetraethylammonium
  • cholinergic blocker etc.
  • the temperature (solution temperature) of the solution on the subcutaneous tissue side and the epidermis side is not particularly limited.
  • the solution on the subcutaneous tissue side is maintained at the body temperature
  • the solution on the epidermis side is maintained at room temperature
  • the subcutaneous tissue side and the epidermis side are maintained.
  • the degree of skin permeability of the transdermal drug or the candidate transdermal drug through the skin transporter can be measured after a predetermined time. It is preferred to maintain the solution at body temperature and the epidermal solution at room temperature.
  • one or two or more measurements of skin saturation, inhibition effect, directionality and energy dependency can be preferably mentioned.
  • the method of evaluating a transdermal drug or a candidate transdermal drug at a low concentration using another high-sensitivity detector is also included in the present invention.In the evaluation, control and comparative evaluation in the absence of a test substance are included in the evaluation. It is preferable to ⁇ .
  • a transdermal drug or a transdermal drug labeled with a radioisotope, a fluorescent substance, or the like is used as the transdermal drug or the candidate transdermal drug.
  • a transdermal candidate agent is used.
  • the subcutaneous tissue has an energy such as a liquid or a Nx solution in which the transdermal drug or the transdermal candidate drug is dissolved.
  • a solution containing a single source can be advantageously used, and a solution containing a single source of energy, such as a solution containing a polyhydric alcohol such as propylene glycol or a nontus solution in which the transdermal drug or a candidate transdermal drug is dissolved on the epidermis side Can be advantageously used. Further, at the time of screening, as in the above-described assay method of the present invention, an unlabeled transdermal drug or transdermal candidate is used.
  • [ 14 C] Indomethacin (740 MBqZmol) and [ 3 H] mantol (740 GBqZmol) were purchased from PerkinElmer Life Sciences, Inc. and American Radiolabeled Chemicals Inc. X, respectively. Fluo-3-AM and FM4-64 were purchased from Dojindani Laboratory and Molecular Probe, respectively. SUPERSCRIPT TM II RNase H— was purchased from Invitrogen Corp. Normal human adult skin cDNA was also purchased from Invitrogen Corp. and BioChain Institute Inc. In addition, 5- to 7-week-old male hairless mice (HR-1) were purchased from Japan SLC, Inc., and 5- to 7-week-old male hairless mice (FVB) were purchased from CLEA Japan. Purchased from the company. FVB / Mrpl (1-Z—) mice were prepared according to the method described in the literature (Nature Med. 3: 1275-1279, 1997). Animal experiments were conducted in accordance with the guidelines on animal experiments at Kanazawa University Takaramachi Campus.
  • Reverse transcription was performed using 200 U of Reverse Transcriptase to prepare cDNA.
  • the mixture after the reaction was subjected to PCR for 30 cycles using an appropriate set of mouse primers (Table 1) and human primers (Table 2).
  • the PCR product is electrophoresed on a 2% agarose gel and brominated. Stained with jam.
  • the amount of each PCR product was measured with an AE-6955 Light Capture instrument (ATTO).
