WO2017183559A1 - Promoteur d'absorption transmucosale pour médicament - Google Patents

Promoteur d'absorption transmucosale pour médicament Download PDF

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WO2017183559A1
WO2017183559A1 PCT/JP2017/015181 JP2017015181W WO2017183559A1 WO 2017183559 A1 WO2017183559 A1 WO 2017183559A1 JP 2017015181 W JP2017015181 W JP 2017015181W WO 2017183559 A1 WO2017183559 A1 WO 2017183559A1
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transmucosal absorption
component
drug
basic amino
solution
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PCT/JP2017/015181
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Japanese (ja)
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真莉子 武田
敬泰 亀井
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学校法人神戸学院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a transmucosal absorption promoter for drugs, a pharmaceutical composition containing the same, and the like.
  • Non-patent Document 3 cell-penetrating peptides
  • CPPs cell-penetrating peptides
  • TAT peptides TAT peptides
  • penetratin cell-penetrating peptides
  • many of these peptides promote the transmucosal absorption of a drug by being used by crosslinking with the drug.
  • a product obtained by crosslinking arginine hexapeptide, which is a cell membrane permeable peptide, to the C-terminal side of leuprolide, which is a prostate cancer therapeutic agent is known (Non-patent Document 4).
  • this technique has low versatility, and there is a possibility that the activity of the drug is reduced by crosslinking.
  • Non-patent Document 5 cell membrane permeation peptides such as arginine oligopeptide can promote transmucosal absorbability of a drug by simply mixing it with the drug. With this technique, since crosslinking is not required, there is a low possibility that the above problems will occur.
  • arginine oligopeptides peptides composed of 6 or more arginines such as decapeptides, octapeptides, hexapeptides have been reported so far.
  • Non-patent Document 5 octapeptide and decapeptide show high transmucosal absorption promoting action, but it is said that hexapeptide having a smaller number of arginine residues has lower transmucosal absorbability.
  • An object of the present invention is to provide an agent for promoting transmucosal absorption of a drug. It is another object of the present invention to provide a transmucosal absorption promoter that does not require crosslinking with a drug and has less adverse effects on the living body.
  • the present invention includes the following embodiments: Item 1. Transmucosal absorption of a drug comprising (a component) a basic amino acid, (b component) a peptide composed of 2 to 5 basic amino acids, and (c component) at least one selected from the group consisting of tryptophan Accelerator.
  • Item 2. Item 2. The transmucosal absorption promoter according to Item 1, wherein the basic amino acid is an L-amino acid.
  • Item 3. Item 3.
  • Item 5. The transmucosal absorption promoter according to any one of Items 1 to 4, wherein the basic amino acid is arginine.
  • Item 6. The transmucosal absorption promoter according to any one of Items 1 to 5, wherein the component b is a peptide composed of 2 to 4 basic amino acids.
  • Item 8. Item 8.
  • Item 9. Item 9. The transmucosal absorption promoter according to any one of Items 1 to 8, wherein the drug has an isoelectric point of 7 or less.
  • Item 10. Item 10. The transmucosal absorption enhancer according to any one of Items 1 to 9, wherein the drug is a peptide or protein.
  • Item 11. A pharmaceutical composition comprising the transmucosal absorption promoter according to any one of Items 1 to 10 and a drug.
  • Item 12. Item 12.
  • Item 13. Item 13.
  • transmucosal absorption promoter that does not require crosslinking with a drug and has less adverse effects on the living body.
  • the drug can be provided in a formulation form (for example, an oral preparation) in which the above problems are less likely to occur.
  • Test Example 1 The result of Test Example 1 is shown.
  • “Insulin” indicates Comparative Example 1
  • “LR” indicates Example 1
  • “L-R2” indicates Example 2
  • “L-R4” indicates Example 3
  • “L-R8” indicates Comparative Example 2 (Table 1). reference).
  • the result of Test Example 2 is shown.
