WO2019215862A1 - Evaluation method for cytochrome p450 metabolic activity - Google Patents

Evaluation method for cytochrome p450 metabolic activity Download PDF

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WO2019215862A1
WO2019215862A1 PCT/JP2018/018052 JP2018018052W WO2019215862A1 WO 2019215862 A1 WO2019215862 A1 WO 2019215862A1 JP 2018018052 W JP2018018052 W JP 2018018052W WO 2019215862 A1 WO2019215862 A1 WO 2019215862A1
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drug
film preparation
cytochrome
molecular species
predetermined molecular
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PCT/JP2018/018052
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French (fr)
Japanese (ja)
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遼 内冨
裕洋 山崎
イェルク ヒュビラー
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救急薬品工業株式会社
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Publication of WO2019215862A1 publication Critical patent/WO2019215862A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • 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
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers

Definitions

  • the present invention relates to a method for evaluating a subject's cytochrome P450 metabolic activity.
  • CYP cytochrome P450
  • the molecular species of CYP includes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, etc. Is involved. From this point of view, it is obliged to evaluate which molecular species of CYP is metabolized for a drug that is to be approved for manufacture in recent years.
  • Non-patent Documents 1 and 2 there are individual differences in what CYP metabolic activity a subject who wants to receive a drug has. Therefore, in order to appropriately perform individual drug therapy (tailor-made drug therapy), it is necessary to evaluate the CYP metabolic activity of each individual subject.
  • evaluating the CYP metabolic activity of a subject there is a method in which a drug is administered and the concentration transition of the drug and drug metabolite in blood is measured. Specifically, a method of intravenously administering a drug solution and measuring unchanged substance and metabolite is performed (Non-patent Documents 1 and 2).
  • the injection solution needs to be diluted when a commercially available injection is used for intravenous administration. Moreover, since only a small amount is used, there is a problem of remaining medicine. In the case of storing a diluted injection solution, there are problems such as drug stability and ensuring a sterile condition. Intravenous administration is also painful. Therefore, it is considered that oral administration is good for the drug administration method. However, an aqueous solution of a drug is poor in stability of the drug or may cause mold, bacteria, etc. in the aqueous solution, so that it is difficult to store for a long period of time, and it is necessary to prepare for use.
  • the aqueous solution has a problem of feeling the bitterness of the drug.
  • the dissolution rate of the tablet in the digestive tract differs depending on the subject, and there is a problem that affects the metabolic activity evaluation. For example, in subjects with low gastric acid or poor gastrointestinal motility, the tablet does not dissolve quickly in the gastrointestinal tract, so the drug slowly elutes from the undissolved tablet, and the above (unchanged) / (Metabolite) ratio may be affected.
  • an object of the present invention is to provide a CYP metabolic activity evaluation means using a composition that can be stored for a long period of time and is not affected by a difference in dissolution rate of a subject.
  • the present inventor has made various studies to solve the above problems, and if a film preparation in which an inactive amount of a test drug is contained in an intraoral fast-dissolving film is used, long-term preservability is good and intraoral It is found that the same unchanged substance / metabolite ratio can be obtained as in the case of administering an aqueous solution of the drug without being affected by the difference in dissolution rate in the digestive tract by the subject.
  • the present invention has been completed.
  • the present invention provides the following [1] to [39].
  • the subject's metabolic activity evaluation of a predetermined molecular species of cytochrome P450 is obtained by orally administering the intraoral fast-dissolving film preparation to the subject, and the concentration of the drug and the drug metabolite in the blood of the subject
  • the film preparation according to any one of [1] to [5], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
  • An intraoral fast-dissolving film preparation for evaluating CYP3A metabolic activity in a subject comprising 5 ⁇ g to 5 mg of midazolam per dosage unit.
  • the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
  • the film preparation according to [11], wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
  • the metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral fast-dissolving film preparation to the subject, and the concentration of the drug and the drug metabolite in the blood of the subject
  • the subject is orally administered with a fast-dissolving film preparation in the oral cavity containing a drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 and is orally administered, and the drug in the blood of the subject And a method for evaluating the metabolic activity of a predetermined molecular species of cytochrome P450 of the subject, wherein the concentration transition of the drug metabolite is measured.
  • the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
  • the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
  • the fast-dissolving film preparation of the present invention is a preparation that, when placed in the oral cavity, can dissolve the preparation quickly with a small amount of saliva and can swallow the drug reliably.
  • the fast dissolving film preparation is a very thin and light preparation. Accordingly, the amount of additives such as excipients is small, and the dissolution rate of the preparation varies depending on the patient's condition like a tablet.
  • the preparation (composition) for evaluating the metabolic activity of a predetermined molecular species of CYP of a subject used in the present invention is an inactive dose of a drug that is specifically metabolized by the predetermined molecular species of CYP.
  • the subject in the present invention is a human who is evaluated for drug metabolic activity, and is usually a human who may receive a drug therapy or a human who is receiving a drug therapy.
  • the drug used for drug therapy and the drug used for evaluation of metabolic activity may be the same or different, but drugs having the same molecular species of CYP undergoing metabolism are preferred.
  • the predetermined molecular species of CYP is one or more molecular species selected from CYP molecular species, and examples include CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A.
  • it is CYP3A involved in the metabolism of many drugs, and more preferably CYP3A4.
  • the drug that is specifically metabolized by a predetermined molecular species of CYP contained in the intraoral fast-dissolving film used in the present invention is a drug that is specifically metabolized by CYP1A, CYP2A, or CYP3A. I just need it.
  • benzopyrene, acetaminophen, propranolol, caffeine, theophylline and the like are listed as drugs that undergo metabolism by CYP1A.
  • Examples of drugs that undergo metabolism by CYP2A include tegafur and nicotine.
  • Examples of drugs that are metabolized by CYP2B include cyclophosphamide, ketamine and the like.
  • Examples of drugs that are metabolized by CYP2C include ibuprofen, diclofenac, phenytoin, warfarin, diazepam, omeprazole, lansoprazole, clopidogrel, and the like.
  • Examples of drugs that undergo metabolism by CYP2D include tamoxifen, fluvoxamine, haloperidol, propranolol, and codeine.
  • Examples of drugs that undergo metabolism by CYP2E include halothane, enflurane, acetaminophen, and the like.
  • drugs that are metabolized by CYP3A include benzodiazepine compounds such as midazolam, amiodarone, paclitaxel, tamoxifen, docetaxel, tacrolimus, carbamazepine, nifedipine, testosterone, and the like.
  • a benzodiazepine compound is preferred, and midazolam is more preferred.
  • a drug known to be specifically metabolized by CYP3A4 is preferable, of which a benzodiazepine compound is preferable, and midazolam is more preferable.
  • the film preparation used in the present invention contains an inactive amount of the above-mentioned drug administered orally.
  • the no-effect level refers to an exposure level (dose) at which no effects including harmful / innocuous effects are observed when toxicity to animals is observed at multiple dose levels in a toxicity test for chemical substances.
  • the dose does not show any effect in oral administration. This amount of no action varies depending on the drug.
  • it is sufficient to contain 5 ⁇ g to 5 mg per dosage unit, preferably 10 ⁇ g to 100 ⁇ g, more preferably 10 ⁇ g to 50 ⁇ g, further preferably 10 ⁇ g to 40 ⁇ g, and further preferably 20 ⁇ g to 40 ⁇ g.
  • the intraoral fast-dissolving film used in the present invention preferably contains 5 to 5 mg of midazolam, more preferably 10 to 100 ⁇ g, more preferably 10 to 40 ⁇ g per unit dose. More preferably, the content is 20 ⁇ g to 40 ⁇ g.
  • the intraoral fast-dissolving film of the present invention is a film that dissolves rapidly in the oral cavity, and its dissolution time in water is preferably 15 minutes or less, more preferably 1 to 15 minutes, further preferably 3 to 15 minutes, More preferably, it is 5 to 10 minutes.
  • the dissolution time is the time until the film becomes transparent when 100 ⁇ g of film is dissolved in 900 mL of pure water at 37.5 ° C. at a paddle rotation speed of 50 rpm in accordance with the paddle test method of the dissolution test method of the Japanese Pharmacopoeia. It is.
  • the intraoral fast-dissolving film of the present invention has a drug layer containing a water-soluble polymer and the drug (preferably a benzodiazepine compound, more preferably midazolam), and a support layer containing a water-soluble polymer on both sides thereof.
  • a film is preferable from the viewpoint of fast solubility and taste (see FIG. 1).
  • the water-soluble polymer used in the drug layer may be any water-soluble polymer having film-forming ability, for example, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose, HPMC), pullulan, hydroxyethylcellulose, carboxy Examples thereof include methyl cellulose / sodium, carboxymethyl cellulose / calcium, carboxymethyl cellulose / potassium, carboxymethyl cellulose and sodium alginate, and one or more selected from these can be used in combination. Of these, it is more preferable to use hydroxypropylmethylcellulose.
  • HPC hydroxypropylcellulose
  • HPMC hypromellose
  • pullulan hydroxyethylcellulose
  • carboxy examples thereof include methyl cellulose / sodium, carboxymethyl cellulose / calcium, carboxymethyl cellulose / potassium, carboxymethyl cellulose and sodium alginate, and one or more selected from these can be used in combination. Of these, it is more preferable to use hydroxypropylmethylcellulose.