  • MRP1 (ABCC 1) 5'-CATGAAGGCCATCGGACTCT-3 "5.CAGGTCCACGTGCAGACAG-3 '259
  • MRPG (ABCC6) 5'-CCCATTGGTCACCTGCTAAACC-3 '5-CAGCTGCAAACACCAGGCCATT-3' 442
  • PEPT1 (SLC15A1) 5'-ACCGCCATCTACCATACGTT-3 '5-GAGCGACACAATGGTCTTGA-3' 105
  • PEPT2 (SLC15A2) 5'-GCCATTOCTGACTCGT £ 3 (3TT-3 '5'-TGTGTACCAC GTCCTCCC-3, 124
  • CT5 (SLC16A5) 5'-AGCTTCTACGCCCTGCAGAA-3 'S'-TTGCCCAACTCACATGGCAG-S' 321
  • NPT1 (SLC17A1) 5'-AACGAG6CCGACTTACTTCTATGA-3 '5'-ACCAGGGAGGATGTGATGTATT-3' 232
  • NPT2 (SLC3 A1) 5 -CCAGAAGGTCATCAATACGGACTTC-3 '5'-ACAGAGGGCAATCTGGAAAGCGCT-3 "274
  • OATP-C SLC21A6 S'-ATCAGTTGCCGGACTAACCAT.B '5' «CATGTGAGGTGCCTCCAAGT ⁇ 3 '368
  • OCT1 (SLC22A1) 5-GATTTAAAGATGCTTTCCCTCGAA-3 '5'-TCCCTCAGCC GAAGACTATGAA-3' 521
  • OCT2 (SLC22A2) 5-TTGCTGGAGGTCTGGTGCTGTT.3 '5'-GGTTGAGTTGTATGGGCTTTGTGATGAG-3' 250
  • OCT3 (SLC22A3) 5'-TGATCATCTTTGGTATCCTGGCATC-3 '5.-MCTTTCTCAAATCCTTGGTCGGCA-3' 562
  • OCTN1 (SLC22A) 5'-TCATTCAACTGGTACCTGTGG-3 '5'-GACTACCCATGACGATGTAG-3'246
  • OCTN2 (SLC22AS) 5'-CCATAATGCTGTGGATGACC-3 '5'-CCAAGGTAAACGAAGTAGGG-3' 412
  • OAT1 (SLC22A6) 5'-T ⁇ 3TCCGAACCTCTCTTGCTGTGC-3 '5'-TTCCTCCTCCTTGTGTGGGTGG-3' 510
  • MRP4 ⁇ _005 ⁇ (MRP5) .NM.001171 (RP6), N _000492 (WRP7) .M55S31 (GLUT5) t N _O03O4O (AE2), N _004174 (NHE3), NM.005073 (PEPT1) .S78203 (PEPT2), MM— 003051 (MCT1). NM_004731 (CT2), NM_00 207 (MCT3). N _00 696 (MCT4), NM— 004695 (CT5), NM_005074 (NPT1), NM_003052 (NPT2), NM_ 134431 (OATP-A).
  • NM_0O7256 (OATP-B), N _006 46 (OATP-C), NM.013272 (OATP-D) .N .01635 (OATP-E), NM_019B44 (OATP-8), NM_003O57 (OCT ", N _003058 (OCT2 ), NM.021977 (OCT3).
  • AB007446 (OCTN1), AB015050 (OCTN2), NM.00 790 (OAT1), NM.006672 (OAT2), N.00 254 (OAT3), NM.018484 (OAT4).
  • NM.153378 U AT1
  • U81375 ENT1
  • NM_001101 ⁇ -actin
  • Indomethacin chloride is a substrate of CMOATZMRP2 (Pharm. Res. 17: 432-438, 2000), and indomethacin is OAT1 (J. Pharmacol. Exp. Ther. 303: 534-539, 2002), OAT2 (J Pharmacol. Exp. Ther. 298: 1179-1184, 2001), OAT3 (J.
  • the directional transdermal permeation of Fluo-3 is converted to a lipid-soluble acetomethyl ester form by converting the carboxyl group of Fluo-3 to cell membrane permeability, and hydrolyzed by intracellular esterase to form Fluo-3.
  • Fig. 7 shows the results.
  • the percutaneous penetration of Fluo-3 produced in the skin tissue was linear, and the direction of absorption (from the inside of the skin tissue to the side of the subcutaneous tissue; the control on the left side of Fig. 7) was the same as that of the secretion.
  • probenecid, FCCP and TEA when FCCP coexisted, the absorption was approximately twice as high as that of Fluo-3 alone.
  • RT-PCR and PCR were performed on the total RNA of the hairless mouse skin (panel A) and the cDNA of normal human skin (panel B), respectively.
