WO2001060353A1 - Liquid preparation with improved absorbability - Google Patents

Abstract

A liquid preparation containing a sparingly water-soluble compound (I) or a salt thereof in which the oral absorbability of these is improved. The liquid preparation comprises the sparingly water-soluble compound (I) or salt, a nontoxic solvent in which the compound (I) and salt are soluble, and a water-soluble polymer.

Description

 Liquids with improved absorbency

 The present invention relates to a solution having improved absorbency, comprising a compound represented by the following formula (I) or a salt thereof, a solvent capable of dissolving the compound or a salt thereof, and a water-soluble polymer. It is used in the medical field. Background art

 Compounds represented by the following formula (I) (hereinafter, referred to as “compound (I)”) are described in International Patent Application Publication No. WO99 / 54284 and tWO 01/057. No. 70, which can be produced by the method described in the publication, and is known to be useful as a cGMP-phosphodiesterase inhibitor.

 However, since compound (I) has low solubility in water, it is hardly absorbed when administered orally in a crystalline state or a fine powder state, and improvement of its absorbability has been desired.

 On the other hand, Japanese Patent Application Laid-Open No. 9-501150 discloses a capsule containing a sparingly soluble compound or a salt thereof, a capsule content liquid, and a diamine or a surfactant and / or a cellulose derivative. . According to this formulation, it is known that when the poorly soluble compound elutes from the capsule, the growth of crystals is suppressed to form fine crystals, and as a result, high bioavailability can be obtained by oral administration. Disclosure of the invention

The inventors of the present invention dissolve the compound (I) or a salt thereof (hereinafter, these are collectively referred to as “main drug”) in a solvent capable of dissolving the main drug, and add a water-soluble polymer thereto. Surprisingly, it was found that the solubility of the active substance in water was improved, and the absorption of the active substance was significantly improved as a result of maintaining the state in which crystals did not precipitate even if the active solubility of the active substance itself exceeded the saturation solubility in water. Heading, completed this invention. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the change over time in the solubility of the liquid preparation (liquid preparation 1) obtained in Example 1 of the present invention and the liquid preparation (liquid preparation A) obtained in Comparative Example 1 in water. BEST MODE FOR CARRYING OUT THE INVENTION

 According to the present invention, formula (I):

[Where,

 When X is CH, the following definition 1:

R ¹ is a hydrogen atom or a halogen atom,

R ² is an electron withdrawing group,

R ³ has the formula: CONH—A—R ¹³ [where

 A is a lower alkylene group,

R ¹³ is a hydrogen atom; a hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl]. And

R ⁴ has the formula: one NH—R ¹⁴ [where,

R ¹⁴ is a lower alkoxy group; a substituted or unsubstituted heterocyclic group, saturated or unsaturated, lower alkyl or halo (lower) alkyl substitution which may be an amino group; the formula: A CH ₂ - R ¹⁵ wherein R ¹⁵ is a cycloalkyl group or an unsaturated heterocyclic group; or a group represented by the formula: CR ¹⁶ R ¹⁷ R ¹⁸ wherein R ¹⁶ and R ¹⁷ are each Independently, a carpoxy group, a protected carboxy group, a labamoyl group optionally substituted with lower alkyl, or a halogen, hydroxy, cyano, azide, lower alkoxy, lower alkylthio, protected alkyl group Poxy, lower alkane sulfonyl, asiloxy, lower alkane sulfonyloxy, aryl, aryloxy (optionally substituted with cyano), unsaturated heterocyclic group (optionally substituted with lower alkyl) guanidino (lower alkyl, cyano and Thiol (optionally substituted with lower alkyl or cyano), and amino (amino, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy) and isothioureido (optionally substituted with lower alkyl or cyano). Or a lower alkyl group which may be substituted with one or more substituents selected from the group consisting of

R ¹⁶ and R ¹⁷ together with the carbon atom to which they are attached, are-a substituted or unsubstituted saturated carbocyclic group or an unsaturated carbocyclic group which may be substituted by hydroxy And R ¹⁸ is a hydrogen atom; a lower alkoxy group; or a hydroxy or lower alkoxy group! /, Which is a lower alkyl group). Is a group represented or has the following definition 2:

R ¹ is a hydrogen atom,

R ² is a halogen atom; a cyano group; a nitro group; a carpamoyl group; a lower alkyl group optionally substituted by a heterocyclic group; a rubamoyl group; a carboxy group; a protected carboxy group; a lower alkyl group; An alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group;

R ³ and R ⁴ together form the formula:

-so, R ^{2 3} is a lower alkyl group, a consequent opening alkyl or heterocyclic group, among these lower alkyl groups are hydroxy, protected human Dorokishi, Ashiru, lower alkoxy-substituted Ararukiruokishi, Amino, lower alkyl Ruamino, Ashiruamino , Lower alkoxycarbonylamino, lower alkane sulfonylamino, ureido, lower alkyl ureido, sulfamoylamino, protected carboxy, carboxy, lower alkane sulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and Cycloalkyl and heterocyclic groups may have from 1 to 3 substituents selected from the group consisting of sulfamoyl; hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, Acylamino, lower alkoxycarbonylamino, lower alkyl sulfonylamino, ureido, lower alkylperido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy (lower) alkyl, protected May have a substituent selected from the group consisting of hydroxy (lower) alkyl, lower alkylenedioxy, sulfamoyl and sulfamoyl;

R ^{2 4,} R ^{2 5} and R ^{2 6} are the same or different, a hydrogen atom, a halogen atom, a lower Arukanoiru group, a carboxy group, a protected carboxy group, the force Rubamoiru group, a nitro group, Shiano group, a lower alkyl group A hydroxy-substituted lower alkyl group, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or any ^{two of} R 24, R ²⁵ and R ²⁶ together form a lower alkylenedioxy group. Y may be an oxygen atom or a sulfur atom,

 m is an integer of 1 or 2] means a group represented by

When X is a nitrogen atom, ¹ , R ² , R ³ and R ⁴ all have the same meaning as in definition 2 above]

A liquid preparation having improved absorbability, comprising: a compound represented by the formula: or a salt thereof; a nontoxic solvent capable of dissolving the compound or a salt thereof; and an ice polymer. Is provided.

 The compound (I) contained in the liquid preparation of the present invention has the following formula (la)

 [Where '

R ¹¹ and R ¹² have the same meanings as R ¹ and R ² in Definition 1 above, respectively.

A, R ¹³ and R ¹⁴ all have the same meaning as in definition 1 above.]

And an anthranilic acid derivative (Ia :) represented by the following formula (Ib):

[Where,

 X is CH or a nitrogen atom,

R ²¹ and R ²² have the same meanings as R ¹ and R ² in Definition 2 above, respectively.

Y, R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and m all have the same meaning as in definition 2 above]

A condensed imidazole derivative (Ib), ie, a benzimidazole derivative (Ib-1) [where X is CH] and an imidazopyridine derivative (Ib-2) [wherein X Is a nitrogen atom].

For details of the above-mentioned anthranilic acid derivative (la) and its production method and pharmacological action, refer to the description in International Patent Application Publication WO 99/54284. Monkey

 Therefore, the description in WO 99/54284 should be understood as forming a part of the present specification.

Preferred among the anthranilic acid derivatives (la) are those wherein in formula (Ia), R ¹¹ is a hydrogen atom, R ¹² is a nitro, cyano or halo (lower) alkyl group, and R ¹³ is Lower alkoxy is a phenyl group substituted with Z or halogen, wherein R ¹⁴ is a group represented by the formula: CR ¹⁶ R ¹⁷ R ¹⁸ wherein R ¹⁶ and R ¹⁷ are each independently substituted with hydroxy Or a lower alkyl group, R ¹⁶ and R ¹⁷ , together with the carbon atom to which they are attached, is a saturated carbocyclic group substituted with an acylamino group, and R ¹⁸ Is a hydrogen atom] and A is a lower alkylene group.

 Particularly preferred compounds among them are

 (R) -N- (3,4-dimethoxybenzyl) 1-2- (2-hydroxy-1-1-methylethylamino) -5-nitrobenzamide,

N— (4-Chloro-3-methoxybenzinole) —2— [2-Hydroxy-1- (hydroxymethynole) ethynoleamino] —5-nitrobenzamide,

N- (3,4-Dimethoxybenzyl) -2-[(trans-4-formamide cyclohexyl) amino] — 5-nitrobenzamide 'dihydrate,

 (S) — 5-cyano N — (3,4-dimethoxybenzyl) -2- (2-hydroxy 1-methylethynoleamino) benzamide and

 N— (3-Mouth 4-Methoxybenzinole)-2-[2-Hydroxy 1- (Hydroxymethyl) ethylamino] —5— (Trifluoromethyl) benzamide.

