KR20150135110A - PHARMACEUTICAL COMPOSITION COMPRISING p-GLYCOPROTEIN INHIBITOR AND p-GLYCOPROTEIN SUBSTRATE DRUG - Google Patents

PHARMACEUTICAL COMPOSITION COMPRISING p-GLYCOPROTEIN INHIBITOR AND p-GLYCOPROTEIN SUBSTRATE DRUG Download PDF

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KR20150135110A
KR20150135110A KR1020150069859A KR20150069859A KR20150135110A KR 20150135110 A KR20150135110 A KR 20150135110A KR 1020150069859 A KR1020150069859 A KR 1020150069859A KR 20150069859 A KR20150069859 A KR 20150069859A KR 20150135110 A KR20150135110 A KR 20150135110A
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glycoprotein
drug
pharmaceutical composition
inhibitor
substrate drug
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KR1020150069859A
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Korean (ko)
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장영길
이재헌
이재구
최경진
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한미정밀화학주식회사
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Abstract

The present invention relates to a pharmaceutical composition including a p-glycoprotein inhibitor and a p-glycoprotein substrate drug. The pharmaceutical composition of the present invention can reduce side effects of a drug caused by activity of p-glycoprotein and furthermore can provide the same pharmaceutical effect even when a smaller amount of the drug is used. Particularly, when dabigatran etexilate, which is the p-glycoprotein substrate drug, and a tetrazole deravative, which is the p-glycoprotein inhibitor, are used at the same time, bioavailability of dabigatran etexilate can be significantly increased. Consequently, a remaining amount of dabigatran etexilate in a gastrointestinal tract can be significantly reduced as the drug has the same level of bioavailability even when a user amount of the drug is reduced. In addition, an exposure amount of the drug in the gastrointestinal tract is reduced. Therefore, the pharmaceutical composition of the present invention can reduce the risk of bleeding, a fatal drawback for patients who takes existing dabigatran etexilate.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING p-GLYCOPROTEIN INHIBITOR AND p-GLYCOPROTEIN SUBSTRATE DRUG [0002] This invention relates to a pharmaceutical composition comprising an inhibitor of p-glycoprotein and a substrate drug of p-

The present invention relates to a pharmaceutical composition comprising an inhibitor of p-glycoprotein and a substrate drug of p-glycoprotein.

Dabigatran etexilate (Pradaxa, Pradaxa) is a thrombin inhibitor effective at preventing stroke in patients with deep vein thrombosis, stroke, and atrial fibrillation, especially atrial fibrillation (AF) It is the first oral anticoagulant to be launched worldwide in about 60 years after warfarin in the prevention of stroke in patients. This drug has fewer drug interactions than warfarin, has a relatively wide therapeutic range, and does not require monitoring of anticoagulant activity.

As shown in Table 1 below, darbigatran was found to be a relatively safe drug due to relatively low intracranial hemorrhage and gastrointestinal bleeding compared to warfarin (Southworth MR et al., N. Eng. J. of Med. , 2013, DOI: DOI: 10.1056 / NEJMp1302834).

RE-LY clinical trial for gastrointestinal bleeding and intracranial hemorrhage of dabigatran and warfarin (71 years, female 36.7%) RE-LY End point Patient (n) Event (n) Event per 100,000 people Dabigatran Gastrointestinal bleeding 10,599 16 1.6 Intracranial hemorrhage 10,587 8 0.8 Warfarin Gastrointestinal bleeding 43,541 160 3.5 Intracranial hemorrhage 43,594 109 2.4

However, on the other hand, as shown in Table 2, contrary to the RE-LY clinical trial results, darbagtran causes gastrointestinal hemorrhage more than twice as much as warfarin, and especially death due to hemorrhage is twice as high (American College of Cardiology 2013 Scientific Sessions; March 10, 2013; San Francisco, CA. Abstract 914-8).