  • the content of the water-soluble polymer in the drug layer is preferably 20 to 90%, more preferably 60 to 85%, still more preferably 65 to 75% based on the drug layer mass.
  • water-soluble polymer used in the support layer examples include water-soluble polymers having the same film-forming ability as described above. That is, for example, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose, HPMC), pullulan, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, sodium alginate, etc. One or more selected from these can be used in combination. Of these, it is more preferable to use hypromellose.
  • the content of the water-soluble polymer in the support layer is preferably 50 to 90%, more preferably 70 to 90%, still more preferably 75 to 85% based on the mass of the support layer.
  • the drug layer and the support layer may contain one or more selected from disintegrants, taste-masking agents, sweeteners, colorants, plasticizers, and fragrances.
  • disintegrants examples include crystalline cellulose, carmellose and salts thereof, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and salts thereof, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene polyoxypropylene Glycol, maltitol, trehalose and the like can be mentioned, and one or a combination of two or more selected from these is preferable.
  • crystalline cellulose is particularly preferable.
  • the content of the disintegrant in the drug layer is preferably 1 to 30% by mass, particularly 5 to 25% by mass.
  • the content of the disintegrant in the support layer is preferably 5 to 60% by mass, particularly 10 to 50% by mass.
  • the corrigent examples include acidulants such as menthol, ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof, and one or a combination of two or more selected from these is preferable. Of these, menthol is particularly preferable.
  • the content of the corrigent in the drug layer is preferably 0.05 to 1% by mass, particularly preferably 0.1 to 0.5% by mass. Further, the content of the corrigent in the support layer is preferably 0.1 to 5% by mass, particularly preferably 1.0 to 2.0% by mass.
  • sweetener examples include aspartame, stevia, sucralose, glycyrrhizic acid or a salt thereof (for example, alkali metal salt), thaumatin, acesulfame potassium, saccharin or a salt thereof (for example, an alkali metal salt), and the like.
  • a seed or a combination of two or more is preferred.
  • glycyrrhizic acid salt, saccharin salt and sucralose are particularly preferable.
  • the content of the sweetening agent in the drug layer is preferably 0.1 to 10% by mass, particularly 0.5 to 5% by mass.
  • the content of the sweetening agent in the support layer is preferably 0.1 to 40% by mass, particularly 1.0 to 20% by mass.
  • the colorant examples include yellow ferric oxide, brown iron oxide, caramel, black iron oxide, titanium oxide, ferric oxide, tar dye, aluminum lake dye, copper chlorophyllin sodium, and the like. Or the combination of 2 or more types is preferable. Of these, titanium oxide and iron sesquioxide are particularly preferable.
  • the content of the colorant in the drug layer is preferably 0.01 to 10% by mass, particularly 0.05 to 5% by mass. Further, the content of the colorant in the support layer is preferably 0.1 to 20% by mass, particularly preferably 0.2 to 15% by mass.
  • plasticizer examples include sesame oil, sorbitol, castor oil, propylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [for example, macrogol 400 (polymerization degree n of oxyethylene unit is 7). ⁇ 9, the same applies hereinafter), macro goal 600 (n is 11 to 13), macro goal 1500 (a mixture of n is 5 to 6 and n is 28 to 36), macro goal 4000 (n is 59 to 84), macrogol 6000 (n is 165 to 210)] and the like, and one or a combination of two or more selected from these is preferable.
  • polyethylene glycol particularly Macrogol 400 is preferable.
  • the content of the plasticizer in the drug layer is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass.
  • the content of the plasticizer in the support layer is preferably 0.1 to 50% by mass, particularly preferably 0.1 to 30% by mass.
  • vanilla flavor, orange flavor, orange peel flavor, strawberry flavor, raspberry flavor, chocolate flavor, grapefruit flavor, cranberry flavor, ume flavor, coconut flavor, herbal flavor, coffee flavor, tea flavor, cinnamon flavor, Honey lemon flavor etc. are illustrated. These can be used alone or in combination.
  • orange flavor and grapefruit flavor are preferable from the viewpoint of improving the refreshing feeling and the refreshing feeling when dissolving the preparation.
  • the film preparation used in the present invention has a three-layer structure in which a support layer, a drug layer, and a support layer are sequentially laminated. When the same kind of layers are laminated adjacently, they are in close contact with each other. However, in order to perform the same function as a unit, the present invention handles substantially one layer.
  • the thickness of the entire film preparation is preferably 50 to 200 ⁇ m, particularly preferably 70 to 180 ⁇ m.
  • the thickness of the drug layer is preferably 10 to 50 ⁇ m, particularly preferably 20 to 40 ⁇ m
  • the thickness of the support layer is preferably 10 to 50 ⁇ m, particularly preferably 20 to 50 ⁇ m. Thereby, it is possible to dissolve quickly in the oral cavity.
  • the size of the film preparation is not particularly limited as long as it is easy to take, but for example, it is preferably about 1 to 5 cm 2 , and the shape is also easy to take. For example, a square, a circle, an ellipse, or the like can be selected as appropriate.
  • the film preparation can be appropriately produced by conventional or known methods. For example, it is manufactured by laminating a first support layer on a release film such as PET (polyethylene terephthalate), then laminating a drug layer, and then laminating a second support layer on the drug layer. Can do. In addition, an intermediate product in which a first support layer is laminated on a release film and a drug layer is further laminated, and an intermediate product in which a second support layer is laminated on the release film and a drug layer is further laminated. It is also possible to produce by manufacturing and then bonding and pressing so that both drug layers face each other.
  • a release film such as PET (polyethylene terephthalate)
  • the film preparation is orally administered to the subject, and the blood concentration of the drug (unmodified) and the drug (metabolite) in the blood of the subject is determined. Just measure. Specifically, the enzyme activity of the drug metabolizing enzyme (CYP) is evaluated from the concentration ratio of (unmodified) / (metabolite) in blood. If the enzymatic activity of CYP is determined by the method of the present invention, the optimal dose, administration interval, etc. of the drug metabolized by the same CYP as this drug can be determined.
  • CYP drug metabolizing enzyme
  • the film preparation of the present invention dissolves rapidly in the oral cavity, so that the drug in the preparation can be swallowed reliably.
  • the concentration of unchanged substance and metabolite in the blood may be measured by collecting blood from the subject at regular intervals after administration and measuring the unchanged concentration and metabolite concentration in the blood.
  • a metabolite of a drug is a component that is known to be metabolized by CYP.
  • the method for measuring the concentrations of these unchanged substances and metabolites may be any method that can quantify the drugs and metabolites.
  • midazolam When midazolam is used, its metabolite is 1-hydroxymidazolam. Midazolam and 1-hydroxymidazolam can be quantified by high performance liquid chromatography.
  • the concentration ratio of (unmodified) / (metabolite) may be measured. By changing this ratio, it can be determined whether the drug is metabolized by CYP.
  • An intraoral fast-dissolving film having the composition described in Table 1 was produced. Each raw material of the drug layer or the support layer was stirred until it became uniform to obtain a drug layer paste and a support layer paste, respectively. First, the support layer solution was spread on a polyester release film and dried to form a support layer, and then the drug layer solution was spread on the support layer and dried to laminate the drug layer. Next, two layers of the obtained laminate were laminated with the drug layer inside, to obtain a three-layer film of support layer / drug layer / support layer. The obtained film was cut into a 14 mm ⁇ 20 mm film.
  • Test Example 1 Solubility test A film obtained by setting the film obtained in the above production example to a size containing 100 ⁇ g of midazolam was used. The film was put into 900 mL of pure water at 37.5 ° C. and stirred at 50 rpm to confirm the solubility. As a result, it was confirmed that almost 100% was dissolved in about 5 to 10 minutes.
  • Test Example 2 (CYP3A metabolic activity measurement test in adults) (1) Twelve healthy adults were orally administered a single oral oral soluble film containing 30 ⁇ g midazolam (obtained in the production example), and the midazolam and 1-hydroxymidazolam plasma concentrations were measured after administration. As a control, a solution containing 30 ⁇ g of midazolam was used. Film administration and aqueous solution administration were crossover tests with a washout period of 7 days. Blood was collected at 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours after oral administration. Midazolam and 1-hydroxymidazolam concentrations were measured by high performance liquid chromatography.
  • FIG. 2 Change in plasma concentration of midazolam is shown in FIG. 2, and change in plasma concentration of 1-hydroxymidazolam is shown in FIG.
  • FIG. 4 shows changes in plasma concentration of midazolam / 1-hydroxymidazolam ratio.
  • the AUC of midazolam and 1-hydroxymidazolam is shown in FIG. 5
  • t max is shown in FIG. 6
  • C max is shown in FIG.
  • the intraoral fast-dissolving film containing a small amount of midazolam showed a CYP3A test activity equivalent to the aqueous solution containing midazolam.

Abstract

Provided is a CYP metabolic activity evaluation means that uses a composition that can be stored for a long time and is not affected by differences in dissolution rate among subjects. An intraoral rapid-soluble film preparation for evaluating the metabolic activity of a prescribed molecular species of cytochrome P450 in a subject. The intraoral rapid-soluble film preparation is characterized by containing an oral dose no-observed-effect level of a drug that is specifically metabolized by the prescribed molecular species of cytochrome P450.