 The details of the benzimidazole derivative (Ib_l) and the diazomidazopyridine derivative (Ib-2) contained in the liquid preparation of the present invention, their production method and pharmacological action are described in International Patent Application Publication WO 01 Reference can be made to the description in JP-A-2005770.

Therefore, the description in WO01 / 05770 should also be understood as forming part of the present specification. Among the benzimidazole derivatives (I b-1) and imidapyridine derivatives (I b -2), preferred are those represented by the formula (I b), wherein X is a nitrogen atom, Y is an oxygen atom, and R ²¹ Is a hydrogen atom, R ²² is a cyano group, R ²³ is a cyclohexyl group substituted with hydroxy or lower alkanoyloxy, R ²⁴ is a hydrogen atom, R ^{25 is a} halogen atom. And R ²⁶ are compounds having a lower alkoxy group.

 Particularly preferred compounds among them are

1- (3-chloro-1-4-benzyl) 16-cyano-3- (trans-4-hydroxycyclohexyl) 1,2,3-dihydro-1 H-imidazo [4,5-b] 1-pyridine-one,

 1- (3-bromo-14-methoxybenzyl) 16-cyano-3- (trans-1

4-Hydroxycyclohexyl) —2,3-dihydroxy-1H—imidazo [4,

5—b] pyridine-1-2-and

 1- (3-Chloro-4-methoxybenzinole) 16-Cyanol 3- (cis-14-hydroxycyclohexyl) 1,2,3-dihydro-1H-imidazo [4,5-b] pyridine-1 2-one is there.

The anthranilic acid derivative ( _Ia ;), the benzimidazole derivative (Ib-1) and the imidaviridine derivative (lb-2) may be in the form of a salt, wherein the salt is a pharmaceutically acceptable salt For example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, organic bases (trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine) , Dibenzylethylenediamine, etc.), organic acids (acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, lactic acid, cunic acid, tartaric acid, dalconic acid, methanesulfonic acid, benzenesulfonic acid, formic acid, Salts with p-toluenesulfonic acid, trifluoroacetic acid, etc., inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid) And phosphoric acid), amino acids (Anoreginin, Asuparagin acid, salts with grayed etc. glutamic acid).

Anthranilic acid derivatives ( _Ia ), benzimidazole derivatives (Ib-1) and imidaviridine derivatives (Ib-2) and their salts are hydrated, It may be in the form of a solvate such as a nolate.

 The solvent used in the present invention may be any as long as it dissolves the active ingredient and is pharmaceutically acceptable. Specifically, polyethylene glycol having an average molecular weight of less than 4,000 (for example, polyethylene glycol 400) ), Polyhydric alcohols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and polyglycerin, fatty acid glycerin esters, fatty acid propylene glycol esters, sesame oil, soybean oil, corn oil, olive oil and the like.

 Of these solvents, more preferred are polyhydric alcohols, even more preferred are polyethylene glycol and propylene glycol having an average molecular weight of less than 4,000, most preferred are polyethylene glycol 400. . '

 The above solvents can be used alone or in combination of two or more.

 The water-soluble polymer used in the present invention may be any pharmaceutically acceptable one.For example, cellulose derivatives such as hydroxypropinoresenolylose, hydroxypropylmethinoresenolose, methylcellulose and carboxymethylcellulose; Polybutylpyrrolidone, polyethylene glycol having an average molecular weight of 4,000 or more (for example, polyethylenedaricol 600,000) and the like can be mentioned.

 Among these water-soluble polymers, more preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose, and polypyrrolidone. Polyethylene glycol having an average molecular weight of 4,000 or more is more preferable. And low polymerization degree, and most preferably low polymerization degree hydroxypropyl cellulose.

 The above water-soluble polymers can be used alone or in combination of two or more.

