WO2007026516A1 - Nouveau système de libération de médicament - Google Patents

Nouveau système de libération de médicament Download PDF

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Publication number
WO2007026516A1
WO2007026516A1 PCT/JP2006/315741 JP2006315741W WO2007026516A1 WO 2007026516 A1 WO2007026516 A1 WO 2007026516A1 JP 2006315741 W JP2006315741 W JP 2006315741W WO 2007026516 A1 WO2007026516 A1 WO 2007026516A1
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WIPO (PCT)
Prior art keywords
tricellulin
drug
pharmaceutical composition
factor
delivery system
Prior art date
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PCT/JP2006/315741
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English (en)
Japanese (ja)
Inventor
Junichi Ikenouchi
Sachiko Tsukita
Shoichiro Tsukita
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Kyoto University
Sachiko Tsukita
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Application filed by Kyoto University, Sachiko Tsukita filed Critical Kyoto University
Publication of WO2007026516A1 publication Critical patent/WO2007026516A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • 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
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to a factor that suppresses the expression of a tricellulin gene or the action of a tricellulin protein.
  • Tight junction is a mechanism that prevents the movement of substances between cells, and is composed of special adhesion molecules. As such adhesion molecules, occuludin and claudin have been studied.
  • the present inventors conducted research on claudin among proteins constituting tight junctions (see Non-Patent Document 1), and in claudin-1 knockout mice, the permeability of the cerebrovascular barrier was investigated. It was clear that the property was increased only for compounds with a molecular weight of 800 or less (see Non-Patent Document 2).
  • the barrier mechanism against the migration of such substances functions only in blood vessels, and thus functions strictly throughout the body such as the digestive tract and skin before reaching the blood. Yes. For this reason, there has long been a demand for a method for transdermally, transmucosally noninvasively and noninvasively transferring drugs into the body.
  • claudin that forms a tight junction
  • a force that can be considered as one possibility to inhibit the function of claudin on the skin and mucous membranes More generally, epithelial cells in many tissues simultaneously form multiple types of claudin force S-tight junctions. Many of them have functional redundancy, so in order to temporarily break tight junctions in each tissue and improve drug migration, Forces that need to inhibit multiple claudin functions at the same time. Such methods are currently difficult.
  • Non-Patent Document 1 Tsukita et al., Nature Review Molecular Cell Biology, Vol. 2, No. 4, 20 April 2001, pages 285-293
  • Non-Patent Document 2 Nitta et al., The Journal of Cell Biology, No. 161, No. 3, May 2003, pages 653–660
  • the problem to be solved by the present invention is to provide a drug delivery system capable of suppressing a barrier mechanism against substance transferability and transferring a drug into the body noninvasively and noninvasively throughout the body. It was to develop methods as well as pharmaceutical compositions.
  • the present inventors have conducted extensive research and have identified a new molecule called tricellulin, which is located in a tricellular junction where three cells face each other.
  • the inventors have found that by using a factor that suppresses the function of the tricellulin gene or tricellulin protein, the substance permeability of the living body can be improved and the drug can be efficiently taken into the body, and the present invention has been completed.
  • the present invention provides:
  • the factor according to (1) selected from the group consisting of siRNA, antisense oligonucleotide, antibody, inhibitory peptide, and dominant negative mutant;
  • the factor according to (1) which is a siRNA having the nucleotide sequence shown in SEQ ID NO: 7 or 8, or a homologous RNA having an equivalent function;
  • the factor according to (1) which is an antisense oligonucleotide against trisenorelin DNA
  • the factor according to (1) which is an antibody against tricellulin protein
  • a drug delivery system comprising the factor according to any one of (1) to (5)
  • a pharmaceutical composition for enhancing the substance permeability of a living body, comprising the factor according to any one of (1) to (5);
  • a pharmaceutical composition comprising the factor and drug according to any one of (1) to (5);
  • composition according to (7) or (8) which is a transdermal dosage form or a transmucosal dosage form;
  • (11) A method for increasing the substance permeability of a living body, comprising using the factor according to any one of (1) to (5);
  • a method for treating and / or preventing a disease characterized by administering the agent of the present invention before administration of a drug or simultaneously with administration of the drug;
  • a drug can be efficiently taken into the body, and in particular, a large number of drugs can be transferred into the body transdermally, transmucosally and noninvasively. it can.
