JP2011231127A - Preparation for improving oral absorption and pharmaceutical composition utilizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique for improving the bioavailability of a medicine by avoiding a decrease in the absorbability of the medicine due to a drug metabolizing enzyme present in the digestive tract or a drug transporter.
SOLUTION: An oral absorption improving agent for a medicine containing a lignan compound having a methylenedioxyphenyl group as an active ingredient, the above lignan compound, a medicine serving as a substrate for the drug metabolizing enzyme CYP3A, a substrate for the drug metabolizing enzyme CYP2C, Or a pharmaceutical composition that is a drug transporter P-glycoprotein substrate.
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Description

  The present invention relates to a pharmaceutical oral absorption improver and a pharmaceutical composition using the same, and more specifically, inhibits the action of drug metabolizing enzymes and drug transporters present in the digestive tract such as the small intestine, thereby absorbing the drug. The present invention relates to an oral absorption-improving agent for improving the pharmacological properties and a pharmaceutical composition using the same.

  2. Description of the Related Art Conventionally, in order to sufficiently exhibit the pharmacological action of a drug, a technique for improving the bioavailability of the drug has been developed. For example, techniques for forming salts and complexes, solubilizing drugs using inclusion compounds and micelles, techniques for sustained release or enteric use of drugs using various polymer compounds, or drugs Prodrugs have been studied.

  However, since these technologies change the physicochemical properties of the drug and improve the drug solubility or gastrointestinal membrane permeability, some drugs do not sufficiently improve bioavailability. There was also.

  That is, there are drug metabolizing enzymes and drug transporters in the digestive tract such as the small intestine. However, in the case of a drug whose absorbability is reduced by these, sufficient improvement in absorption cannot be obtained even by the above technique. There was a problem.

  Accordingly, an object of the present invention is to provide a technique for avoiding a decrease in absorbability of a drug due to a drug metabolizing enzyme present in the digestive tract or a drug transporter.

  As a result of intensive studies to solve the above problems, the present inventors inhibited the action of drug metabolizing enzymes in the gastrointestinal tract and drug transporters if a specific lignan was also administered when a drug was orally administered. And the present invention was completed by finding that high bioavailability of medicines can be obtained.

  That is, the present invention provides a pharmaceutical oral absorption improving agent containing a lignan compound having a methylenedioxyphenyl group as an active ingredient.

  The present invention also provides a pharmaceutical composition comprising the above lignan compound and a drug that is a substrate for the drug metabolizing enzyme CYP3A.

  Furthermore, the present invention provides a pharmaceutical composition comprising the above lignan compound and a drug that is a substrate for the drug metabolizing enzyme CYP2C.

  Furthermore, the present invention provides a pharmaceutical composition comprising the above lignan compound and a drug that is a substrate for a drug transporter P-glycoprotein.

  The lignan compound of the present invention is a highly safe lignan contained in natural products such as sesame, and simultaneously inhibits drug metabolizing enzymes and drug transporters present in the small intestine and liver. Therefore, an oral absorption improving agent containing this as an active ingredient can be obtained in a high bioavailability by orally administering it together with a medicine and does not cause safety problems.

  In addition, a pharmaceutical composition obtained by combining the lignan compound of the present invention and a medicine is more convenient because a high bioavailability of the medicine can be obtained by a single administration.

  In particular, the present invention is highly useful in that it can be administered orally if used in a medicine that has been conventionally metabolized in the small intestine and thus difficult to be administered orally. In the case of a medicine that exhibits side effects, the amount of use can be reduced, so that safety can be improved.

It is drawing which shows the relationship between the concentration and the inhibitory action of various drug-metabolizing enzymes about asalinin. It is drawing which shows the relationship between the density | concentration and the inhibitory action of various drug-metabolizing enzymes about sesamin. It is drawing which shows the relationship between the density | concentration and the inhibitory action of various drug-metabolizing enzymes about hinokinin. It is a figure which shows the influence of sesamin with respect to the transcellular transport activity of digoxin.

  A lignan compound having a methylenedioxyphenyl group (hereinafter referred to as “the lignan compound of the present invention”) used as an active ingredient in the oral absorption improver (hereinafter referred to as “absorption improver”) of the medicament of the present invention; Is a lignan having at least one methylenedioxyphenyl group in its structure. Specific examples of the lignan compound of the present invention include sesamin, sesamorin, asalinin, hinokinin and the like.

  Among these, sesamin, sesamolin and asalinin are lignans contained in sesame and each have the following structural formula. As understood from this structural formula, sesamin and asalinin are compounds having an optical isomerism relationship.

  Hinokinin is a lignan contained in hinoki heartwood and resin, and has the following structural formula.

  As apparent from the formula, all of the above compounds have two methylenedioxyphenyl groups in the structure.

  As the lignan compound of the present invention, the above compounds can be preferably used, but it is needless to say that the present invention is not limited thereto.