  • the vertical axis indicates the human insulin concentration in plasma
  • the horizontal axis indicates the elapsed time after administration
  • PBS represents Solution 1
  • Insulin represents Solution 2
  • L-R represents Solution 3
  • Sodium taurodeoxycholate represents Solution 4.
  • the vertical axis shows the human insulin concentration in plasma
  • the horizontal axis shows the elapsed time after administration
  • “Insulin” indicates Comparative Example 1
  • “L-R1” indicates Example 5
  • “L-R1 + L-W1” indicates Example 8 (see Table 4).
  • the result of Test Example 7 is shown.
  • the vertical axis represents the human insulin concentration in plasma
  • the horizontal axis represents the elapsed time after administration
  • “Insulin” indicates Comparative Example 1
  • the result of Test Example 8 is shown.
  • “Insulin” represents Comparative Example 1
  • “16 ⁇ m” represents Example 11
  • “32 ⁇ m” represents Example 12 (see Table 6).
  • the result of Test Example 9 is shown.
  • the vertical axis represents the LDH (lactate dehydrogenase) concentration in the intestinal fluid
  • the present invention relates to a drug comprising (a component) a basic amino acid, (b component) a peptide composed of 2 to 5 basic amino acids, and (c component) at least one selected from the group consisting of tryptophan A transmucosal absorption enhancer (also referred to herein as “the transmucosal absorption enhancer of the present invention”), and a pharmaceutical composition (the present invention) containing the transmucosal absorption enhancer of the present invention and a drug. In the specification, it may be referred to as “the pharmaceutical composition of the present invention”). These will be described below.
  • the basic amino acid is not particularly limited as long as the amino acid has a basic functional group in the side chain and an isoelectric point in the alkaline region (preferably an ⁇ -amino acid).
  • Examples of the basic functional group include a guanidino group, an amino group, an imidazolyl group and the like, preferably a guanidino group and an amino group, and more preferably a guanidino group.
  • the isoelectric point of the basic amino acid is, for example, more than 7, preferably 7.5 or more, more preferably 9 or more, and further preferably 10 or more. Although the upper limit of an isoelectric point is not specifically limited, For example, it is 14.
  • basic amino acids include natural amino acids such as arginine, lysine, histidine, ornithine and citrulline.
  • natural amino acids such as arginine, lysine, histidine, ornithine and citrulline.
  • arginine, lysine and the like are preferable, and arginine is more preferable.
  • the configuration of the basic amino acid is not particularly limited, and may be either L-form or D-form. From the viewpoint that the transmucosal absorption promoting effect is higher and / or the transmucosal absorption promoting effect is further improved in a dose-dependent manner, the basic amino acid is preferably an L-amino acid.
  • a peptide composed of basic amino acids is a peptide formed by peptide bonding of a plurality of basic amino acids (preferably an amino group and a carboxyl group on the main chain of the basic amino acid), and is not particularly limited as long as this is the case. .
  • the number of basic amino acids constituting the peptide is 2-5, preferably 2-4.
  • the peptide may be composed of only one basic amino acid or may be composed of two or more basic amino acids.
  • tryptophan is not particularly limited, and may be either L-form or D-form. From the viewpoint that the transmucosal absorption promoting effect is higher and / or the transmucosal absorption promoting effect is further improved in a dose-dependent manner, tryptophan is preferably L-form.
  • the basic amino acid, the peptide composed of the basic amino acid, and tryptophan may be chemically modified as long as they have a transmucosal absorption promoting effect.
  • the presence or absence of the transmucosal absorption promoting effect can be determined according to or according to a known method. For example, it can be determined according to or according to the method described in Test Example 1 described later.
  • carboxyl group at the end of the main chain is either carboxylate (—COO ⁇ ), amide (—CONH 2 ) or ester (—COOR) Also good.