  • FIG. 2 shows an image stained with a fluorescently labeled antibody of tricellulin (left) and an image stained with a fluorescently labeled antibody of otaldine (right).
  • FIG. 3 shows the results of examining the suppression of tricellulin protein production by siRNA by Western blotting.
  • WT is a wild type Eph4 cell
  • KD-1 is an Eph4 cell into which an HI promoter vector is introduced so as to express the siRNA shown in SEQ ID NO: 7 (see Example 2)
  • KD-2 is an siRNA shown in SEQ ID NO: 8. This is an Eph4 cell (see Example 2) into which a HI promoter vector has been introduced so as to express.
  • FIG. 4 shows the results of examining suppression of tricellulin protein production by siRNA by the fluorescent antibody method.
  • WT, KD-1 and KD-2 have the same meaning as in Figure 2.
  • siRNA-introduced cells The top row shows the results for tricellulin, and the bottom row shows the results for E-force doherin.
  • the scale bar in the lower right panel indicates 10 ⁇ m.
  • FIG. 5 shows the histological observation results obtained by the fluorescent antibody method in wild-type cells and cells in which expression of tricellulin has been lost by siRNA (KD-1 and KD-2).
  • WT, KD-1 and KD_2 have the same meaning as in Figure 2.
  • the top row shows the results for tricellulin, and the bottom row shows the results for E-cadherin.
  • the scale bar in the upper right panel indicates 10 ⁇ m, and the scale bar in the lower right panel indicates 3 x m.
  • FIG. 6 shows the results of examining tricellulin expression inhibitory effect of siRNA by quantifying the permeability in the cell gap using the TER method.
  • WT, KD-1 and KD-2 have the same meaning as in Figure 2.
  • FIG. 7 shows the results of examining the effect of siRNA on the suppression of tricellulin expression by examining changes in permeability to dextran having various molecular weights labeled with FITC.
  • WT, KD-1 and KD-2 have the same meaning as in Figure 2.
  • the target molecule of the present invention is a tricellulin gene or tricellulin protein. Therefore, in one embodiment, the present invention relates to a factor that suppresses the function of a tricellulin gene or tricellulin protein. In other words, by suppressing the function of the tricellulin gene or tricellulin protein, the permeability of substances passing through the tricellular junction and tight junction can be increased, and the drug can be efficiently taken into the body. Many drugs can be transferred into the body non-mucosally and noninvasively.
  • the tight junction is formed by a pair of adhesion molecules (cludins) between adjacent cells.
  • the structure that seals such cells has three cells. Are weakened in the tricellular junction structure facing each other.
  • Figure 1 shows a schematic diagram of the tricellular junction structure.
  • the Tricellular Large Cyan has only been described morphologically so far, and its molecular construction was completely unknown.
  • the present inventors have identified the adhesion protein tricellulin localized in the tricellular junction, and revealed the nucleotide sequence of the DNA and the amino acid sequence encoded thereby.
  • Tricellular junction structures and tricellulin are widely distributed in mammals.
  • nucleotide sequence (Genebank Accession number AB219936) of DNA encoding human 'Tricellulin is shown in SEQ ID NO: 1
  • amino acid sequence of human' Tricellulin is shown in SEQ ID NO: 2.
  • nucleotide sequence of the DNA encoding another form of human 'tricellulin is shown in SEQ ID NO: 3
  • amino acid sequence of another form of human' tricerulin is shown in SEQ ID NO: 4.
  • the target molecules of the present invention are a tricellulin gene and a tricellulin protein, and preferred target molecules are a human-derived tricellulin gene and a tricellulin protein.