Side effects of warfarin and darbigatran reported to the FDA End point Warfarin Dabigatran Total adverse events reported (n) 4,524 12,581 Bleeding event, n (%) 590 (13) 2453 (19) female (%) 54 48 Age (y) 68.5 75 Weight (kg) 85 82 Incident Warfarin Dabigatran Total bleeding (n) 590 2453 Gastrointestinal bleeding, n (%) 162 (27) 1352 (55) Intracranial hemorrhage, n (%) 69 (12) 280 (11) Bleeding related death, n (%) 47 (8) 393 (16)

Dabigatran etexilate is not only very low in solubility as a prodrug but is also a substrate of p-glycoprotein, inhibiting its absorption by p-glycoprotein in the intestinal tract, resulting in oral bioavailability of 6 %. As can be seen from this low oral bioavailability, some of the dabigatranectectylate is absorbed in the digestive tract and the remainder remains in the GI tract and eventually excreted in the feces. During this route, (Jay Desai et al . , Trombo Haemost. 10 (2), 205-12 (2013); see Fig. 1) by the digestive tract gut esterase.

When Darbaganthenecetylate is orally ingested, Darbaganthenecetylate, a substrate of p-glycoprotein, is absorbed from the digestive tract and transported through the gut wall to the blood vessels, where some of the dabigatran etexilate After being converted to a mono-prodrug from the barrier, it enters the blood vessel and is converted to the active darbagatran, and some of the dabigatranethexylate is replaced by the p-glycoprotein in the fused- . Therefore, the absorption of darbagtran is limited and thus the bioavailability is lowered. Especially, as antiglutan, an anticoagulant activity, is mostly present in the lumen of the gastrointestinal tract rather than the blood vessel, lesion) can cause bleeding. Therefore, it is necessary to reduce the dose of darbagtran in the gastrointestinal tract, since the extent of residual darbagatran in the gastrointestinal tract is a major factor in the degree of bleeding.

 Southworth MR etc., N. Eng. J. of Med., 2013; DOI: DOI: 10.1056 / NEJMp1302834  American College of Cardiology 2013 Scientific Sessions; March 10, 2013; San Francisco, CA. Abstract 914-8  Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013)

Accordingly, it is an object of the present invention to provide a pharmaceutical composition which can increase the pharmacological effect of a substrate drug of p-glycoprotein including darbagtran, reduce side effects, and effectively administer the drug in a small amount.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising an inhibitor of p-glycoprotein and a substrate drug of p-glycoprotein.

The pharmaceutical composition of the present invention can reduce the adverse effects of drugs caused by the activity of p-glycoprotein, and can also provide an equivalent pharmacological effect using smaller amounts of the drug. Particularly, when the p-glycoprotein substrate drug dabigatranethexylate and the p-glycoprotein inhibitor tetrazole derivative are used together, the bioavailability of dabigatran etexilate can be remarkably increased, and as a result, Even if the amount is reduced, the same level of bioavailability can be obtained, which can significantly reduce the residual amount of darbagtran in the gastrointestinal tract. This also reduces drug exposure in the gastrointestinal tract, thereby reducing the risk of bleeding, a fatal disadvantage of patients taking conventional darbiganteethicillate.

FIG. 1 is a schematic diagram showing the pathway of absorption of dabigatran etexilate by the p-glycoprotein in the gastrointestinal tract.
FIG. 2 shows the results of a single dose administration of darbigatran (-? -) in rats; Dabigatran etexylate mesylate (DAEM, - • -) alone; And the plasma concentration of darbagtran over time during the simultaneous (- - -) administration of DAEM and tetrazole derivative.
FIG. 3 is a graph showing the results of a single dose administration of DABIGA tranethexylate mesylate (DAEM) in rats; And the concentration of darbagtran in the small intestine and the large intestine with the lapse of time in the case of using the combination of DAEM and tetrazole derivative.

The present invention provides a pharmaceutical composition comprising an inhibitor of p-glycoprotein and a substrate drug of p-glycoprotein.

<Inhibitors of p-glycoprotein>

Preferred examples of the inhibitor of the p-glycoprotein used in the composition of the present invention include a tetrazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

&Lt; Formula 1 >

Figure pat00001
.

The tetrazole derivatives of Formula 1 are known to be effective p-glycoprotein inhibitors (see U.S. Patent No. 7,625,926), and can be easily prepared according to known methods. The pharmaceutically acceptable salt of the tetrazole derivative includes all the salt forms prepared using an organic acid or an inorganic acid.