Description

シトクロムＰ４５０代謝活性の評価方法Method for evaluating cytochrome P450 metabolic activity
　本発明は、対象者のシトクロムＰ４５０代謝活性の評価方法に関する。 The present invention relates to a method for evaluating a subject's cytochrome P450 metabolic activity.
　薬物に対する応答性に大きな個人差があることは古くから知られており、その代表格が薬物代謝能の個人差、すなわちシトクロムＰ４５０（ＣＹＰ）代謝活性の個人差である。ＣＹＰには、１７種類の主な分子種があり、現在上市されている薬物の９０％以上の代謝にＣＹＰが関与している。ＣＹＰの分子種としては、ＣＹＰ１Ａ１、ＣＹＰ１Ａ２、ＣＹＰ２Ａ６、ＣＹＰ２Ｂ６、ＣＹＰ２Ｃ８、ＣＹＰ２Ｃ９、ＣＹＰ２Ｄ６、ＣＹＰ２Ｅ１、ＣＹＰ３Ａ４、ＣＹＰ３Ａ５等が存在するが、ＣＹＰ３Ａ４及びＣＹＰ３Ａ５等のＣＹＰ３ＡはＣＹＰが関与する薬物の代謝の約半数に関与している。かかる観点から、近年製造承認を受けようとする薬物については、どのＣＹＰの分子種によって代謝されるかを評価することが義務付けられている。 It has been known for a long time that there is a large individual difference in the responsiveness to drugs, and the representative is the individual difference in drug metabolic ability, that is, the individual difference in cytochrome P450 (CYP) metabolic activity. There are 17 main molecular species of CYP, and CYP is involved in the metabolism of 90% or more of drugs currently on the market. The molecular species of CYP includes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, etc. Is involved. From this point of view, it is obliged to evaluate which molecular species of CYP is metabolized for a drug that is to be approved for manufacture in recent years.
　一方で、薬物投与を受けようとする対象者が、どのようなＣＹＰ代謝活性を有しているかについては、個人差がある。従って、個別薬物療法（テーラーメイド薬物療法）を適確に行うためには、対象者個別のＣＹＰ代謝活性を評価する必要がある。対象者のＣＹＰ代謝活性の評価にあたっては、薬物を投与し、血液中の薬物及び薬物代謝物の濃度推移を測定する方法がある。具体的には、薬物溶液を静脈内投与し、未変化体と代謝物を測定する方法が行なわれている（非特許文献１、２）。 On the other hand, there are individual differences in what CYP metabolic activity a subject who wants to receive a drug has. Therefore, in order to appropriately perform individual drug therapy (tailor-made drug therapy), it is necessary to evaluate the CYP metabolic activity of each individual subject. In evaluating the CYP metabolic activity of a subject, there is a method in which a drug is administered and the concentration transition of the drug and drug metabolite in blood is measured. Specifically, a method of intravenously administering a drug solution and measuring unchanged substance and metabolite is performed (Non-patent Documents 1 and 2).
　しかしながら、薬効を発現しない薬物の投与量で代謝酵素活性を測定する場合、静脈内投与では市販の注射剤を用いる時には、注射液を希釈する必要がある。また、少量しか使用しないので残薬の問題がある。希釈した注射液を保管する場合は、薬物の安定性、無菌状態の確保等の問題を有している。また、静脈内投与は苦痛を伴う問題もある。
　従って、薬物投与方法は経口投与が良いと考えられる。ところが、薬物の水溶液は、薬物の安定性が悪かったり、水溶液にカビ、雑菌等が発生する恐れがあるので、長期間保存することは困難であり用事調製する必要があった。また、代謝活性評価では、一定量の薬物を確実に投与する必要があるので、液剤の服用では、薬物の水溶液がカップに残り一定量を投与できない問題があった。また、水溶液では薬物の苦味を感じる問題もあった。
　薬物を錠剤で投与する場合、対象者により消化管内での錠剤の溶解速度が異なり、代謝活性評価に影響を及ぼす問題があった。例えば、胃酸が少なかったり、消化管の運動が悪い対象者では、錠剤が速やかに消化管内で溶解しないために、溶け残った錠剤から薬物がゆっくりと溶出してしまい、前述の（未変化体）／（代謝物）の比率に影響を及ぼす恐れがある。 However, when the metabolic enzyme activity is measured at a dose of a drug that does not exhibit a medicinal effect, the injection solution needs to be diluted when a commercially available injection is used for intravenous administration. Moreover, since only a small amount is used, there is a problem of remaining medicine. In the case of storing a diluted injection solution, there are problems such as drug stability and ensuring a sterile condition. Intravenous administration is also painful.
Therefore, it is considered that oral administration is good for the drug administration method. However, an aqueous solution of a drug is poor in stability of the drug or may cause mold, bacteria, etc. in the aqueous solution, so that it is difficult to store for a long period of time, and it is necessary to prepare for use. In addition, since it is necessary to reliably administer a certain amount of drug in metabolic activity evaluation, there has been a problem that taking a liquid agent leaves an aqueous solution of the drug remaining in the cup and cannot administer a certain amount. In addition, the aqueous solution has a problem of feeling the bitterness of the drug.
When a drug is administered as a tablet, the dissolution rate of the tablet in the digestive tract differs depending on the subject, and there is a problem that affects the metabolic activity evaluation. For example, in subjects with low gastric acid or poor gastrointestinal motility, the tablet does not dissolve quickly in the gastrointestinal tract, so the drug slowly elutes from the undissolved tablet, and the above (unchanged) / (Metabolite) ratio may be affected.
　従って、本発明の課題は、長期間保存可能で、対象者の溶解速度の差に影響を受けない組成物を用いたＣＹＰ代謝活性評価手段を提供することにある。 Therefore, an object of the present invention is to provide a CYP metabolic activity evaluation means using a composition that can be stored for a long period of time and is not affected by a difference in dissolution rate of a subject.
　そこで本発明者は、前記課題を解決すべく種々検討したところ、被験薬物の無作用量を、口腔内速溶性フィルム中に含有させたフィルム製剤を用いれば、長期保存性が良好で、口腔内で速やかに溶解するため、対象者による消化管内での溶解速度の差に影響を受けずに、薬物の水溶液を投与した場合と同様の未変化体／代謝物の比率が得られることを見出し、本発明を完成した。 Therefore, the present inventor has made various studies to solve the above problems, and if a film preparation in which an inactive amount of a test drug is contained in an intraoral fast-dissolving film is used, long-term preservability is good and intraoral It is found that the same unchanged substance / metabolite ratio can be obtained as in the case of administering an aqueous solution of the drug without being affected by the difference in dissolution rate in the digestive tract by the subject. The present invention has been completed.
　すなわち、本発明は、次の〔１〕～〔３９〕を提供するものである。 That is, the present invention provides the following [1] to [39].
〔１〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有することを特徴とする、対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価用口腔内速溶性フィルム製剤。
〔２〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである〔１〕記載のフィルム製剤。
〔３〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である〔１〕記載のフィルム製剤。
〔４〕前記フィルム製剤の水に対する溶解時間が、１０分以下である〔１〕～〔３〕のいずれかに記載のフィルム製剤。
〔５〕対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである〔１〕～〔４〕のいずれかに記載のフィルム製剤。
〔６〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である〔１〕～〔５〕のいずれかに記載のフィルム製剤。
〔７〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである〔１〕～〔５〕のいずれかに記載のフィルム製剤。
〔８〕ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有することを特徴とする、対象者のＣＹＰ３Ａ代謝活性評価用口腔内速溶性フィルム製剤。
〔９〕前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである〔８〕記載のフィルム製剤。
〔10〕薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する〔９〕記載のフィルム製剤。
〔11〕対象者のシトクロムＰ４５０の所定の分子種の代謝活性を評価するための、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルム製剤。
〔12〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである〔１１〕記載のフィルム製剤。
〔13〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である〔１１〕記載のフィルム製剤。
〔14〕前記フィルム製剤の水に対する溶解時間が、１０分以下である〔１１〕～〔１３〕のいずれかに記載のフィルム製剤。
〔15〕対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである〔１１〕～〔１４〕のいずれかに記載のフィルム製剤。
〔16〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である〔１１〕～〔１５〕のいずれかに記載のフィルム製剤。
〔17〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである〔１１〕～〔１５〕のいずれかに項記載のフィルム製剤。
〔18〕対象者のＣＹＰ３Ａ代謝活性を評価するための、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルム製剤。
〔19〕前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである〔１８〕記載のフィルム製剤。
〔20〕薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する〔１９〕記載のフィルム製剤。
〔21〕対象者に、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルム製剤を経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することを特徴とする、当該対象者のシトクロムＰ４５０の所定の分子種の代謝活性の評価方法。
〔22〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである〔２１〕記載の評価方法。
〔23〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である〔２１〕記載の評価方法。
〔24〕前記フィルム製剤の水に対する溶解時間が、１０分以下である〔２１〕～〔２３〕のいずれかに記載の評価方法。
〔25〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である〔２１〕～〔２４〕のいずれかに記載の評価方法。
〔26〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである〔２１〕～〔２４〕のいずれかに記載の評価方法。
〔27〕対象者に、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルム製剤を経口投与し、当該対象者の血液中のミダゾラム及びミダゾラム代謝物の濃度推移を測定することを特徴とする、当該対象者のＣＹＰ３Ａ代謝活性の評価方法。
〔28〕前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである〔２７〕記載の評価方法。
〔29〕前記薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する〔２８〕記載の評価方法。
〔30〕対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価用口腔内速溶性フィルム製剤を製造するための、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルムの使用。
〔31〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである〔３０〕記載の使用。
〔32〕シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である〔３０〕記載の使用。
〔33〕前記フィルム製剤の水に対する溶解時間が、１０分以下である〔３０〕～〔３２〕のいずれかに記載の使用。
〔34〕対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである〔３０〕～〔３３〕のいずれかに記載の使用。
〔35〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である〔３０〕～〔３４〕のいずれかに記載の使用。
〔36〕シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである〔３０〕～〔３４〕のいずれかに記載の使用。
〔37〕対象者のＣＹＰ３Ａ代謝活性評価用口腔内速溶性フィルム製剤を製造するための、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルムの使用。
〔38〕前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである〔３７〕記載の使用。
〔39〕薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する〔３８〕記載の使用。 [1] Intraoral rapid dissolution for evaluating metabolic activity of a predetermined molecular species of cytochrome P450 of a subject, containing a non-acting dose of a drug that is specifically metabolized by the predetermined molecular species of cytochrome P450 Film formulation.