  • tricellulin gene is included, and in this case, "tricellulin DNA” is included. Therefore, “expression of tricellulin gene” includes “expression of tricellulin DNA”.
  • gene or “oligonucleotide” refers to DNA. And both RNA. In the present specification, the nucleotide sequence is indicated with 5 'force and 3' direction to the left and right.
  • factors that suppress the expression of the tricellulin gene include, but are not limited to, factors and drugs such as siRNA, antisense oligonucleotides, antibodies, inhibitory peptides, and dominant negative mutants.
  • factors and drugs such as siRNA, antisense oligonucleotides, antibodies, inhibitory peptides, and dominant negative mutants.
  • a method using a vector for example, a method using an adenovirus vector, etc.
  • cell fusion for example, a method using an adenovirus vector, etc.
  • electoporation for example, cell fusion
  • gene gun for example, cell fusion
  • lipofection for example, lipofection
  • a direct introduction method etc.
  • Those skilled in the art can appropriately select and use these methods according to the type of cells at the desired site, the type of factors used, and the like.
  • expression of the trisenorelin gene can also be suppressed by methods other than those described above known in the art.
  • Examples of preferable factors that suppress the expression of the tricellulin gene used in the present invention include tricellulin siRNA, antisense oligonucleotides to the tricellulin gene, and the like.
  • Anti-sense oligo for tricellulin siRNA and tricellulin gene Nucleotides have the advantage of high knock-down specificity for the tricellulin gene, high knock-out efficiency, and low risk of side effects.
  • Methods for producing antisense oligonucleotides and siRNA, preferred sequences and sequences are also known to those skilled in the art, and can be easily obtained.
  • Methods for introducing antisense oligonucleotides and siRNA into cells have also been established, which has the advantage of being easy to introduce and use.
  • a method for introducing the siRNA of the present invention into the body a known method such as a direct introduction method, a method using an adenovirus vector, a transdermal lipofusion, or an electoral position can be used.
  • a preferred method for introducing the siRNA of the present invention into the body is a direct introduction method. By adopting the direct introduction method, it is possible to simplify the configuration and use of the drug delivery system and the pharmaceutical composition described below. Conditions and factors for direct introduction of siRNA can be appropriately selected by those skilled in the art.
  • siRNA homologue of the siRNA having the nucleotide sequence shown in SEQ ID NO: 7 or 8 means all the tricellulin gene expression inhibitory effects equivalent to the siRNA having the nucleotide sequence shown in SEQ ID NO: 7 or 8.
  • siRNA homologue RNA of the present invention has one to several nucleotides deleted, substituted and / or added (set of them) in the nucleotide sequence shown in SEQ ID NO: 7 or SEQ ID NO: 8. (Which may be combined).
  • the term “several” means usually 5, preferably 3, more preferably 2, and most preferably 1.
  • “suppressing the function” of a protein includes reducing the function of the protein below a normal level and completely eliminating the function.
  • “suppressing the function” of a protein includes reducing the function of the protein below a normal level and completely eliminating the function.
  • proteins of the same kind for example, isozymes
  • one or more of them may be suppressed, or all functions may be suppressed.
  • Examples of factors that suppress the function of tricellulin include, but are not limited to, a tricellulin antibody, a tricellulin-inhibiting peptide, and a dominant-negative mutant of tricellulin.
  • An example of a preferable factor that suppresses the function of tricellulin used in the present invention is an antibody against trisenorelin protein.
  • Various antibodies are known, such as polyclonal antibodies. It may be an internal antibody or a monoclonal antibody. Chimeric antibodies and humanized antibodies may be prepared and used. Methods for producing antibodies are known to those skilled in the art, and can be appropriately selected depending on the type and use of the antibody to be prepared.
  • the cells at the desired site to be delivered with these factors trycellulin in the cells at the desired site. Can be suppressed.
  • the cells may be treated with a gene encoding a factor that suppresses the function of these tricellulins.
  • Methods for treating cells with these factors and genes for example, methods for contacting or introducing these factors or genes encoding these factors into cells are known in the art, and those skilled in the art can These methods can be appropriately selected and used according to the type, the type of factor, and the like.