  In order to produce the absorption improver of the present invention using the above-described lignan compound of the present invention, it may be in the form of an oral preparation in combination with a lignan compound and a pharmaceutically acceptable carrier according to a conventional method.

  The compounding amount of the lignan compound of the present invention in this absorption improver is not particularly limited, but generally, it is a formulation that is about 10 mg to 2000 mg, preferably about 100 mg to 500 mg per administration per adult. What is necessary is just to prepare.

  Also, the dosage form of this absorption improver is not particularly limited as long as it can be administered orally, and may be solid forms such as powders, powders, granules, tablets, capsules, and various liquids. it can.

  Examples of the drug that can improve bioavailability by combining with the absorption improver of the present invention include a drug absorbed in the small intestine. In particular, since the lignan compound of the present invention inhibits the drug metabolizing enzymes CYP3A and CYP2C, or the drug transporter P glycoprotein, an excellent bioavailability-improving action can be obtained when combined with a drug as a substrate thereof. Can do.

  Specific examples of pharmaceuticals that are particularly effective in combination with the absorption improver of the present invention include cyclosporine, amiodarone, erythromycin, etoposide, lidocaine, lovastatin, midazolam, omeprazole, tacrolimus, taxol, verapamil and other CYP3A substrates. A drug that becomes a substrate of CYP2C, such as omeprazole, propranolol, imipramine, trans Examples include drugs that serve as substrates for porter P glycoprotein.

  On the other hand, the pharmaceutical composition of the present invention is prepared by combining the lignan compound of the present invention with a drug that is a substrate for CYP3A, a drug that is a substrate for CYP2C, or a drug that is a substrate for drug transporter P glycoprotein. .

  The lignan compound of the present invention used in this pharmaceutical composition, the drug serving as the substrate for CYP3A, the drug serving as the substrate for CYP2C or the drug serving as the substrate for the drug transporter P glycoprotein are as described above.

  The blending ratio of the above-mentioned pharmaceutical and the lignan compound of the present invention varies depending on the components used, but is generally about 1: 0.5 to 100, preferably about 1: 1 to 20.

  In the combination of the lignan compound of the present invention and the above medicine, a known carrier and other necessary pharmaceutical additives can also be used. Furthermore, the form of the pharmaceutical composition of the present invention can be any form such as a solid preparation or a liquid as long as it is suitable for oral administration.

  The pharmaceutical composition thus obtained is convenient for treatment since the medicine and the absorption composition can be taken by one dose.

[Action]
The metabolic enzyme present in the living body has an action of converting / decomposing a foreign substance into another substance, and the transporter has a function of controlling the entry of the foreign substance into the body. These actions prevent foreign substances from entering the living body.

  Thus, metabolic degradation enzymes and transporters have an important role of defense of the body. Conversely, when a drug is administered, they function and inhibit the absorption of the drug.

  In particular, many drugs are administered orally, but these are metabolized by drug metabolizing enzymes present in the small intestine and drug metabolizing enzymes present in the liver, and absorption from the intestinal tract wall is inhibited by drug transporters. There was a problem that the utilization rate in was low.

  The lignan compound of the present invention used in the present invention is characterized by simultaneously inhibiting a drug metabolizing enzyme (mainly CYP3A) existing in the small intestine and a drug metabolizing enzyme (mainly CYP2C) existing in the liver and a drug transporter. By being orally administered together with a medicine, these effects of inhibiting the absorption of the medicine can be suppressed, and as a result, high bioavailability by oral administration can be obtained.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples.

Example 1
In vivo absorbability test:
Digoxin was used as a medicine, and the in vivo absorbability with sesamin was investigated. As experimental animals, three Crj male rats (7 weeks old) per group were used. The test composition was prepared by suspending digoxin and sesamin in a 0.5 w / v aqueous solution of sodium carboxymethylcellulose. They were prepared and used at 0.2 mg / kg and 500 mg / kg, respectively.

  The rats were fasted from 16 hours after the administration of each test composition, and each test composition was administered intragastrically using a syringe with an oral sonde.

  Blood was collected over time from the rat tail vein, and the digoxin concentration in the plasma was measured. As a control, only digoxin was used. The results are shown in Table 1.

Example 2
Drug metabolism enzyme inhibition test:
According to a conventional method, the inhibitory action of various drug metabolizing enzymes was examined on the lignan compound of the present invention. As lignan compounds of the present invention, asalinin, sesamin and hinokinein were used, and their concentrations were 0.5, 1, 2, 4, 8, 16, 32 and 64 μmol / L. In addition, CYP1A2, CYP2C9 * 1, CYP2C19, CYP2D6 * 1, CYP2E1 and CYP3A4 were used as drug-metabolizing enzymes, and the conditions for measuring each enzyme activity were as shown in Table 2. The results are shown in FIGS.

  As shown in this figure, asalinin, sesamin and hinokine all inhibited CYP2C19 and CYP3A4 in a dose-dependent manner. In addition, asarinin inhibited CYP2C9 * 1, sesamin inhibited CYP1A2 and CYP2C9 * 1, and hinokinin inhibited CYP1A2, CYP2C9 * 1 and CYP2D6 * 1, respectively.