The liquid preparation of the present invention may appropriately contain a pharmaceutically acceptable natural or synthetic surfactant in addition to the water-soluble polymer. Examples of natural surfactants include various substances derived from animals or plants, and synthetic surfactants. Examples include cationic, anionic or nonionic surfactants. Examples of such synthetic surfactants include polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl mono fatty acid ester, polyoxyethylene propylene glycol mono fatty acid ester, polyoxyethylene sorbitol fatty acid ester, Natural fats and oils and polyoxyethylene derivatives of polyethylene, polyethylene daricol fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene-polyoxypropylene copolymer and block copolymer type surfactant surfactant, alkyl Examples include sulfates, phospholipids, bile salts, fatty acids, monohydric alcohol fatty acid esters, ethylene glycol fatty acid esters, and polyhydric alcohol fatty acid esters.

 The above surfactants can be used alone or in combination of two or more.

 In addition, the liquid preparation of the present invention may appropriately contain commonly used general-purpose additives such as a brightener, a flavor, and the like.

 The liquid preparation of the present invention can be usually produced by dissolving the active ingredient in a solvent, and mixing this solution with a water-soluble polymer and, if desired, a surfactant and other additives.

 In the liquid preparation of the present invention, the water-soluble polymer may be suspended in a solvent.

 The liquid preparation of the present invention can be made into a capsule preparation by filling the liquid preparation into a capsule.

 The capsule may be either a soft capsule or a hard capsule. In the case of a hard capsule, the cap and the body are sealed by a conventional method so that the liquid content does not leak. The size of the capsule is appropriately determined depending on the type of the active ingredient and its concentration.

 The mixing ratio of the solvent and the water-soluble polymer can be appropriately selected according to the content of the active ingredient, or the elution pattern and duration of action of the intended active ingredient.

— For example, the solvent is 1 to 100 parts by weight, the water-soluble polymer is 0.05 to 20 parts by weight, more preferably 0.5 to 1 part by weight, based on 1 part by weight of the active ingredient. 0 parts by weight, More preferably, it is about 0.5 to 3.0 parts by weight.

 The active ingredient of the present invention is useful as a cGMP-phosphodiesterase inhibitor. Specifically, for example, angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, glomerular disease (eg, diabetic glomerulosclerosis) , Tubule-interstitial disease (for example, nephropathy induced by tacrolimus, cyclosporin, etc.), renal failure, atherosclerosis, vascular stenosis (such as after percutaneous transluminal coronary angioplasty) , Peripheral vascular disease, seizures, chronic reversible obstructive pulmonary disease (eg, bronchitis or asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, gut motility disorder ( Irritable bowel syndrome), erectile dysfunction (eg, organic or psychological erectile dysfunction), female sexual dysfunction, impotence Or diabetic complications (eg, diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic skin disorder, diabetic neuropathy, diabetic cataract or diabetic retinopathy) It is useful for treating and / or preventing various diseases.

 The dose of the active substance depends on the age and symptoms of the patient, but for systemic administration, it is usually 0.01 to 0.5 mg, lmg, 5 mg, 10 mg, 50 mg, 100 mg, 25 Omg and 50 Omg per dose. And an amount of about 0.01 to 1000 mg, preferably 0.2 to 500 mg, more preferably 0.5 to 10 Omg per day is administered. For long-term administration, the daily dose will range from about 0.3 mg to: L00 Omg.

 Hereinafter, the present invention will be described with reference to Examples .; Φ: The present invention is not limited to these Examples. Example 1

Ν— (3,4-dimethoxybenzyl) 1-2-[(trans-4-formamidocyclohexyl) amino] —5-nitrobenzamide 'dihydrate (hereinafter referred to as “drug 1”) (0 5 g) was dissolved in polyethylene glycol 400 (PEG-400) (about 30 mL). Was added and dissolved, and then PEG-400 was further added to adjust the total amount to 5 OmL.

The composition per 1 mL of the solution is as follows.

Active agent 11 Omg Low polymerization degree hydroxypropylcellulose 30 mg

PEG—400

Whole mL Comparative Example

 The active substance 1 (0.5 g) was dissolved in PEG-400 (about 30 mL), and PEG-400 was further added to this solution to make a total volume of 5 OmL. The composition per mL of solution is as follows.