  • R in the ester for example, a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl; for example, a C 3-8 cycloalkyl group such as cyclopentyl, cyclohexyl; C 6-12 aryl groups such as ⁇ -naphthyl; phenyl-C 1-2 alkyl groups such as benzyl and phenethyl; C 7- such as ⁇ -naphthyl-C 1-2 alkyl groups such as ⁇ -naphthylmethyl; 14 aralkyl group; pivaloyloxymethyl group and the like are used.
  • a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl
  • a C 3-8 cycloalkyl group such as cyclopentyl, cyclohex
  • the main chain terminal amino group protecting group e.g., formyl groups, C such as C 1-6 alkanoyl such as acetyl group 1-6
  • an acyl group or the like, or a substituent on the side chain is an appropriate protecting group (for example, a C 1-6 alkanoyl group such as a formyl group or an acetyl group)
  • a C 1-6 alkanoyl group such as a formyl group or an acetyl group
  • the like protected with a C 1-6 acyl group such as and the like.
  • the basic amino acid, the peptide composed of the basic amino acid, and tryptophan may be in the form of a pharmaceutically acceptable salt with an acid or a base.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and either an acidic salt or a basic salt can be employed.
  • acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate; acetate, propionate, tartrate, fumarate, maleate, apple Organic acid salts such as acid salts, citrate salts, methanesulfonate salts, and paratoluenesulfonate salts; and amino acid salts such as aspartate salts and glutamate salts.
  • basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts.
  • the basic amino acid, the peptide composed of the basic amino acid, and tryptophan may be in the form of a solvate.
  • the solvent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include water, ethanol, glycerol, acetic acid and the like.
  • Basic amino acids (component a) can be used singly or in combination of any two or more.
  • a peptide composed of basic amino acids (component b) can be used alone or in combination of any two or more.
  • Tryptophan (component c) can be used singly or in combination of any two or more.
  • the transmucosal absorption promoter of the present invention is not particularly limited as long as it contains at least one selected from the group consisting of a component, b component, and c component as an active ingredient. From the viewpoint that the transmucosal absorption promotion effect is higher, and / or from the viewpoint that the living body is inoculated daily and the safety is higher, the transmucosal absorption promoter of the present invention has an a component and a c component as active ingredients. It is preferable to contain at least one selected from the group consisting of, more preferably only at least one selected from the group consisting of a component and c component as active ingredients, and only c component as active ingredients It is more preferable to contain.
  • a component, the b component, and the c component commercially available products can be used as they are, or they can be produced according to or according to a known synthesis method.
  • the mechanism of the present invention in the case of employing the a component and the b component is considered as follows.
  • Known cell membrane permeable peptides that contain many basic amino acids, such as arginine octapeptide improve the transmucosal absorbability of the drug by forming a complex with the drug due to its positive charge and permeating the cell membrane (Non-Patent Documents 6 and 7). Therefore, the a component and the b component, which are effective components of the present invention, also have a positive charge, and are considered to exhibit the effect based on the same mechanism.
  • the drug targeted by the transmucosal absorption enhancer of the present invention has biological activity, particularly when the a component and the b component are adopted, and is combined with the a component and / or the b component by electrical interaction.
  • the drug is not particularly limited as long as it is a drug capable of forming a body.
  • the isoelectric point (pI) is from a neutral region to an acidic region, preferably pI: 7 or less (or less than 7), more preferably pI: 7 to 0.01. More preferably, the drug has a pI of 6 to 0.1, and even more preferably a pI of 6 to 1.
  • the molecular weight of the drug is not particularly limited.
  • a drug having a molecular weight of 100 to 1000000, preferably 300 to 200000, more preferably 800 to 100000, still more preferably 1500 to 50000, and still more preferably 2000 to 10,000 can be mentioned.
  • drugs include peptides, proteins, sugars, polysaccharides, nucleic acids, low molecular compounds, and the like. More specifically, for example, insulin, gastrin, Exendin-4, GLP1, leuprolide, calcitocin, interferon ⁇ , PEGylated protein, dextran, nanoparticles and the like can be mentioned.