Example 3
Drug permeability test:
Caco-2 cells derived from human colon cancer were used to examine the effect of sesamin on the transcellular transport activity of digoxin. First, Caco-2 cells were cultured using a 75 cm ² flask and subcultured every 4 to 5 days. Then, using a Falcon culture insert, Caco-2 cells were seeded at a density of 3 × 10 ⁴ cells / insert in DMEM medium, and then cultured in a CO ₂ incubator (37 ° C., CO ₂ 0.5%) for 21 days. A single layer film was prepared. During this culture, the medium was changed every 2-3 days.

After the monolayer was formed, the culture insert and the medium in the plate were removed by aspiration, replaced with HBSS containing each concentration of sesamin, and preincubated at 37 ° C. for 1 hour. Either apical (top side of cells; 250 μl) or basal (basal side of cells; 950 μl) was replaced with HBSS solution of ³ H-digoxin (50 nmol / L) containing each concentration of sesamin at 37 ° C. Incubated.

After 1 hour, 50 μl of HBSS was collected from the side not treated with ³ H-digoxin, 10 ml of scintillator (HINONIC-FLUOR; manufactured by Packard) was added, and the amount of radioactivity was measured using a liquid scintillation counter. From this radiation dose, the amount of ³ H-digoxin was measured.

From the amount of ³ H-digoxin thus measured, the permeability coefficient of ³ H-digoxin in the apical to basal direction (A to B) and the basal to apical direction (B to A) was determined according to the following formula. The result is shown in FIG.

[Formula 1]

As is apparent from this result, it was shown that the permeability coefficient of A to B of digoxin approaches the permeability coefficient of B to A depending on the concentration of sesamin. This indicates that P-glycoprotein is inhibited by sesamin.

more than

Claims (15)

  An oral absorption improving agent for pharmaceuticals comprising a lignan compound having a methylenedioxyphenyl group as an active ingredient.   2. The oral absorption improving agent for pharmaceuticals according to claim 1, wherein the lignan compound having a methylenedioxyphenyl group is sesamin, sesamorine, asarinin or hinokinin.   3. The oral absorption improving agent for pharmaceuticals according to claim 1 or 2, wherein the pharmaceutical for improving oral absorption becomes a substrate for the drug metabolizing enzyme CYP3A.   3. The oral absorption improving agent for pharmaceuticals according to claim 1 or 2, wherein the pharmaceutical for improving oral absorption serves as a substrate for the drug metabolizing enzyme CYP2C.   The pharmaceutical agent for improving oral absorption according to claim 1 or 2, wherein the pharmaceutical agent for improving oral absorption serves as a substrate for drug transporter P-glycoprotein.   The pharmaceutical agent for improving oral absorption according to any one of claims 1 to 5, wherein the pharmaceutical agent for improving oral absorption is absorbed in the small intestine.   Drugs that improve oral absorption are cyclosporine, amiodarone, erythromycin, etoposide, lidocaine, lovastatin, midazolam, omeprazole, tacrolimus, taxol, verapamil, propranolol, imipramine, amiodarone, cefazoline, diltiazem, fluphenazine, morphine, The oral absorption improving agent for pharmaceuticals according to claim 1, which is selected from prazosin, topotecan, indinavir, domperidone, dexamethasone, digoxin or losartan.   The pharmaceutical oral absorption improving agent according to any one of claims 1 to 3, wherein 100 mg to 500 mg is administered as a lignan compound having a methylenedioxyphenyl group once per person.   A pharmaceutical composition comprising a lignan compound having a methylenedioxyphenyl group and a drug which is a substrate for the drug metabolizing enzyme CYP3A.   A pharmaceutical composition comprising a lignan compound having a methylenedioxyphenyl group and a drug which is a substrate for the drug metabolizing enzyme CYP2C.   A pharmaceutical composition comprising a lignan compound having a methylenedioxyphenyl group and a drug which is a substrate for a drug transporter P-glycoprotein.   12. The pharmaceutical composition according to any one of claims 9 to 11, wherein the lignan compound having a methylenedioxyphenyl group is sesamin, sesamorine, asalinine or hinokinin.   The pharmaceutical composition according to any one of claims 9 to 11, comprising 1 to 20 parts by weight of a lignan compound having a methylenedioxyphenyl group per 1 part by weight of the medicine.   The pharmaceutical composition according to any one of claims 9 to 13, wherein the medicine is absorbed in the small intestine.   The drugs are cyclosporine, amiodarone, erythromycin, etoposide, lidocaine, lovastatin, midazolam, omeprazole, tacrolimus, taxol, verapamil, propranolol, imipramine, amiodarone, cefazoline, diltiazem, fluphenazine, morphine, nicardipine The pharmaceutical composition according to any one of claims 9 to 14, which is selected from ru, domperidone, dexamethasone, digoxin or losartan.

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