[2] The film preparation according to [1], wherein the predetermined molecular species of cytochrome P450 is CYP3A.
[3] The film preparation according to [1], wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
[4] The film preparation according to any one of [1] to [3], wherein the dissolution time of the film preparation in water is 10 minutes or less.
[5] The subject's metabolic activity evaluation of a predetermined molecular species of cytochrome P450 is obtained by orally administering the intraoral fast-dissolving film preparation to the subject, and the concentration of the drug and the drug metabolite in the blood of the subject The film preparation according to any one of [1] to [4], which is evaluated by measuring a transition.
[6] The film preparation according to any one of [1] to [5], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
[7] The film preparation according to any one of [1] to [5], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
[8] An intraoral fast-dissolving film preparation for evaluating CYP3A metabolic activity in a subject, comprising 5 μg to 5 mg of midazolam per dosage unit.
[9] The film preparation according to [8], wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
[10] The film preparation according to [9], wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
[11] A fast-dissolving film in the oral cavity containing a drug capable of being metabolized specifically by a predetermined molecular species of cytochrome P450 for evaluating the metabolic activity of the subject's specific molecular species of cytochrome P450 Formulation.
[12] The film preparation according to [11], wherein the predetermined molecular species of cytochrome P450 is CYP3A.
[13] The film preparation according to [11], wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
[14] The film preparation according to any one of [11] to [13], wherein the dissolution time of the film preparation in water is 10 minutes or less.
[15] The metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral fast-dissolving film preparation to the subject, and the concentration of the drug and the drug metabolite in the blood of the subject The film preparation according to any one of [11] to [14], which is evaluated by measuring a transition.
[16] The film preparation according to any one of [11] to [15], wherein the drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
[17] The film preparation according to any one of [11] to [15], wherein the drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
[18] An intraoral fast-dissolving film preparation containing 5 μg to 5 mg of midazolam per dosage unit for evaluating the subject's CYP3A metabolic activity.
[19] The film preparation according to [18], wherein the film preparation has a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
[20] The film preparation according to [19], wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
[21] The subject is orally administered with a fast-dissolving film preparation in the oral cavity containing a drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 and is orally administered, and the drug in the blood of the subject And a method for evaluating the metabolic activity of a predetermined molecular species of cytochrome P450 of the subject, wherein the concentration transition of the drug metabolite is measured.
[22] The evaluation method according to [21], wherein the predetermined molecular species of cytochrome P450 is CYP3A.
[23] The evaluation method according to [21], wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
[24] The evaluation method according to any one of [21] to [23], wherein the dissolution time of the film preparation in water is 10 minutes or less.
[25] The evaluation method according to any one of [21] to [24], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
[26] The evaluation method according to any one of [21] to [24], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
[27] To orally administer a fast-dissolving film preparation of oral cavity containing 5 μg to 5 mg of midazolam per dosage unit to a subject and measure the transition of midazolam and midazolam metabolites in the blood of the subject A method for evaluating the CYP3A metabolic activity of the subject.
[28] The evaluation method according to [27], wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
[29] The evaluation method according to [28], wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
[30] Oral administration of a drug that is specifically metabolized to a predetermined molecular species of cytochrome P450 for the production of an intraoral fast-dissolving film preparation for evaluating the metabolic activity of the predetermined molecular species of cytochrome P450 of the subject Use of intraoral fast-dissolving film containing a quantity.
[31] The use according to [30], wherein the predetermined molecular species of cytochrome P450 is CYP3A.
[32] The use according to [30], wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
[33] The use according to any one of [30] to [32], wherein the dissolution time of the film preparation in water is 10 minutes or less.
[34] The metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral rapidly soluble film preparation to the subject, and the concentration of the drug and the drug metabolite in the blood of the subject The use according to any one of [30] to [33], which is evaluated by measuring a transition.
[35] The use according to any one of [30] to [34], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
[36] The use according to any one of [30] to [34], wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
[37] Use of an intraoral fast-dissolving film containing 5 μg to 5 mg of midazolam per dosage unit for producing an intraoral fast-dissolving film preparation for evaluating CYP3A metabolic activity of a subject.
[38] The use according to [37], wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
[39] The use according to [38], wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
　本発明の口腔内速溶性フィルム製剤を用いれば、薬物の水溶液を用いた場合と同様の未変化体／代謝物の血液濃度推移が得られ、対象者毎の正確な薬物代謝活性が測定できる。
　本発明の速溶型フィルム製剤は、口腔内に入れると、少量の唾液で製剤が速やかに溶解し、薬物を確実に嚥下することができる製剤である。また、速溶型フィルム製剤は、非常に薄く軽い製剤である。
　従って、賦形剤等製剤の添加物の量が少なく、錠剤のように患者の状態により製剤の溶解速度が変動する恐れが小さい特性を有している。
　これらの特徴により、経口液剤や錠剤が有する、薬物の安定性、用事調製、投与量の変動、製剤の溶解速度の変動により、誤った代謝酵素評価をする恐れ等の問題を解決することができる。 If the intraoral fast-dissolving film preparation of the present invention is used, the same blood concentration transition of unchanged substance / metabolite as in the case of using an aqueous solution of a drug can be obtained, and accurate drug metabolic activity for each subject can be measured.
The fast-dissolving film preparation of the present invention is a preparation that, when placed in the oral cavity, can dissolve the preparation quickly with a small amount of saliva and can swallow the drug reliably. The fast dissolving film preparation is a very thin and light preparation.
Accordingly, the amount of additives such as excipients is small, and the dissolution rate of the preparation varies depending on the patient's condition like a tablet.
These characteristics can solve problems such as the risk of incorrect metabolic enzyme evaluation due to the stability of drugs, preparation of preparations, fluctuations in dosage, fluctuations in the dissolution rate of preparations, etc. possessed by oral liquids and tablets. .
口腔内速溶性フィルムの一形態を示す図である。It is a figure which shows one form of the intraoral quick melt film. ミダゾラムの血漿中濃度推移を示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。The time course of plasma concentration of midazolam is shown. Solution: Aqueous solution. Film: film. １－ヒドロキシミダゾラムの推移を示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。1 shows the transition of 1-hydroxymidazolam. Solution: Aqueous solution. Film: film. 血漿中ミダゾラム／ヒドロキシミダゾラム比の推移を示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。The transition of plasma midazolam / hydroxymidazolam ratio is shown. Solution: Aqueous solution. Film: film. ミダゾラム及び１－ヒドロキシミダゾラムのＡＵＣ0-12（１２時間血漿中濃度曲線下面積）を示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。AUC 0-12 (area under the 12-hour plasma concentration curve) for midazolam and 1-hydroxymidazolam is shown. Solution: Aqueous solution. Film: film. ミダゾラム及び１－ヒドロキシミダゾラムのｔmaxを示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。The t max for midazolam and 1-hydroxymidazolam is shown. Solution: Aqueous solution. Film: film. ミダゾラム及び１－ヒドロキシミダゾラムのＣmaxを示す。Ｓｏｌｕｔｉｏｎ：水溶液。Ｆｉｌｍ：フィルム。The C max for midazolam and 1-hydroxymidazolam is shown. Solution: Aqueous solution. Film: film.
　本発明に用いられる対象者のＣＹＰの所定の分子種の代謝活性を評価するための製剤（組成物）は、ＣＹＰの所定の分子種に特異的に代謝を受ける薬物を経口投与の無作用量を含有する口腔内速溶性フィルム組成物である。 The preparation (composition) for evaluating the metabolic activity of a predetermined molecular species of CYP of a subject used in the present invention is an inactive dose of a drug that is specifically metabolized by the predetermined molecular species of CYP. Is an intraoral fast-dissolving film composition containing
　本発明における対象者とは、薬物代謝活性の評価を受けるヒトであり、通常は薬物療法を受ける可能性のあるヒト又は薬物療法を受けているヒトである。ここで、薬物療法に用いられる薬物と、代謝活性の評価に用いる薬物とは同一でも異なっていてもよいが、代謝を受けるＣＹＰの分子種が同じである薬物が好ましい。 The subject in the present invention is a human who is evaluated for drug metabolic activity, and is usually a human who may receive a drug therapy or a human who is receiving a drug therapy. Here, the drug used for drug therapy and the drug used for evaluation of metabolic activity may be the same or different, but drugs having the same molecular species of CYP undergoing metabolism are preferred.