Active agent 1 1 Omg

PEG—400

Total lmL Test Example 1 (Pharmaceutical solubility test)

 The liquid agent obtained in Example 1 (hereinafter, referred to as “liquid agent 1”) and the liquid agent obtained in Comparative Example 1 (hereinafter, referred to as “liquid agent A”) were compared for the solubility of the main drug when added to water. did. The test was conducted in accordance with the Dissolution Test Method 2 described in the 13th Revised Japanese Pharmacopoeia. That is, the solubility of the main drug was measured when 5 mL (5 Omg as the main drug 1) of each of Liquid Formulation 1 and Liquid Formulation A was added to a test solution consisting of 90 OmL of water at a paddle rotation speed of 50 rpm. Figure 1 shows the results.

The solubility of Active Substance 1 in water was 0.4 pg / mL, whereas Liquid A showed a solubility of about 45 μg / mL immediately after addition, but the solubility decreased with time. . In contrast, the solution 1 of the present invention maintained a solubility of about 45 μg ZniL or more immediately after the addition and after 120 minutes. From these results, it can be seen that the solubility of the active substance 1 when the liquid preparation 1 is diluted with water is remarkably superior to that of the liquid preparation A. Test example 2 (oral absorption test of main drug)

 (1) Test preparation

 Capsules (hereinafter referred to as “capsule 1” and “capsule A”, respectively) in which the above liquid 1 and liquid A were filled into hard capsules, respectively, were used.

 (2) Test method

 The above capsules were orally administered once orally to male beagle dogs (body weight 9.0 to 12. Ok g, 3 animals per group) fasted overnight.

 The capsenole was prepared so that the dose of the active drug 1 was 3.2 mg / kg.

 In addition, bioavailability (BA) was calculated based on the area under the one-hour curve (AUC) when the PEG-400 solution of the active substance 1 was administered intravenously and when the forcepsel agent 1 or A was administered. ).

 (3) Test results

Maximum plasma concentration after oral administration (Cmax), time to reach Cmax (Tmax), AUC. Table 1 shows _{24 hr} and BA. Each numerical value in the table is shown as “average soil standard error”.

表 1から明らかなように、 本発明の液剤 1を含むカプセル剤 1は優れた過飽 和溶解度の維持特性を反映しており、 力プセル剤 Aと比較した場合、 Cma X および AUC。 _24hrのいずれもが約 1. 6倍高い値を示した。 また、 カプセル 剤 1の BAは約 90%で、主薬 1がほぼ完全に吸収されていることが分かった。 実施例 2

As is evident from Table 1, Capsule 1 containing Liquid 1 of the present invention reflects the excellent properties of maintaining supersaturated solubility, and shows Cma X and AUC when compared to Forcepsel A. _Each of the _{24 hours} showed a value about _1.6 times higher. Also capsule The BA of drug 1 was about 90%, indicating that drug 1 was almost completely absorbed. Example 2

 (R) -N- (3,4-dimethoxybenzyl) 1-2- (2-hydroxy-11-methylethylamino) -1-5-nitrobenzamide (hereinafter referred to as the "drug 2") (15 g) Was dissolved in PEG-400 (6585 g), and to this solution was added low-polymerization-hydroxypropylcellulose (150 g) and dissolved. This solution was filled into a soft capsule to obtain a force capsule agent.

 The composition per capsule is as follows.

Active ingredient 2 lmg Low polymerization degree hydroxypropyl cellulose 10 mg

PEG—400 439 mg 450 mg in total Example 3

 N- (4-Methoxy-1-benzyl) —2 -— [2-Hydroxy-1- (hydroxymethyl) ethylamino] —5-nitrobenzamide (hereinafter referred to as “drug 3”) (37. 5 g) of PEG-400 (6562.5 g) was added, and to this solution was added low-polymerized hydroxypropylcellulose (150 g) and dissolved. This solution was filled into soft capsules to obtain capsules.

 The composition per capsule is as follows.

Active agent 32.5 mg Low polymerization degree hydroxypropyl cellulose 10 mg

PEG—400 437.5 mg Total 450 mg Example 4

The active substance 1 (15 g) was dissolved in PEG-400 (645 g), and to this solution was added low-density hydroxypropylcellulose (15 g) and dissolved. This solution The capsule was filled into a soft capsule to obtain a forcepsel agent.