  • the means and method as described above can be used.
  • the present invention is a factor that suppresses the expression of the tricellulin gene or the function of the tricellulin protein (hereinafter, “ The present invention relates to a drug delivery system characterized by using the “factor of the present invention”.
  • the factor of the present invention By applying the factor of the present invention to a living body and increasing the permeability of the applied portion, the drug can be transferred into the body in a large amount, rapidly, noninvasively and noninvasively.
  • the agent of the present invention may be applied to the drug application site in advance, and the permeability of the drug application site may be increased to administer the drug with force.
  • the agent of the present invention may be administered to the application site together with the drug.
  • a drug delivery device for example, an application brush, a patch, an eye drop container, etc.
  • a technique that increases penetration into the skin by mixing a drug to be permeated into a fat-soluble cream or the like by using a tight seal may be applied.
  • the drug delivery system of the present invention it is possible to suppress the expression of the tricellulin gene or the function of the tricellulin protein, increase the permeability of the drug to the cell layer, and deliver a large amount of drug to the body quickly and forcefully. Can do. In other words, drugs that could not be delivered to the body by administration to these sites or could not be delivered to the body. By applying the drug delivery system of the invention to these sites, the amount of force can be transferred into the body in a noninvasive and noninvasive manner. This also reduces the burden on the target.
  • the drug delivered by the drug delivery system of the present invention may be one type or multiple types.
  • the application site of the drug delivery system of the present invention is not particularly limited, and may be applied to 2 or more sites.
  • Preferred delivery forms include transdermal, transmucosal, or ophthalmic.
  • Preferable application sites include skin, mucous membrane, eyeball, especially cornea.
  • the amount of the factor of the present invention is not particularly limited and can be set according to the purpose. For example, the amount and number of uses of the factor of the present invention can be changed according to the required degree of permeability, the drug to be delivered, the type of disease, the state of the subject, the application site, and the like.
  • drug refers to a substance that has or is expected to have a desired therapeutic or prophylactic effect when administered.
  • the present invention relates to a pharmaceutical composition for increasing the substance permeability of a living body, comprising the factor of the present invention.
  • the pharmaceutical composition of the present invention suppresses the expression of the tricellulin gene or the function of the tricellulin protein by the action of the factor of the present invention, thereby increasing the permeability of the substance to the cell layer and thus increasing the substance permeability of the living body. Can be increased. Therefore, by administering the pharmaceutical composition of the present invention, it is possible to promote the transfer of a drug administered at the same time or later into the body. Therefore, a large amount of drugs can be quickly transferred into the body.
  • the pharmaceutical composition of the present invention may be administered to a drug administration site to increase the substance permeability at that site, and then the drug may be administered to the site. Further, for example, the pharmaceutical composition of the present invention and the drug may be simultaneously administered to a desired site in the living body.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the agent according to any one of claims:! To 5 and a drug.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited, but is preferably a transdermal dosage form (such as lotion, cream, ointment, clothing agent) or transmucosal dosage form. Or eye drops.
  • the manufacturing method of these dosage forms is well-known, and those skilled in the art can select suitably.
  • the present invention relates to a method for enhancing substance permeability of a living body, characterized by using the factor of the present invention.
  • the present invention relates to a method for delivering a drug, characterized in that the agent of the present invention is used.
  • the factor of the present invention may be applied before the drug administration, or the factor of the present invention may be applied simultaneously with the drug administration.
  • the drug delivery is preferably a force transcutaneous or transmucosal that can be performed by any means or method. Delivery by eye drops is also preferred. The drug delivery is as described above.
  • the present invention also relates to a method for treating and / or preventing a disease, characterized in that the agent of the present invention is administered before or simultaneously with the administration of the drug.
  • the agent of the present invention is administered before or simultaneously with the administration of the drug.
  • the present invention relates to the use of the agent of the present invention for producing the drug delivery system or pharmaceutical composition of the present invention described above.