　ＣＹＰの所定の分子種としては、ＣＹＰの分子種から選ばれる１種又は２種以上の分子種であり、ＣＹＰ１Ａ、ＣＹＰ２Ａ、ＣＹＰ２Ｂ、ＣＹＰ２Ｃ、ＣＹＰ２Ｄ、ＣＹＰ２Ｅ、ＣＹＰ３Ａ等が挙げられる。好ましくは、多くの薬物の代謝に関与しているＣＹＰ３Ａであり、より好ましくはＣＹＰ３Ａ４である。 The predetermined molecular species of CYP is one or more molecular species selected from CYP molecular species, and examples include CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A. Preferably, it is CYP3A involved in the metabolism of many drugs, and more preferably CYP3A4.
　本発明に用いられる口腔内速溶性フィルムに含まれるＣＹＰの所定の分子種に特異的に代謝を受ける薬物としては、ＣＹＰ１Ａ、ＣＹＰ２Ａ又はＣＹＰ３Ａに特異的に代謝を受けることが知られている薬物であればよい。例えば、ＣＹＰ１Ａに代謝を受ける薬物としては、ベンゾピレン、アセトアミノフェン、プロプラノロール、カフェイン、テオフィリン等が挙げられる。ＣＹＰ２Ａに代謝を受ける薬物としては、テガフール、ニコチン等が挙げられる。ＣＹＰ２Ｂに代謝を受ける薬物としては、シクロホスファミド、ケタミン等が挙げられる。ＣＹＰ２Ｃに代謝を受ける薬物としては、イブプロフェン、ジクロフェナク、フェニトイン、ワルファリン、ジアゼパム、オメプラゾール、ランソプラゾール、クロピドグレル等が挙げられる。ＣＹＰ２Ｄに代謝を受ける薬物としては、タモキシフェン、フルボキサミン、ハロペリドール、プロプラノロール、コデイン等が挙げられる。ＣＹＰ２Ｅに代謝を受ける薬物としては、ハロタン、エンフルラン、アセトアミノフェン等が挙げられる。ＣＹＰ３Ａに代謝を受ける薬物としては、ミダゾラム等のベンゾジアゼピン系化合物、アミオダロン、パクリタキセル、タモキシフェン、ドセタキセル、タクロリムス、カルバマゼピン、ニフェジピン、テストステロン等が挙げられるが、安全域が高いこと、ＣＹＰ３Ａに対する特異性の点から、ベンゾジアゼピン系化合物が好ましく、ミダゾラムがより好ましい。
　本発明においては、ＣＹＰ３Ａ４に特異的に代謝を受けることが知られている薬物が好ましく、そのうち、ベンゾジアゼピン系化合物が好ましく、ミダゾラムがより好ましい。 The drug that is specifically metabolized by a predetermined molecular species of CYP contained in the intraoral fast-dissolving film used in the present invention is a drug that is specifically metabolized by CYP1A, CYP2A, or CYP3A. I just need it. For example, benzopyrene, acetaminophen, propranolol, caffeine, theophylline and the like are listed as drugs that undergo metabolism by CYP1A. Examples of drugs that undergo metabolism by CYP2A include tegafur and nicotine. Examples of drugs that are metabolized by CYP2B include cyclophosphamide, ketamine and the like. Examples of drugs that are metabolized by CYP2C include ibuprofen, diclofenac, phenytoin, warfarin, diazepam, omeprazole, lansoprazole, clopidogrel, and the like. Examples of drugs that undergo metabolism by CYP2D include tamoxifen, fluvoxamine, haloperidol, propranolol, and codeine. Examples of drugs that undergo metabolism by CYP2E include halothane, enflurane, acetaminophen, and the like. Examples of drugs that are metabolized by CYP3A include benzodiazepine compounds such as midazolam, amiodarone, paclitaxel, tamoxifen, docetaxel, tacrolimus, carbamazepine, nifedipine, testosterone, and the like. A benzodiazepine compound is preferred, and midazolam is more preferred.
In the present invention, a drug known to be specifically metabolized by CYP3A4 is preferable, of which a benzodiazepine compound is preferable, and midazolam is more preferable.
　本発明に用いるフィルム製剤には、前記薬物を経口投与の無作用量を含有する。ここで、無作用量とは、化学物質の毒性試験で、複数の用量段階で動物への毒性を観察したとき、有害／無害を含めた影響が認められない暴露量（投与量）をいう。本発明では、経口投与において何らの作用を示さない用量である。
　この無作用量は、薬物によって異なる。ミダゾラムの場合には、１回投与単位あたり５μｇ～５ｍｇ含有すればよく、１０μｇ～１００μｇが好ましく、１０μｇ～５０μｇがより好ましく、１０μｇ～４０μｇがさらに好ましく、２０μｇ～４０μｇがさらに好ましい。
　すなわち、本発明に用いられる口腔内速溶性フィルムには、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有するのが好ましく、１０μｇ～１００μｇ含有するのがより好ましく、１０μｇ～４０μｇ含有するのがさらに好ましく、２０μｇ～４０μｇ含有するのがさらに好ましい。 The film preparation used in the present invention contains an inactive amount of the above-mentioned drug administered orally. Here, the no-effect level refers to an exposure level (dose) at which no effects including harmful / innocuous effects are observed when toxicity to animals is observed at multiple dose levels in a toxicity test for chemical substances. In the present invention, the dose does not show any effect in oral administration.
This amount of no action varies depending on the drug. In the case of midazolam, it is sufficient to contain 5 μg to 5 mg per dosage unit, preferably 10 μg to 100 μg, more preferably 10 μg to 50 μg, further preferably 10 μg to 40 μg, and further preferably 20 μg to 40 μg.
That is, the intraoral fast-dissolving film used in the present invention preferably contains 5 to 5 mg of midazolam, more preferably 10 to 100 μg, more preferably 10 to 40 μg per unit dose. More preferably, the content is 20 μg to 40 μg.
　本発明の口腔内速溶性フィルムは、口腔内で速やかに溶解するフィルムであり、その水に対する溶解時間は、１５分以下が好ましく、１～１５分がより好ましく、３～１５分がさらに好ましく、５～１０分がさらに好ましい。ここで、溶解時間は、日本薬局方の溶出試験法のパドル試験法に準じパドル回転数５０ｒｐｍで３７．５℃の純水、９００ｍＬに１００μｇのフィルムを溶解させたとき、透明になるまでの時間である。 The intraoral fast-dissolving film of the present invention is a film that dissolves rapidly in the oral cavity, and its dissolution time in water is preferably 15 minutes or less, more preferably 1 to 15 minutes, further preferably 3 to 15 minutes, More preferably, it is 5 to 10 minutes. Here, the dissolution time is the time until the film becomes transparent when 100 μg of film is dissolved in 900 mL of pure water at 37.5 ° C. at a paddle rotation speed of 50 rpm in accordance with the paddle test method of the dissolution test method of the Japanese Pharmacopoeia. It is.
　本発明の口腔内速溶性フィルムは、水溶性高分子と前記薬物（好ましくはベンゾジアゼピン系化合物、より好ましくはミダゾラム）を含有する薬物層とその両側に水溶性高分子を含有する支持層とを有するフィルムであるのが、速溶性及び味の点から好ましい（図１参照）。 The intraoral fast-dissolving film of the present invention has a drug layer containing a water-soluble polymer and the drug (preferably a benzodiazepine compound, more preferably midazolam), and a support layer containing a water-soluble polymer on both sides thereof. A film is preferable from the viewpoint of fast solubility and taste (see FIG. 1).
　薬物層に用いられる水溶性高分子としては、フィルム形成能を有する水溶性高分子であればよく、例えば、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒプロメロース（ヒドロキシプロピルメチルセルロース、ＨＰＭＣ）、プルラン、ヒドロキシエチルセルロース、カルボキシメチルセルロース・ナトリウム、カルボキシメチルセルロース・カルシウム、カルボキシメチルセルロース・カリウム、カルボキシメチルセルロース及びアルギン酸ナトリウム等が挙げられ、これらから選ばれる１種又は２種以上を組み合せて用いることができる。このうち、ヒドロキシプロピルメチルセルロースを用いるのがより好ましい。 The water-soluble polymer used in the drug layer may be any water-soluble polymer having film-forming ability, for example, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose, HPMC), pullulan, hydroxyethylcellulose, carboxy Examples thereof include methyl cellulose / sodium, carboxymethyl cellulose / calcium, carboxymethyl cellulose / potassium, carboxymethyl cellulose and sodium alginate, and one or more selected from these can be used in combination. Of these, it is more preferable to use hydroxypropylmethylcellulose.
　薬物層中の水溶性高分子の含有量は、薬物層質量に対して２０～９０％が好ましく、６０～８５％がより好ましく、６５～７５％がさらに好ましい。 The content of the water-soluble polymer in the drug layer is preferably 20 to 90%, more preferably 60 to 85%, still more preferably 65 to 75% based on the drug layer mass.