  • Human cDNA was obtained from three 80-year-old Z females (panels B-I), 44-year-old Z males (panel B- ⁇ ) and 44-year-old Z males, 58-year-old Z females, and 65-year-old Z females. The mixture (panels B-III) was used.
  • PCR products were analyzed by 2% agarose gel electrophoresis and stained with bromide tube.
  • Fig. 8 shows the results.
  • one to 32 lanes include 1, Mdrla; 2, Mdrlb; 3, Mrpl; 4, Mrp2; 5, Mrp3; 6, Mrp4; 7, Mrp5; 8, Mrp6; 9, Smvt; 10 , PepTl; ll, PepT2; 12, Mctl; 13, Mct2; 14, Mct3; 15, Mct4; 16, Nptl; 17, Oatpl; 18, Oapt2; 19, Oapt 3; 20, Oatp4; 21, Oatp5; 22, Oatpll; 23, Oatpl4; 24, mPGT; 25, Octl; 26, Oct2; 27, Oct3; 28, Octnl; 29, Octn2; 30, Octn3; 31, Oatl; 32 and Oat2, respectively.
  • lane 1-38 of panel B contains 1, j8-actin; 2, Uratl; 3, Mrpl; 4, and Mrp2.
  • MRP1, MRP3, MRP4, MRP5 peptide transporter 1 (PEPT1), PEPT2, monocarboxylic acid transporter 1 (MCT1), MCT2, MCT4, ⁇ 3, ⁇ 11, prostaglandin
  • PPT peptide transporter 1
  • MCT1 monocarboxylic acid transporter 1
  • MCT2 MCT4, ⁇ 3, ⁇ 11, prostaglandin
  • PTT transporter
  • OCT3 organic cation transporter 3
  • OC TNI organic cation Z-calcin transporter 1
  • OCTN2 and OCTN3 was observed (FIG. 8A).
  • MRP1, MRP3, MRP4 in normal human skin MRP5, MRP6, GLUT5, AE2, MCT1, MCT4, MCT5, OATP-B, OATP-D, OATP-E, OCTNl, OCTN2 and ENT1 expression were observed (Fig. 8-B).
  • MRP2, MDR1, PEPT1, PEPT2, MCT2, MCT3, OCT1, OCT3 and URAT1 was detected in some donors, suggesting that there is individual difference in expression.
  • MCT1 monocarboxylic acid transporter 1
  • OATP-D translocated prostaglandins to special tissues and cells. It plays an important role when locating (Am. J. Physiol. Renal Physiol 285: F1188-1197, 2003). Immunohistochemical staining revealed that OATP-B force was expressed in all layers of the epidermis but not subcutaneously. In addition, the OATP family substrate, taurocholate, reduced estrone sulfate uptake by 33% in normal human epidermal keratinocytes. (J. Invest. Dermatol. 120: 285-291, 2003).
  • MCT1, MCT2 and MCT5 expression was detected in human skin. Expression of MCT2 and MCT3 could be detected in only a few cases (FIG. 8). MCT1 and MCT4 were detected in multiple skin-derived cell lines, suggesting that MCT is a major determinant of pH adjustment in melanoma (Mol. Cancer Ther. 1: 617-628, 2002).
  • MCT1 played an important role in the transport of monocarboxylic acids, including benzoic acid and exogenous and endogenous weak organic acids such as lactic acid in the small intestine and brain.
  • monocarboxylic acids including benzoic acid and exogenous and endogenous weak organic acids such as lactic acid in the small intestine and brain.
  • MCTs in the skin may indicate a role in skin pH regulation and transport of weak organic acids.
  • OCTN family members was observed in all individuals (FIG. 8). The OCTN family is involved in the transport of caltin, a cofactor essential for the long-chain fatty acid oxidation.