  • the drug delivery system or pharmaceutical composition produced using the factor of the present invention is a drug delivery system or pharmaceutical composition that cannot be transferred to the body by the conventional drug delivery system or pharmaceutical composition. It can be transferred to the body in a large amount, promptly, and noninvasively and noninvasively, and the burden on the subject can be reduced.
  • the above description applies to the delivery system or pharmaceutical composition produced.
  • the delivery system or pharmaceutical composition produced by the above use may not contain a drug. In such cases, the delivery system or pharmaceutical composition is applied or administered prior to administration of the drug, or at the same time as administration of the drug.
  • the manufactured delivery system or pharmaceutical composition may contain a drug.
  • Application or administration of the delivery system or pharmaceutical composition to the living body may be by any means, but those applied or administered transdermally or transmucosally are preferred. Also preferred are those that are applied or administered by eye drops.
  • mice tricellulin The N-terminal and C-terminal cytoplasmic regions of mouse tricellulin were expressed in E. coli in the form of GST fusion proteins and purified by conventional methods. Purified protein mixed well with Mycobacterium tuberculosis adjuvant was injected subcutaneously into rabbits and rats. Polyclonal antibodies were made from rabbits and monoclonal antibodies were made from rats. Secondary antibodies include commercially available donkey anti-rabbit IgG with FITC and Cy3 fluorescent dyes, or donkey anti-rat IgG with FITC and Cy3 fluorescent dyes. Using. When cultured epithelial cells (Eph4) derived from the mammary gland of mice were stained with the fluorescent antibody method, as shown in Fig. 2 (left), a signal for tricellulin was observed only in the tricellular large junction formed by three cells. . Figure 2 (right) is an antibody staining image of otaldine that is normally found between cells.
  • Eph4 epithelial cells
  • nucleotides 1542 to 1560 (GAATGA of the protein coding region of mouse 'Tricellulin cDNA
  • Each of the prepared vectors was introduced into cultured mammary gland-derived epithelial cells (Eph4) using lipofectamin plus from Invitrogen and cultured in DMEM medium for 48 hours. Thereafter, the cells were cultured for about 2 weeks in a DMEM medium containing neomycin (400 ug / ml) to obtain cells having acquired neomycin resistance (that is, having stably acquired the HI promoter vector).
  • RNAi against trisenorelin lost about 95% of the tricellulin protein (Fig. 3). Also by the fluorescent antibody method, it was confirmed that RNAi for tricellulin has lost the protein of tricellulin. That is, compared to wild-type (WT) cells, the fluorescence in the tricellular junction disappeared in the cells (KD-1 and KD-2) in which the expression of tricellulin disappeared (FIG. 4, upper panel).
  • E cadherin (adherens junction adhesion molecule) does not change.
  • Figure 4 bottom As shown in Fig. 5, in cells where the expression of tricellulin was lost in cultured epithelial cells (Fig. 5, upper panel, middle and right panels), the ability to construct tight junctions (1) Compared to the normal formation of the crossing point (tricellular center) in the wild type (WT) (Fig. 5, upper panel, left panel), cells in which the expression of tricellulin disappeared (KD_1 and KD-2) was confirmed to be open, and (2) as shown by the arrowheads, KD-1 and KD-2 were found to be vulnerable to tight junction formation between the two cells. I was strong. These results were judged by comparison with staining for otaldin (a membrane protein localized at the tit junction) (bottom of Fig. 5).
  • otaldin a membrane protein localized at the tit junction
  • Permeability in the cell gap was quantified using the TER (trans-mark ithelial electrical resistance) method, which is one of the functional quantification methods of tight junctions.
  • TER trans-mark ithelial electrical resistance
  • epithelial cells are cultured in a two-chamber culture dish, and the electrical resistance values (TER) generated above and below the epithelial cell sheet are measured to facilitate the permeation of solutes between epithelial cells. It is a means to measure.
  • cells in which expression of tricellulin disappeared KD-1 and KD-2) were cultured in a DMEM medium using a two-chamber culture dish. The results are shown in Fig. 6.