　支持層に用いられる水溶性高分子としては、前記と同様のフィルム形成能を有する水溶性高分子が挙げられる。すなわち、例えば、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒプロメロース（ヒドロキシプロピルメチルセルロース、ＨＰＭＣ）、プルラン、ヒドロキシエチルセルロース、カルボキシメチルセルロース・ナトリウム、カルボキシメチルセルロース・カルシウム、カルボキシメチルセルロース・カリウム、カルボキシメチルセルロース及びアルギン酸ナトリウム等が挙げられ、これらから選ばれる１種又は２種以上を組み合せて用いることができる。このうち、ヒプロメロースを用いるのがより好ましい。 Examples of the water-soluble polymer used in the support layer include water-soluble polymers having the same film-forming ability as described above. That is, for example, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose, HPMC), pullulan, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, sodium alginate, etc. One or more selected from these can be used in combination. Of these, it is more preferable to use hypromellose.
　支持層中の水溶性高分子の含有量は、支持層質量に対して５０～９０％が好ましく、７０～９０％がより好ましく、７５～８５％がさらに好ましい。 The content of the water-soluble polymer in the support layer is preferably 50 to 90%, more preferably 70 to 90%, still more preferably 75 to 85% based on the mass of the support layer.
　薬物層及び支持層には、前記薬物及び水溶性高分子以外に、崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有させることができる。 In addition to the drug and the water-soluble polymer, the drug layer and the support layer may contain one or more selected from disintegrants, taste-masking agents, sweeteners, colorants, plasticizers, and fragrances.
　崩壊剤としては、例えば、結晶セルロース、カルメロース及びその塩、デンプン、ショ糖脂肪酸エステル、ゼラチン、炭酸水素ナトリウム、デキストリン、デヒドロ酢酸及びその塩、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレンポリオキシプロピレングリコール、マルチトール、トレハロース等が挙げられ、これらから選ばれる１種又は２種以上の組み合せが好ましい。中でも、結晶セルロースが特に好ましい。
　薬剤層中の崩壊剤の含有量は、１～３０質量％、特に５～２５質量％であることが好ましい。
　また、支持層中の崩壊剤の含有量は、５～６０質量％、特に１０～５０質量％が好ましい。 Examples of disintegrants include crystalline cellulose, carmellose and salts thereof, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and salts thereof, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene polyoxypropylene Glycol, maltitol, trehalose and the like can be mentioned, and one or a combination of two or more selected from these is preferable. Among these, crystalline cellulose is particularly preferable.
The content of the disintegrant in the drug layer is preferably 1 to 30% by mass, particularly 5 to 25% by mass.
The content of the disintegrant in the support layer is preferably 5 to 60% by mass, particularly 10 to 50% by mass.
　矯味剤としては、例えば、メントール、アスコルビン酸、酒石酸、クエン酸、リンゴ酸及びこれらの塩等の酸味剤等が挙げられ、これらから選ばれる１種又は２種以上の組み合せが好ましい。中でも、メントールが特に好ましい。
　薬物層中の矯味剤の含有量は、０．０５～１質量％、特に０．１～０．５質量％が好ましい。
　また、支持層中の矯味剤の含有量は、０．１～５質量％、特に１．０～２．０質量％が好ましい。 Examples of the corrigent include acidulants such as menthol, ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof, and one or a combination of two or more selected from these is preferable. Of these, menthol is particularly preferable.
The content of the corrigent in the drug layer is preferably 0.05 to 1% by mass, particularly preferably 0.1 to 0.5% by mass.
Further, the content of the corrigent in the support layer is preferably 0.1 to 5% by mass, particularly preferably 1.0 to 2.0% by mass.
　甘味剤としては、アスパルテーム、ステビア、スクラロース、グリチルリチン酸又はその塩（例えば、アルカリ金属塩）、ソーマチン、アセスルファムカリウム、サッカリン又はその塩（例えば、アルカリ金属塩）等が挙げられ、これらから選ばれる１種又は２種以上の組み合せが好ましい。中でも、グリチルリチン酸の塩、サッカリンの塩及びスクラロースが特に好ましい。
　薬物層中の甘味剤の含有量は、０．１～１０質量％、特に０．５～５質量％が好ましい。
　また、支持層中の甘味剤の含有量は、０．１～４０質量％、特に１．０～２０質量％が好ましい。 Examples of the sweetener include aspartame, stevia, sucralose, glycyrrhizic acid or a salt thereof (for example, alkali metal salt), thaumatin, acesulfame potassium, saccharin or a salt thereof (for example, an alkali metal salt), and the like. A seed or a combination of two or more is preferred. Among them, glycyrrhizic acid salt, saccharin salt and sucralose are particularly preferable.
The content of the sweetening agent in the drug layer is preferably 0.1 to 10% by mass, particularly 0.5 to 5% by mass.
The content of the sweetening agent in the support layer is preferably 0.1 to 40% by mass, particularly 1.0 to 20% by mass.
　着色剤としては、例えば、黄色三二酸化鉄、褐色酸化鉄、カラメル、黒酸化鉄、酸化チタン、三二酸化鉄、タール色素、アルミニウムレーキ色素、銅クロロフィリンナトリウム等が挙げられ、これらから選ばれる１種又は２種以上の組み合せが好ましい。中でも、酸化チタン、三二酸化鉄が特に好ましい。
　薬物層中の着色剤の含有量は、０．０１～１０質量％、特に０．０５～５質量％が好ましい。
　また、支持層中の着色剤の含有量は、０．１～２０質量％、特に０．２～１５質量％が好ましい。 Examples of the colorant include yellow ferric oxide, brown iron oxide, caramel, black iron oxide, titanium oxide, ferric oxide, tar dye, aluminum lake dye, copper chlorophyllin sodium, and the like. Or the combination of 2 or more types is preferable. Of these, titanium oxide and iron sesquioxide are particularly preferable.
The content of the colorant in the drug layer is preferably 0.01 to 10% by mass, particularly 0.05 to 5% by mass.
Further, the content of the colorant in the support layer is preferably 0.1 to 20% by mass, particularly preferably 0.2 to 15% by mass.
　可塑剤としては、例えば、ゴマ油、ソルビトール、ヒマシ油、プロピレングリコール、ポリソルベート８０（ポリオキシエチレン(20)ソルビタンオレイン酸エステル）、ポリエチレングリコール［例えば、マクロゴール４００（オキシエチレン単位の重合度ｎが７～９、以下、同様）、マクロゴール６００（ｎが１１～１３）、マクロゴール１５００（ｎが５～６と、ｎが２８～３６との等量混合物）、マクロゴール４０００（ｎが５９～８４）、マクロゴール６０００（ｎが１６５～２１０）］等が挙げられ、これらから選ばれる１種又は２種以上の組み合せが好ましい。中でも、ポリエチレングリコール、特にマクロゴール４００が好ましい。
　薬物層中の可塑剤の含有量は、０．１～２０質量％が好ましく、０．５～１５質量％が更に好ましく、１～１０質量％が特に好ましい。
　また、支持層中の可塑剤の含有量は、０．１～５０質量％、特に０．１～３０質量％が好ましい。 Examples of the plasticizer include sesame oil, sorbitol, castor oil, propylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [for example, macrogol 400 (polymerization degree n of oxyethylene unit is 7). ~ 9, the same applies hereinafter), macro goal 600 (n is 11 to 13), macro goal 1500 (a mixture of n is 5 to 6 and n is 28 to 36), macro goal 4000 (n is 59 to 84), macrogol 6000 (n is 165 to 210)] and the like, and one or a combination of two or more selected from these is preferable. Among these, polyethylene glycol, particularly Macrogol 400 is preferable.
The content of the plasticizer in the drug layer is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and particularly preferably 1 to 10% by mass.
In addition, the content of the plasticizer in the support layer is preferably 0.1 to 50% by mass, particularly preferably 0.1 to 30% by mass.
　香料としては、例えば、バニラフレーバー、オレンジフレーバー、オレンジ皮フレーバー、ストロベリーフレーバー、ラズベリーフレーバー、チョコレートフレーバー、グレープフルーツフレーバー、クランベリーフレーバー、ウメフレーバー、コクトウフレーバー、ハーブフレーバー、コーヒーフレーバー、紅茶フレーバー、シナモンフレーバー、ハチミツレモンフレーバー等が例示される。これらは、単独で又は組み合わせて使用することができる。中でも、製剤溶解時の清涼感及び爽快感の向上の観点から、オレンジフレーバー、グレープフルーツフレーバーが好適である。 As a fragrance, for example, vanilla flavor, orange flavor, orange peel flavor, strawberry flavor, raspberry flavor, chocolate flavor, grapefruit flavor, cranberry flavor, ume flavor, coconut flavor, herbal flavor, coffee flavor, tea flavor, cinnamon flavor, Honey lemon flavor etc. are illustrated. These can be used alone or in combination. Among these, orange flavor and grapefruit flavor are preferable from the viewpoint of improving the refreshing feeling and the refreshing feeling when dissolving the preparation.