  • OCTN1 functions as a multi-selective, pH-dependent organic cation transporter that can function in the apical membrane of kidney and other tissues as proton Z organic cation antiporter and Z or organic cation Z cation exchanger (J. Pharmacol. Exp. Ther. 289: 768-773, 1999).
  • OCTN2 is thought to be a multi-selective transporter that mediates both organic cation transport and carnitine transport (J. Biol. Chem. 275: 40064-40072, 2000).
  • OCTN family members in the skin may be involved in the uptake of carnitine or organic cation conjugates.
  • these transporters in the skin indicates that they may be involved in substrate transport as active skin barrier systems .
  • a transporter (one or more) is involved in transdermal penetration of a transdermal drug such as indomethacin or a transdermal candidate drug.
  • a transdermal drug such as indomethacin or a transdermal candidate drug.
  • mRNA expression of multiple transporters of the MRP, OATP, MCT, and OCTN families was observed in both hairless mouse skin and normal human skin.
  • the presence of these diverse transporter types indicates a potential role for active noria in controlling transdermal penetration of xenobiotics.
  • INDUSTRIAL APPLICABILITY According to the present invention, it becomes possible to develop an excellent transdermal drug delivery system for transdermal drugs and cosmetics that can be used without further clarification of the physiological role of transporters in the skin.

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Abstract

Une méthode de test de la perméabilité dermique d'un médicament transdermique, dans laquelle l'on mesure et évalue le degré de perméabilité dermique d'un médicament transdermique convoyé par un transporteur dermique ; une méthode de criblage d'une substance capable d'améliorer la suppression de la perméabilité dermique d'un médicament transdermique convoyé par un transporteur. Fourniture d'une chambre dans laquelle on sépare l'une de l'autre une paroi épidermique et une paroi de tissus sous-cutanés d'un segment de peau. On injecte dans la paroi épidermique un glycol de propylène contenant une solution dans laquelle est dissous un médicament transdermique, comme de l'indométhacine, tandis qu'une solution contenant du glucose et d'autres sources d'énergie, comme une solution de Hanks, est injectée dans la paroi du tissu sous-cutané. Après l'écoulement d'une période donnée, dans des conditions de vie convenables pour le segment de peau, de préférence lorsque la solution de la paroi de tissu sous-cutané est maintenue à température du corps tandis que la solution de la paroi épidermique est maintenue à température ambiante, on mesure et on évalue le degré de perméabilité dermique du médicament transdermique convoyé par un transporteur dermique.
PCT/JP2004/013219 2004-03-10 2004-09-10 Méthode de test de la perméabilité dermique d'un médicament transdermique convoyé par un transporteur dermique WO2005088299A1 (fr)

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WO2009057112A2 (fr) 2007-10-29 2009-05-07 Transpharma Medical, Ltd. Séchage vertical de timbres transdermiques
JP2011106846A (ja) * 2009-11-13 2011-06-02 Hamamatsu Univ School Of Medicine 新規ｎｓａｉｄ潰瘍リスク判定方法
US8281675B2 (en) 2007-10-17 2012-10-09 Syneron Medical Ltd Dissolution rate verification
CN114034608A (zh) * 2021-11-12 2022-02-11 深圳市萱嘉生物科技有限公司 一种基于人工皮肤模型测甘油葡糖苷皮肤渗透效率的方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8281675B2 (en) 2007-10-17 2012-10-09 Syneron Medical Ltd Dissolution rate verification
WO2009057112A2 (fr) 2007-10-29 2009-05-07 Transpharma Medical, Ltd. Séchage vertical de timbres transdermiques
JP2011106846A (ja) * 2009-11-13 2011-06-02 Hamamatsu Univ School Of Medicine 新規ｎｓａｉｄ潰瘍リスク判定方法
CN114034608A (zh) * 2021-11-12 2022-02-11 深圳市萱嘉生物科技有限公司 一种基于人工皮肤模型测甘油葡糖苷皮肤渗透效率的方法

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