Also, in another embodiment of the invention, a p-glycoprotein inhibitor is a substance known as a third generation p-glycoprotein inhibitor such as LY 335979, XR 9576, OC 144-093, quercetin, Rutin, J. Pharm. Pharmaceut. Sci., 12 (1): 46-78, 2009) or mixtures thereof.

p-glycoprotein is a substance responsible for multi-drug resistance (MDR) of cancer cells, and is a transporter (excretory transport carrier) involved in the excretion of many drugs. They are distributed throughout the body such as the kidney, liver, and brain barrier. Particularly, the p-glycoprotein present in the small intestine epithelium disrupts drug absorption in the intestinal tract by dissolving the drug into the gastrointestinal tract in the direction opposite to gastrointestinal absorption.

On the other hand, p-glycoprotein inhibitors such as verapamil or cyclosporine have strong pharmacological actions themselves, and when used with these drugs, side effects such as blood pressure lowering or immunosuppression are clinically present (Cancer Res., 41, 1967-1972, 1981). Thus, such pharmacologically active substances can not be used in combination with a substrate drug of the p-glycoprotein of the present invention, such as darbiganthenecetrate.

<Substance Drug of p-Glycoprotein>

Substrate drugs of p-glycoprotein used in the compositions of the present invention include dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib, Meloxicam, Clarithromycine, Clopidogrel, Aspirin, Duloxetine, Silodosin, pharmaceutically acceptable precursors thereof, pharmaceutically acceptable salts thereof, and the like, , And mixtures thereof.

In a preferred embodiment of the present invention, the substrate drug of the p-glycoprotein may be darbagtranectecylate of the formula 2 or a pharmaceutically acceptable salt thereof:

(2)

Figure pat00002
.

Preferable examples of the pharmaceutically acceptable salt of Darvagtranectexylate include, but are not limited to, Darviganthenecetylate mesylate.

In the pharmaceutical composition of the present invention, the substrate drug of the p-glycoprotein may be used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents based on the p-glycoprotein inhibitor.

In addition to the two above-mentioned active ingredients, the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable additives such as carriers, excipients and the like.

In addition, the pharmaceutical composition of the present invention can be formulated into various oral administration forms.

The present inventors have studied how to reduce the exposure of dabigatran to the gastrointestinal tract, considering the fact that dabigatran etexilate is a p-glycoprotein substrate, dabigatran etexilate or its pharmaceutically acceptable It was determined that administration of a possible salt together with a p-glycoprotein inhibitor would reduce the dose of darbastran in the gastrointestinal tract, and the present invention was developed.

According to previous studies, the risk of major intestinal hemorrhage in patients receiving twice daily doses of dabigatran etexilate at a dose of 110 mg was similar to warfarin, but the risk of intestinal bleeding was not reported when twice daily dosing at 75 mg low dose (Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013)). This result suggests that darbagatran can lower the risk of intestinal bleeding by as much as a high dose of 110 mg at a low dose of 75 mg.

The pharmaceutical compositions of the present invention may reduce the dose of the p-glycoprotein substrate drug, reduce drug exposure in the gastrointestinal tract, and may have an improved effect of reducing gastrointestinal-related side effects such as ulcers.

According to the results of the experiment according to the present invention, when darbagatran ethylcellulose mesylate was administered to rats without or with the use of p-glycoprotein inhibitor and the concentration of darbastran in the gastrointestinal tract was examined, The concentration of dabigatran in the gastrointestinal tract was lower than in the case of using a glycoprotein inhibitor. From these results, it can be inferred that the combined administration of p-glycoprotein inhibitor and p-glycoprotein substrate drug can lower bleeding cases in vulnerable lesions.

Manufacturing example  1: N- (2- (2- (4- (2- (6,7- Dimethoxy -3,4- Dihydroisoquinoline -2 (lH) -yl) ethyl) Phenyl ) -2H- Tetrazole -5-yl) -4,5- Dimethoxyphenyl ) -4-oxo-4H- Kromen -2- Carboxamide  (1) Tetrazole  Derivatives)

Yl) ethyl) phenyl) -2H-tetrazol-5-yl) - (2-methyl- 0.85 g of 4,5-dimethoxybenzeneamine and 0.75 g of 4-oxo-4H-chromene-2-carboethanoic acid S-benzothiazol-2-yl ester were added to 5 mL of dichloromethane, Lt; / RTI &gt; After the completion of the reaction, the reaction solution was washed with 50 mL of distilled water, and the organic layer was dried over magnesium sulfate, and then filtered under reduced pressure and distilled under reduced pressure to obtain a residue. The obtained residue was separated and purified by column chromatography to obtain the title compound (1.0 g).