　本発明に用いるフィルム製剤は、支持層、薬物層、支持層が順次積層された３層構造を基本形態とするものであるが、同一種の層を隣接して積層した場合、それらは互いに密着し一体となって同一の機能を奏するため、本発明においては実質的に一層として取り扱うものとする。なお、フィルム製剤全体の厚みは、好ましくは５０～２００μｍ、特に好ましくは７０～１８０μｍである。その場合、薬物層の厚みは、好ましくは１０～５０μｍ、特に好ましくは２０～４０μｍであり、また支持層の厚みは、好ましくは１０～５０μｍ、特に好ましくは２０～５０μｍである。これにより、口腔内において速やかに溶解させることが可能である。また、フィルム製剤の大きさは、服用しやすいものであれば特に限定されるものではないが、例えば、１～５ｃｍ2程度の大きさにすることが好ましく、その形状も服用しやすいものであれば特に限定されるものではなく、例えば、方形、円形、楕円形等を適宜選択することが可能である。 The film preparation used in the present invention has a three-layer structure in which a support layer, a drug layer, and a support layer are sequentially laminated. When the same kind of layers are laminated adjacently, they are in close contact with each other. However, in order to perform the same function as a unit, the present invention handles substantially one layer. The thickness of the entire film preparation is preferably 50 to 200 μm, particularly preferably 70 to 180 μm. In this case, the thickness of the drug layer is preferably 10 to 50 μm, particularly preferably 20 to 40 μm, and the thickness of the support layer is preferably 10 to 50 μm, particularly preferably 20 to 50 μm. Thereby, it is possible to dissolve quickly in the oral cavity. The size of the film preparation is not particularly limited as long as it is easy to take, but for example, it is preferably about 1 to 5 cm 2 , and the shape is also easy to take. For example, a square, a circle, an ellipse, or the like can be selected as appropriate.
　フィルム製剤は、慣用又は公知の方法により適宜製造することができる。例えば、ＰＥＴ（ポリエチレンテレフタレート）等の剥離フィルム上に、第一の支持層を積層し、次いで薬物層を積層した後、更に当該薬物層上に第二の支持層を積層することにより製造することができる。また、剥離フィルム上に、第一の支持層を積層し、更に薬物層を積層した中間製品と、別途、剥離フィルム上に第二の支持層を積層し、更に薬物層を積層した中間製品を作製し、次いで両者の薬物層同士が対向するように貼り合わせて圧着することによっても製造することが可能である。 The film preparation can be appropriately produced by conventional or known methods. For example, it is manufactured by laminating a first support layer on a release film such as PET (polyethylene terephthalate), then laminating a drug layer, and then laminating a second support layer on the drug layer. Can do. In addition, an intermediate product in which a first support layer is laminated on a release film and a drug layer is further laminated, and an intermediate product in which a second support layer is laminated on the release film and a drug layer is further laminated. It is also possible to produce by manufacturing and then bonding and pressing so that both drug layers face each other.
　本発明によって対象者のＣＹＰ代謝活性を評価するには、前記フィルム製剤を対象者に経口投与し、当該対象者の血液中の薬物（未変化体）及び薬物（代謝物）の血液中濃度を測定すればよい。具体的には、血液中の（未変化体）／（代謝物）の濃度比から、薬物代謝酵素（ＣＹＰ）の酵素活性を評価する。本発明方法により、ＣＹＰの酵素活性が判明すれば、この薬物と同じＣＹＰにより代謝される薬物の最適な投与量、投与間隔等を決定することができる。 In order to evaluate the subject's CYP metabolic activity according to the present invention, the film preparation is orally administered to the subject, and the blood concentration of the drug (unmodified) and the drug (metabolite) in the blood of the subject is determined. Just measure. Specifically, the enzyme activity of the drug metabolizing enzyme (CYP) is evaluated from the concentration ratio of (unmodified) / (metabolite) in blood. If the enzymatic activity of CYP is determined by the method of the present invention, the optimal dose, administration interval, etc. of the drug metabolized by the same CYP as this drug can be determined.
　本発明のフィルム製剤を経口投与すれば、当該製剤が口腔内で速やかに溶解するので、製剤中の薬物を確実に嚥下することができる。 If the film preparation of the present invention is orally administered, the preparation dissolves rapidly in the oral cavity, so that the drug in the preparation can be swallowed reliably.
　血液中の未変化体及び代謝物の濃度の測定は、投与後一定時間経過毎に対象者から採血し、血液中の未変化濃度及び代謝物濃度を測定すればよい。ここで薬物の代謝物は、その薬物がＣＹＰによって代謝されることが知られている成分である。また、これらの未変化体及び代謝物の濃度の測定法は、その薬物及び代謝物を定量できる方法であればよい。
　ミダゾラムを用いる場合、その代謝物は１－ヒドロキシミダゾラムである。ミダゾラム及び１－ヒドロキシミダゾラムの定量法は、高速液体クロマトグラフィーにより行うことができる。 The concentration of unchanged substance and metabolite in the blood may be measured by collecting blood from the subject at regular intervals after administration and measuring the unchanged concentration and metabolite concentration in the blood. Here, a metabolite of a drug is a component that is known to be metabolized by CYP. The method for measuring the concentrations of these unchanged substances and metabolites may be any method that can quantify the drugs and metabolites.
When midazolam is used, its metabolite is 1-hydroxymidazolam. Midazolam and 1-hydroxymidazolam can be quantified by high performance liquid chromatography.
　ＣＹＰの酵素活性を評価するには、（未変化体）／（代謝物）の濃度比を測定すればよい。この比の変化により、その薬物がＣＹＰにより代謝を受けるかを判断することができる。 In order to evaluate the enzyme activity of CYP, the concentration ratio of (unmodified) / (metabolite) may be measured. By changing this ratio, it can be determined whether the drug is metabolized by CYP.
　次に実施例を挙げて本発明を更に詳細に説明する。 Next, the present invention will be described in more detail with reference to examples.
製造例
　表１に記載の組成の口腔内速溶性フィルムを製造した。
　薬物層又は支持層の各原料を均一になるまで撹拌し、薬物層ペースト及び支持層ペーストをそれぞれ得た。
　先ず、ポリエステル製剥離フィルム上に支持層溶液を展延し乾燥して支持層を形成した後、該支持層上に薬物層溶液を展延し乾燥して薬物層を積層させた。次いで、得られた積層体を、薬物層を内側にして２枚重ねることにより、支持層／薬物層／支持層の３層フィルムを得た。得られたフィルムは１４ｍｍ×２０ｍｍフィルムに切断した。 Production Example An intraoral fast-dissolving film having the composition described in Table 1 was produced.
Each raw material of the drug layer or the support layer was stirred until it became uniform to obtain a drug layer paste and a support layer paste, respectively.
First, the support layer solution was spread on a polyester release film and dried to form a support layer, and then the drug layer solution was spread on the support layer and dried to laminate the drug layer. Next, two layers of the obtained laminate were laminated with the drug layer inside, to obtain a three-layer film of support layer / drug layer / support layer. The obtained film was cut into a 14 mm × 20 mm film.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
試験例１（溶解性試験）
　前記製造例で得られたフィルムをミダゾラム１００μｇ含有する大きさにセットしたものを用いた。３７．５℃の純水９００ｍＬにフィルムを入れ、５０ｒｐｍで攪拌して溶解性を確認した。その結果、約５～１０分でほぼ１００％が溶解することが確認された。 Test Example 1 (Solubility test)
A film obtained by setting the film obtained in the above production example to a size containing 100 μg of midazolam was used. The film was put into 900 mL of pure water at 37.5 ° C. and stirred at 50 rpm to confirm the solubility. As a result, it was confirmed that almost 100% was dissolved in about 5 to 10 minutes.
試験例２（成人におけるＣＹＰ３Ａ代謝活性測定試験）
（１）１２名の健常成人に、３０μｇミダゾラムを含む口腔内速溶性フィルム（製造例で得たもの）を単回経口投与し、投与後ミダゾラム及び１－ヒドロキシミダゾラムの血漿中濃度を測定した。対照としてミダゾラム３０μｇ含有溶液を用いた。フィルム投与と水溶液投与とは、７日間のウォッシュアウト期間を設けたクロスオーバー試験とした。
　経口投与後１０分、２０分、３０分、４５分、１時間、１．５時間、２時間、３時間、４時間、６時間、８時間、１０時間及び１２時間後に採血し、血漿中のミダゾラム及び１－ヒドロキシミダゾラム濃度を高速液体クロマトグラフィーで測定した。 Test Example 2 (CYP3A metabolic activity measurement test in adults)
(1) Twelve healthy adults were orally administered a single oral oral soluble film containing 30 μg midazolam (obtained in the production example), and the midazolam and 1-hydroxymidazolam plasma concentrations were measured after administration. As a control, a solution containing 30 μg of midazolam was used. Film administration and aqueous solution administration were crossover tests with a washout period of 7 days.
Blood was collected at 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours after oral administration. Midazolam and 1-hydroxymidazolam concentrations were measured by high performance liquid chromatography.
（２）ミダゾラムの血漿中濃度推移を図２に、１－ヒドロキシミダゾラムの血漿中濃度推移を図３にそれぞれ示す。またミダゾラム／１－ヒドロキシミダゾラム比の血漿中濃度推移を図４に示す。
　ミダゾラム及び１－ヒドロキシミダゾラムのＡＵＣを図５に、ｔmaxを図６に、Ｃmaxを図７に示す。 (2) Change in plasma concentration of midazolam is shown in FIG. 2, and change in plasma concentration of 1-hydroxymidazolam is shown in FIG. FIG. 4 shows changes in plasma concentration of midazolam / 1-hydroxymidazolam ratio.