  • the mucosa that is the target of the transmucosal absorption enhancer of the present invention is not particularly limited.
  • examples of the mucosa include intestinal mucosa, gastric mucosa, nasal mucosa, oral mucosa, lung mucous membrane, and the like, preferably intestinal mucosa.
  • the pharmaceutical composition of the present invention is not particularly limited as long as it contains the above-described transmucosal absorption promoter of the present invention and a drug, and may contain other components as necessary.
  • the other components are not particularly limited as long as they are pharmaceutically acceptable components.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it is a dosage form that can be absorbed from mucous membranes.
  • Oral preparations such as sustained release capsules, chewing tablets, drops, pills, liquids for internal use, confectionery tablets, sustained release agents, sustained release granules, etc .; nasal drops, inhalants, rectal suppositories, inserts, External preparations such as enemas and jelly agents can be mentioned.
  • the pharmaceutical composition of the present invention may be any of a solid agent, a semisolid agent and a liquid agent, preferably a solid agent and a semisolid agent, more preferably a solid agent.
  • the content of the drug in the pharmaceutical composition of the present invention depends on the type of drug, the subject to be administered, the administration route, the dosage form, the patient's condition, the judgment of the doctor, etc., and is not limited, for example, For example, it can be 0.0001 to 95% by weight, preferably 0.001 to 50% by weight.
  • the total content of component a and component b in the pharmaceutical composition of the present invention depends on the type of drug, administration subject, administration route, dosage form, patient condition, doctor's judgment, etc. For example, it may be 0.0001 to 95% by weight, preferably 0.001 to 50% by weight.
  • the pharmaceutical composition of the present invention has a total dose of component a and component b per 1 kg body weight of the subject to be administered, for example, 1 ⁇ g to 200 mg, preferably 10 ⁇ g to 150 mg, more preferably 100 ⁇ g. It is preferably used in an amount of ⁇ 100 mg, more preferably 500 ⁇ g ⁇ 50 mg.
  • Test Example 1 Evaluation of transmucosal absorption promoting action of arginine or arginine peptide ⁇
  • Test Example 1-1 Preparation of administration solution> Various amounts of recombinant human insulin (27.5 IU / mg) (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved in 50 ⁇ L of a 0.1N aqueous hydrochloric acid solution in a polypropylene tube, and this was then added to 1.4% containing methylcellulose at a concentration of 0.001%. The solution was diluted with mL of PBS solution (pH 6.0), and further standardized with 50 ⁇ L of 0.1N sodium hydroxide aqueous solution to obtain an insulin solution.
  • PBS solution pH 6.0
  • Test Example 1-2 Administration test> A male SD (Sprague Dawley) rat (body weight 180-220 g) (manufactured by SLC) was used for the administration test. A midline incision was made in the abdomen of the anesthetized rat fixed on the plate to expose the ileum. A cannula was inserted proximal to the ileocecum and ligated tightly to prevent fluid loss and then returned to its original position in the abdominal cavity. PBS (37 ° C.) was circulated through the cannula (5.0 mL / min, 4 minutes) using an infusion pump. The cannula tube was removed and the part closed. In order to reverse the increase in blood glucose level due to surgery, the rat was left for 30 minutes.
  • Test Example 1-1 0.5 mL of the administration solution obtained in Test Example 1-1 was directly administered into the ileal loop.
  • Table 1 shows the insulin dose and the type and concentration of the test substance in the administration solution.
  • the concentrations of the test substances in Examples 1 to 3 and Comparative Example 2 are adjusted so that the concentrations when converted to arginine monomers are the same (8 mM).
  • Test Example 1-3 Evaluation of transmucosal absorption promoting action>
  • blood was collected before administration and after 5, 10, 15, 30, 60, 120, and 180 minutes after administration.
  • the obtained blood was centrifuged (13,400 g, 1 minute) to obtain plasma.
  • the concentration of human insulin in plasma ie, insulin that was administered and then absorbed through the intestinal mucosa
  • the measurement results are shown in FIG.