Preparation Example 2. Preparation of N- (2- (2- (4- (2- (6,7-dimethoxy-3,4-dihydroisoquinolin-2 5-yl) -4,5-dimethoxyphenyl) -4-oxo-4H-chromene-2-carboxamide methanesulfonate (methanesulfonate of tetrazole derivative of formula

Ethyl) phenyl) -2H-tetrazole-5-carboxylic acid ethyl ester was used in place of N- (2- (2- (4- (2- (6,7- dimethoxy-3,4-dihydroisoquinolin- -4,5-dimethoxyphenyl) -4-oxo-4H-chromene-2-carboxamide (1.4 g) was added to 3 mL of ethyl acetate, and then 0.2 g of methanesulfonic acid was added thereto. Lt; / RTI &gt; The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (1.2 g).

Manufacturing example  3: Dabigatran Ethoxylate Of mesylate (DAEM)  Produce

20 g of 4chembiogenix was added to 112 mL of acetone and then dissolved at about 40 to 50 DEG C to dissolve. The dissolved reaction solution was slowly cooled to about 30 to 36 占 폚. Meanwhile, a solution obtained by dissolving 3.5 g of mesyl acid (MSA) in 10 mL of acetone was slowly added to the reaction solution for 15 to 40 minutes while maintaining the temperature at 30 to 36 ° C. The reaction solution was stirred for 40 to 60 minutes while maintaining the temperature at 26 to 33 ° C, cooled again to 17 to 23 ° C and stirred for 40 to 60 minutes. Then, the obtained reaction solution (mother liquor) was filtered and the filtered crystals were washed with 60 mL of acetone. Thereafter, the resulting crystals were dried under a warm air at about 40 ° C to obtain 19.6 g (yield: 85.3%) of the title compound.

Purity: 99.3% by HPLC

Endothermic peak of DSC: 179 ° C

Example  1: Bioavailability comparison of combination of p-glycoprotein inhibitor and p-glycoprotein substrate drug

The bioavailability of the p-glycoprotein substrate drug in combination with the p-glycoprotein inhibitor and the p-glycoprotein substrate drug was examined. Specifically, three rats were treated with 4 chembiogenix alone, a combination of DABEM and tetrazole derivatives prepared in Preparation Example 3 (DAEM) and a tetrazole derivative (Preparation 2), respectively, After administration, plasma concentration of darbagtran over time was measured.

Vehicle used was a mixture of PEG400, Tween 20 and distilled water (1/1/8; v / v / v), darbagtran alone 0.5 mg / kg (mpk), darbiganthenecylate mesyl The tetrazole derivative was prepared by mixing 20 g of tetrazole derivative as a mixture of distilled water / propylene glycol: HCl = 70: 30: 0.02 (v / v / v) mg / kg was used.

The experimental results are shown in Fig. As shown in Fig. 2, the combination administration of tetracosyltartrate and tetracosylate mesylate showed a higher plasma concentration in rats than in the case of only tetacellate mesylate and dabigatran alone .

Also, the curve in rats according to the combination of the protein and inhibitor protein substrates per drug per p- p- analyzed enemy (AUC 0 -24), maximum plasma concentration (C max), half-life and bioavailability (BA). The results are shown in Table 3.

Dabigatran alone DAEM alone Combination of DAEM and tetrazole derivative AUC 0 -24 (ng · hr / mL) 1337.5 2583.8 5754.6 C max (ng / mL) 2605.5 1259.3 2008.0 T 1/2 (hr) 4.4 1.1 4.6 BA (%) - 9.7 21.5

As shown in Table 3, bioavailability was 9.7% when dabigatran etexylate mesylate alone was administered, while bioavailability was 21.5% when administered in combination with tetrazole derivatives, Respectively.