  • TER Compared to normal wild type cells (WT), TER was greatly reduced in cells in which expression of tricellulin was lost (KD-1 and KD-2). This result indicates that the function of the tight junction due to the disappearance of trisenorelin is reduced, and the permeability of ions in the cell gap is increased.
  • the present invention can be used in fields such as pharmaceutical development and manufacture, and medicine, physiology, and pharmaceutical research.
  • SEQ ID NO: 1 shows the nucleotide sequence of DNA encoding human tricellulin.
  • SEQ ID NO: 2 shows the amino acid sequence of human tricellulin.
  • SEQ ID NO: 3 shows the nucleotide sequence of DNA encoding another form of human 'Tricellulin.
  • SEQ ID NO: 4 shows the amino acid sequence of another form of human tricellulin.
  • SEQ ID NO: 5 shows the nucleotide sequence of DNA encoding mouse 'Tricellulin.
  • SEQ ID NO: 6 shows the amino acid sequence of mouse 'Tricellulin.
  • SEQ ID NO: 7 shows the nucleotide sequence of the siRNA of the present invention that suppresses the expression of the tricellulin gene.
  • SEQ ID NO: 8 shows the nucleotide sequence of the siRNA of the present invention that suppresses the expression of the tricellulin gene.

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Abstract

La présente invention concerne un système de libération de médicament ou un procédé de composition pharmaceutique pouvant supprimer le mécanisme de barrière contre le transfert d’une substance pour transférer une substance médicinale dans toutes les parties du corps d’une façon non invasive et sans transfusion. Un facteur capable de supprimer l’expression du gène de tricelluline ou la fonction de la protéine de tricelluline ; un système de libération de médicament ou un procédé employant le facteur ; une composition pharmaceutique comprenant le facteur ; et un animal non humain ayant un gène de tricelluline endormi.
PCT/JP2006/315741 2005-08-09 2006-08-09 Nouveau système de libération de médicament WO2007026516A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009118807A (ja) * 2007-11-16 2009-06-04 Jentekku:Kk Ｄｒｐ１欠損非ヒト哺乳動物
WO2016190310A1 (fr) * 2015-05-26 2016-12-01 国立大学法人名古屋大学 Agent limitant les effets des jonctions serrées, produit auxiliaire favorisant l'absorption de médicaments, renfermant ledit agent, et composition médicamenteuse comprenant celui-ci

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029423A2 (fr) * 2001-10-02 2003-04-10 Curagen Corporation Polypeptides therapeutiques, acides nucleiques codant ceux-ci et procedes d'utilisation

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2003029423A2 (fr) * 2001-10-02 2003-04-10 Curagen Corporation Polypeptides therapeutiques, acides nucleiques codant ceux-ci et procedes d'utilisation

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Title
DATABASE GENBANK [online] XP003002172, accession no. EMBL Database accession no. (BC033689) *
IKENOUCHI J. ET AL.: "Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells", J. CELL BIOL., vol. 171, no. 6, 19 December 2005 (2005-12-19), pages 939 - 945, XP003002174 *
SCHULTE J. ET AL.: "Gliotactin, a novel marker of tricellular junctions, is necessary for septate junction development in Drosophila", J. CELL BIOL., vol. 161, no. 5, 2003, pages 991 - 1000, XP003002173 *
WALKER D.C. ET AL.: "A re-assessment of the tricellular region of epithelial cell tight junctions in trachea of guinea pig", ACTA ANAT., vol. 122, no. 1, 1985, pages 35 - 38, XP008072481 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009118807A (ja) * 2007-11-16 2009-06-04 Jentekku:Kk Ｄｒｐ１欠損非ヒト哺乳動物
WO2016190310A1 (fr) * 2015-05-26 2016-12-01 国立大学法人名古屋大学 Agent limitant les effets des jonctions serrées, produit auxiliaire favorisant l'absorption de médicaments, renfermant ledit agent, et composition médicamenteuse comprenant celui-ci

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