  • insulin absorption was enhanced by administering arginine or arginine oligopeptide with insulin.
  • arginine (Example 1: LR)> arginine dipeptide (Example 2: L-R2)> arginine tetrapeptide (Example 3: L-R4)> arginine octapeptide ( Comparative Example 2: L-R8).
  • Test Example 2 Evaluation of dose-dependent transmucosal absorption promoting action of arginine Tests were conducted in the same manner as in Test Example 1 except that the types and concentrations of the test substances in the administration solution were as shown in Table 2. The results are shown in FIG. As shown in FIG. 2, arginine promoted insulin absorption in a dose-dependent manner.
  • Test Example 3 Evaluation of transmucosal absorption promoting action of basic amino acid Test was conducted in the same manner as in Test Example 1 except that the type and concentration of the test substance in the administration solution were as shown in Table 3. The results are shown in FIG. As shown in FIG. 3, even basic amino acids other than arginine promoted insulin absorption. Moreover, the order of the strength of the absorption promoting action was arginine (Example 1: LR)> lysine (Example 6: LK)> histidine (Example 7: LH).
  • Test Example 4 Evaluation of the effect of intestinal epithelial tissue on integrity 1 After Test Example 1, the ileum was treated with 20 mL of PBS (37 ° C.) and then air was passed through. 0.5 mL of the solution was administered directly into the ileal loop.
  • Solution 3 PBS containing L-arginine at a concentration of 40 mM
  • Solution 4 PBS containing sodium taurodeoxycholate at a concentration of 5% (w / v).
  • LDH lactate dehydrogenase
  • Test Example 5 Evaluation 1 of the effect of the epithelial tissue on the tight junction structure The influence of the test substance on the tight junction structure was evaluated based on the electrical resistance (TEER) of the cultured cell layer after the test substance such as arginine was allowed to act. Specifically, it was performed as follows.
  • Human colon cancer-derived cells (Caco-2 cells) are seeded in a 12-well transwell plate (1.0 ⁇ 10 5 cells / cm 2 ) and cultured in DMEM medium for 21 days (constant TEER (> 500 ⁇ cm 2 ) (single It was shown that tight junctions were formed in the layer.
  • 500 ⁇ L of transport buffer 1 (HBSS buffered with 10 mM MES) was added to the apical side of the transwell, and buffered with 1.5 mL of transport buffer 2 (10 mM HEPES (pH 7.4)) on the basal side HBSS) was added and a 30 minute preincubation was performed.
  • TEER was measured using a voltage resistance meter (Millicell ERS-2, manufactured by Millipore), and the obtained value was defined as TEER (T 0 ) at the start of the test.
  • 100 ⁇ L of the apical side transport buffer 1 was replaced with 100 ⁇ L of a test substance-containing test solution, and incubated for 2 hours.
  • Test solution 1 insulin 15 ⁇ M Test solution 2: insulin 15 ⁇ M, L-arginine 480 ⁇ M Test solution 3: insulin 15 ⁇ M, L-arginine 960 ⁇ M Test solution 4: insulin 15 ⁇ M, D-arginine 480 ⁇ M Test solution 5: insulin 15 ⁇ M, D-arginine 960 ⁇ M Test solution 6: insulin 15 ⁇ M, D-arginine octapeptide 60 ⁇ M.
  • FIG. 5 shows a value obtained by dividing TEER (T 120 ) after the test by TEER (T 0 ) at the start of the test and multiplying by 100. As shown in FIG. 5, there was almost no change in TEER even when arginine was allowed to act at a very high concentration. From this, it was shown that arginine is a highly safe component that has very little influence on the tight junction structure of the intestinal epithelial tissue.
  • Test Example 6 Evaluation of transmucosal absorption promoting effect by combined use of basic amino acid and tryptophan Test was conducted in the same manner as in Test Example 1 except that the type and concentration of the test substance in the administration solution were as shown in Table 4. The results are shown in FIG. As shown in FIG. 6, insulin absorption was further promoted by using tryptophan in combination with a basic amino acid.