Example  2: Concentration and pharmacokinetic characterization of p-glycoprotein substrate drug in small intestine and large intestine by combination of p-glycoprotein inhibitor and p-glycoprotein substrate drug

The concentration of the p-glycoprotein substrate drug in the small intestine and large intestine according to the combination of the p-glycoprotein inhibitor and the p-glycoprotein substrate drug was analyzed.

Specifically, in the case of the control group, 10.0 mg / kg of DABG (DAEM) was administered orally to rats (n = 3) and to the rats (n = 3) The concentration of darbastran in the small intestine (SI) and large intestine (LI) was measured after oral administration of gatran etexilate mesylate 5.0 mg / kg and tetrazole derivative (Preparation Example 2) 20.0 mg / kg .

The results are shown in Fig.

As shown in Fig. 3, the control group in which dabigatran etexilate mesylate was administered alone had a high concentration of dabigatran in the small intestine and large intestine, while the combination of dabigatran etexilate mesylate and tetrazole derivative The experimental group showed a relatively low concentration of Darbygatran. The results show that the combined administration of p-glycoprotein inhibitor and p-glycoprotein substrate drug can lower gastrointestinal side effects due to p-glycoprotein substrate drug.

(AUC 0 -24 ), maximum plasma concentration, half-life and bioavailability in the small intestine and large intestine of rats following combination of p-glycoprotein inhibitor and p-glycoprotein substrate drug were analyzed. The results are shown in Table 4.

Control group Experimental group Intestine Leader Intestine Leader AUC 0 -24 (ng · hr / mL) 10165.7 4945.5 4379.9 2114.5 C max (ng / mL) 5909.3 2749.3 2025.3 892.0 T 1/2 (hr) 0.5 4.0 1.0 4.0 BA (%) 7.7 3.8 7.1 3.4

As shown in Table 4, the experimental group administered with the combination of darbigatran etexilate mesylate and tetrazole derivative showed a similar level of bioavailability to that of the control group, although the dose was smaller than that of the control group. The above results show that the combined use of the p-glycoprotein inhibitor and the p-glycoprotein substrate drug can achieve a superior pharmacological effect despite the use of a small amount of the p-glycoprotein substrate drug, thereby reducing the side effects of the drug Respectively.

Claims (4)

inhibitors of p-glycoprotein; And a substrate drug of a p-glycoprotein.
2. The pharmaceutical composition according to claim 1, wherein the inhibitor of the p-glycoprotein is a tetrazole derivative of the following formula 1 or a pharmaceutically acceptable salt thereof:
&Lt; Formula 1 >
Figure pat00003
.
The method of claim 1, wherein the substrate drug of the p-glycoprotein is selected from the group consisting of dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib, Meloxicam Clarithromycine, Clopidogrel, Aspirin, Duloxetine, Silodosin, pharmaceutically acceptable precursors thereof, pharmaceutically acceptable salts thereof, and the like, &Lt; / RTI &gt; and mixtures thereof.
The pharmaceutical composition according to claim 3, wherein the substrate drug of the p-glycoprotein is darbagatran etexilate mesylate.
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Cited By (2)

* Cited by examiner, † Cited by third party
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DE102016117976A1 (en) 2015-09-24 2017-03-30 Lg Display Co., Ltd. Display device with touchscreen function
CN107970225A (en) * 2017-12-22 2018-05-01 重庆植恩药业有限公司 A kind of dabigatran etcxilate solid lipid nano granule and preparation method thereof

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* Cited by examiner, † Cited by third party
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KR100557093B1 (en) * 2003-10-07 2006-03-03 한미약품 주식회사 Tetrazole derivatives having inhibitory activity against multi-drug resistance and preparation thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102016117976A1 (en) 2015-09-24 2017-03-30 Lg Display Co., Ltd. Display device with touchscreen function
DE102016117976B4 (en) 2015-09-24 2018-10-31 Lg Display Co., Ltd. Display device with touchscreen function
CN107970225A (en) * 2017-12-22 2018-05-01 重庆植恩药业有限公司 A kind of dabigatran etcxilate solid lipid nano granule and preparation method thereof
CN107970225B (en) * 2017-12-22 2022-06-03 植恩生物技术股份有限公司 Dabigatran etexilate solid lipid nanoparticle and preparation method thereof

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