The AUC of midazolam and 1-hydroxymidazolam is shown in FIG. 5, t max is shown in FIG. 6, and C max is shown in FIG.
　これらの結果から、ミダゾラム微量含有口腔内速溶性フィルムは、ミダゾラム含有水溶液と同等のＣＹＰ３Ａ試験活性を示した。 From these results, the intraoral fast-dissolving film containing a small amount of midazolam showed a CYP3A test activity equivalent to the aqueous solution containing midazolam.

Claims (39)

  1. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有することを特徴とする、対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価用口腔内速溶性フィルム製剤。 Intraoral fast-dissolving film preparation for evaluating metabolic activity of a predetermined molecular species of cytochrome P450 of a subject, comprising an inactive amount of a drug that is specifically metabolized by the predetermined molecular species of cytochrome P450 .
  2. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである請求項１記載のフィルム製剤。 2. The film preparation according to claim 1, wherein the predetermined molecular species of cytochrome P450 is CYP3A.
  3. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である請求項１記載のフィルム製剤。 2. The film preparation according to claim 1, wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
  4. 　前記フィルム製剤の水に対する溶解時間が、１０分以下である請求項１～３のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 1 to 3, wherein the dissolution time of the film preparation in water is 10 minutes or less.
  5. 　対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである請求項１～４のいずれか１項記載のフィルム製剤。 Metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral fast-dissolving film preparation to the subject, and measuring the concentration transition of the drug and the drug metabolite in the blood of the subject The film preparation according to any one of claims 1 to 4, which is evaluated by
  6. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である請求項１～５のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 1 to 5, wherein the drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
  7. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである請求項１～５のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 1 to 5, wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
  8. 　ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有することを特徴とする、対象者のＣＹＰ３Ａ代謝活性評価用口腔内速溶性フィルム製剤。 An intraoral fast-dissolving film preparation for evaluating CYP3A metabolic activity in subjects characterized by containing 5 μg to 5 mg of midazolam per dosage unit.
  9. 　前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである請求項８記載のフィルム製剤。 The film preparation according to claim 8, wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
  10. 　薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する請求項９記載のフィルム製剤。 10. The film preparation according to claim 9, wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
  11. 　対象者のシトクロムＰ４５０の所定の分子種の代謝活性を評価するための、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルム製剤。 Oral fast-dissolving film preparation containing an orally administered inactive amount of a drug that specifically metabolizes to a predetermined molecular species of cytochrome P450 for evaluating the metabolic activity of the predetermined molecular species of cytochrome P450 of the subject.
  12. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである請求項１１記載のフィルム製剤。 The film preparation according to claim 11, wherein the predetermined molecular species of cytochrome P450 is CYP3A.
  13. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である請求項１１記載のフィルム製剤。 The film preparation according to claim 11, wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
  14. 　前記フィルム製剤の水に対する溶解時間が、１０分以下である請求項１１～１３のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 11 to 13, wherein the dissolution time of the film preparation in water is 10 minutes or less.
  15. 　対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである請求項１１～１４のいずれか１項記載のフィルム製剤。 Metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral fast-dissolving film preparation to the subject, and measuring the concentration transition of the drug and the drug metabolite in the blood of the subject The film preparation according to any one of claims 11 to 14, which is evaluated by
  16. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である請求項１１～１５のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 11 to 15, wherein the drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
  17. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである請求項１１～１５のいずれか１項記載のフィルム製剤。 The film preparation according to any one of claims 11 to 15, wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
  18. 　対象者のＣＹＰ３Ａ代謝活性を評価するための、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルム製剤。 Intraoral fast-dissolving film preparation containing 5 μg to 5 mg of midazolam per dosage unit for evaluating the subject's CYP3A metabolic activity.
  19. 　前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである請求項１８記載のフィルム製剤。 The film preparation according to claim 18, wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
  20. 　薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する請求項１９記載のフィルム製剤。 20. The film preparation according to claim 19, wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
  21. 　対象者に、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルム製剤を経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することを特徴とする、当該対象者のシトクロムＰ４５０の所定の分子種の代謝活性の評価方法。 The subject is orally administered with a fast-dissolving film preparation in the oral cavity containing a drug that is specifically metabolized by a predetermined molecular species of cytochrome P450, and is orally administered, and the drug in the blood of the subject and the drug A method for evaluating the metabolic activity of a predetermined molecular species of cytochrome P450 of the subject, characterized by measuring a concentration transition of a metabolite.
  22. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである請求項２１記載の評価方法。 The evaluation method according to claim 21, wherein the predetermined molecular species of cytochrome P450 is CYP3A.
  23. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である請求項２１記載の評価方法。 The evaluation method according to claim 21, wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
  24. 　前記フィルム製剤の水に対する溶解時間が、１０分以下である請求項２１～２３のいずれか１項記載の評価方法。 The evaluation method according to any one of claims 21 to 23, wherein the dissolution time of the film preparation in water is 10 minutes or less.
  25. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である請求項２１～２４のいずれか１項記載の評価方法。 The evaluation method according to any one of claims 21 to 24, wherein the drug that is specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
  26. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである請求項２１～２４のいずれか１項記載の評価方法。 The evaluation method according to any one of claims 21 to 24, wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
  27. 　対象者に、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルム製剤を経口投与し、当該対象者の血液中のミダゾラム及びミダゾラム代謝物の濃度推移を測定することを特徴とする、当該対象者のＣＹＰ３Ａ代謝活性の評価方法。 The subject is orally administered with a fast-dissolving film preparation of oral cavity containing 5 μg to 5 mg of midazolam per dosage unit, and the change in the concentration of midazolam and midazolam metabolites in the blood of the subject is measured. A method for evaluating CYP3A metabolic activity of the subject.
  28. 　前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである請求項２７記載の評価方法。 The evaluation method according to claim 27, wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
  29. 　前記薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する請求項２８記載の評価方法。 The evaluation method according to claim 28, wherein the drug layer and / or the support layer further contains one or more selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer, and a fragrance.
  30. 　対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価用口腔内速溶性フィルム製剤を製造するための、シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物を経口投与無作用量含有する口腔内速溶性フィルムの使用。 Contains orally administered inactive amount of a drug that is specifically metabolized by the predetermined molecular species of cytochrome P450 for producing a fast-dissolving film preparation in the oral cavity for evaluating metabolic activity of the predetermined molecular species of cytochrome P450 of the subject Use of fast-dissolving film in the oral cavity.
  31. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａである請求項３０記載の使用。 The use according to claim 30, wherein the predetermined molecular species of cytochrome P450 is CYP3A.
  32. 　シトクロムＰ４５０の所定の分子種が、ＣＹＰ３Ａ４である請求項３０記載の使用。 The use according to claim 30, wherein the predetermined molecular species of cytochrome P450 is CYP3A4.
  33. 　前記フィルム製剤の水に対する溶解時間が、１０分以下である請求項３０～３２のいずれか１項記載の使用。 The use according to any one of claims 30 to 32, wherein the dissolution time of the film preparation in water is 10 minutes or less.
  34. 　対象者のシトクロムＰ４５０の所定の分子種の代謝活性評価が、前記口腔内速溶性フィルム製剤を対象者に経口投与し、当該対象者の血液中の前記薬物及び前記薬物代謝物の濃度推移を測定することにより評価するものである請求項３０～３３のいずれか１項記載の使用。 Metabolic activity evaluation of a predetermined molecular species of cytochrome P450 of the subject is performed by orally administering the intraoral fast-dissolving film preparation to the subject and measuring changes in the concentration of the drug and the drug metabolite in the blood of the subject The use according to any one of claims 30 to 33, which is evaluated by
  35. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ベンゾジアゼピン系化合物である請求項３０～３４のいずれか１項記載の使用。 The use according to any one of claims 30 to 34, wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is a benzodiazepine compound.
  36. 　シトクロムＰ４５０の所定の分子種に特異的に代謝を受ける薬物が、ミダゾラムである請求項３０～３４のいずれか１項記載の使用。 The use according to any one of claims 30 to 34, wherein the drug specifically metabolized by a predetermined molecular species of cytochrome P450 is midazolam.
  37. 　対象者のＣＹＰ３Ａ代謝活性評価用口腔内速溶性フィルム製剤を製造するための、ミダゾラムを１回投与単位あたり５μｇ～５ｍｇ含有する口腔内速溶性フィルムの使用。 Use of an intraoral fast-dissolving film containing 5 μg to 5 mg of midazolam per dosage unit for producing an intraoral fast-dissolving film preparation for evaluating CYP3A metabolic activity of the subject.
  38. 　前記フィルム製剤が、水溶性高分子及びミダゾラムを含有する薬物層とその両側に水溶性高分子を含有する支持層を有するフィルムである請求項３７記載の使用。 The use according to claim 37, wherein the film preparation is a film having a drug layer containing a water-soluble polymer and midazolam and a support layer containing a water-soluble polymer on both sides thereof.
  39. 　薬物層及び／又は支持層が、さらに崩壊剤、矯味剤、甘味剤、着色剤、可塑剤及び香料から選ばれる１種以上を含有する請求項３８記載の使用。 The use according to claim 38, wherein the drug layer and / or the support layer further contains at least one selected from a disintegrant, a corrigent, a sweetener, a colorant, a plasticizer and a fragrance.
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