  • Test Example 7 Evaluation of transmucosal absorption promoting action of L-tryptophan alone Tested in the same manner as in Test Example 1 except that the type and concentration of the test substance in the administration solution were as shown in Table 5. The results are shown in FIG. As shown in FIG. 7, L-tryptophan further promoted insulin absorption.
  • Test Example 8 Evaluation of transmucosal absorption promoting action of D-tryptophan alone Tested in the same manner as in Test Example 1 except that the type and concentration of the test substance in the administration solution were as shown in Table 6. The results are shown in FIG. As shown in FIG. 8, insulin absorption was further promoted by D-tryptophan.
  • Test Example 9 Evaluation of the effect of intestinal epithelial tissue on the integrity 2 The test was conducted in the same manner as in Test Example 4 except that the following seven solutions were used as the administration solutions:
  • Solution A PBS containing methylcellulose at a concentration of 0.001%
  • Solution B PBS containing insulin (insulin content: 50 IU / body weight (kg))
  • Solution C PBS containing L-arginine at a concentration of 40 mM
  • D PBS containing L-tryptophan at a concentration of 16 mM Solution
  • E PBS containing L-tryptophan at a concentration of 32 mM
  • F PBS containing L-arginine at a concentration of 40 mM and L-tryptophan at a concentration of 50 mM
  • G PBS containing sodium taurodeoxycholate at a concentration of 5% (w / v).
  • the measurement results are shown in FIG. As shown in FIG. 9, when sodium taurodeoxycholate, which is a positive control, was administered, the LDH concentration in the intestinal fluid was extremely higher than when PBS was administered. This indicates that the integrity of the intestinal epithelium was disrupted by sodium taurodeoxycholate, so that LDH originally present in the cell leaked through the intestinal epithelium. On the other hand, the LDH concentration in the intestinal fluid when tryptophan was administered had almost no change from that when PBS was administered, so tryptophan has very little effect on the integrity of the intestinal epithelial tissue and is safe. It was shown to be a high component.
  • Test Example 10 In vivo oral administration test In mice after a 24-hour fast, insulin (50 IU / kg), L-arginine (200 mM), or insulin and L-arginine (40 or 200 mM) (100 ⁇ L) mixed solution was orally administered using an oral sonde (i..d. 0.9 ⁇ length 50 mm) (Natsume Seisakusho Co., Ltd., Tokyo, Japan). Before administration, and 15, 30, 60, 120, 180, 240, 300, and 360 minutes after administration, blood was collected from the tail vein (one drop), and blood glucose level was measured over time with One Touch Ultra View (Johnson & Johnson KK, Tokyo, Japan).
  • the measurement results are shown in FIG. As shown in FIG. 10, the blood glucose level was not suppressed by oral administration of insulin or L-arginine alone, but the blood glucose level was suppressed by oral administration of insulin with L-arginine.

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Abstract

La présente invention aborde le problème de l'obtention d'un promoteur d'absorption transmucosale pour un médicament. Ce problème est résolu en utilisant au moins un élément choisi dans le groupe constitué par : (constituant a) un acide aminé basique ; (constituant b) un peptide constitué de 2 à 5 acides aminés basiques ; et (constituant c) du tryptophane.
PCT/JP2017/015181 2016-04-19 2017-04-13 Promoteur d'absorption transmucosale pour médicament WO2017183559A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424239A (zh) * 2018-07-11 2021-02-26 学校法人常翔学园 高分子化合物及使用了该高分子化合物的细胞内化合物导入促进剂
JP2021520391A (ja) * 2018-04-06 2021-08-19 シプルメット・ゲーエムベーハー 治療用ペプチド及び治療用タンパク質の経粘膜送達のための薬学的組成物
US11857547B2 (en) 2018-11-06 2024-01-02 Purdue Pharma L.P. Compositions and methods for opioid antagonist delivery

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