The composition per capsule is as follows _c

Active agent 1 10 mg Low polymerization degree hydroxypropyl cellulose 10 mg

PEG—400 43 Omg Total 4 b 0 mg Example 5

 Active agent 2 (0.5 g) was dissolved in PEG-400 (about 30 mL), hydroxypropylmethylcellulose (1.5 g) was added to this solution, and then PEG-400 was added to make a total volume of 5 OmL. .

The composition per 1 mL of the solution is as follows.

Active ingredient 21 Omg Hydroxypropyl methylcellulose 3 Omg. PEG-400 Appropriate amount Total lmL Example 6

 Dissolve drug substance 3 (0.5 g) in PEG-400 (approximately 3 OmL), add polybutylpyrrolidone (1.5 g) to this solution, dissolve, and add PEG-400 to the total volume. To 5 OmL.

The composition per 1 mL of the solution is as follows.

Active ingredient 31 Omg Polypyrrolidone 3 Omg PEG— 400

Overall Example 7

(S) —5—Cyanone N— (3,4-Dimethoxybenzyl) -2- (2—H Droxy-1 1-methylethylamino) benzamide (hereinafter referred to as “drug 4”) (0.5 g) dissolved in PEG-400 (about 30L)? Then, polyethylene glycol 6000 (1.5 g) was added to this solution and dissolved.

0 was added to bring the total volume to 5 OmL.

The composition per 1 mL of the solution is as follows.

Active agent 4 1 Omg Polyethylene glycol 6000 3 Omg

P EG-400

Total lmL Example 8

 N- (3-chloro-1-4-benzyl) 1-2- [2-hydroxy-1- (hydroxymethyl) ethylamino] -15- (trifluoromethyl) benzamide (hereafter referred to as the active drug 5j) (0.05 g) was dissolved in propylene glycol (approximately 3 OmL). To this solution was added low-polymerization hydroxypropylcellulose (0.5 g), and then propylene glycol was added to reduce the total amount. It was 5 OmL.

The composition per 1 mL of the solution is as follows.

King's drug 5 1 mg Low polymerization degree hydroxypropyl cellulose 10 mg Propylene glycol

Whole ml Example 9

 The active drug 3 (0.05 g) was dissolved in propylene glycol (about 3 OmL), hydroxypropylmethylcellulose (0.5 g) was added to this solution, and propylene glycol was further added to make a total amount of 5 g. OmL was used.

The composition per 1 mL of the solution is as follows.

Active agent 3 1 mg Hydroxypropyl methylcellulose 1 Omg Propylene dalicol

1 mL total Example 10

 Active substance 1 (0.05 g) is dissolved in propylene glycol (about 30 mL), and polyvinylpyrrolidone (0.5 g) is added to this solution, and then dissolved in propylene glycol. OmL was used.

The composition per 1 mL of the solution is as follows.

Active ingredient 1 lmg Polyvininolepyrrolidone 10 mg Propylene glycolone

1 mL total Example 11

 Dissolve drug substance 2 (0.05 g) in propylene glycol (approximately 3 OmL), add polyethylene glycol 6000 (0.5 g) to this solution, dissolve, and then add propylene glycol to make a total volume of 5 OmL. And

The composition per 1 mL of the solution is as follows.

Active ingredient 2 lmg Polyethylene glycol 6000 1 Omg Propylene glycol

Whole mL Example 12

The main drug 2 (37.5 g) was dissolved in PEG-400 (6562.5 g), and low-polymerized hydroxypropylcellulose (150 g) was added to this solution and dissolved. This solution is filled into a hard capsule, and a seal liquid containing gelatin as a main component is used to seal between the body and the cap of the hard capsule to prevent leakage of the content liquid. A capsule was obtained.

The composition per capsule is as follows _c

Active substance 22.5 mg Low polymerization degree hydroxypropyl pill cellulose 1 Omg PEG- 400 437.5 mg Total 450 mg Example 13

 1- (3-chloro-1--4-benzyl) 16-cyano-3- (trans-4-hydroxycyclohexynole) -2,3-dihydro-1H-imidazo [4,5-b] pyridine Dissolve 2-one (hereinafter referred to as “drug 6”) (0.5 g) in PE G-400 (approximately 30 mL), add low-polymerized hydroxypropylcellulose (1.5 g) to this solution and dissolve. After that, PEG-400 was further added to bring the total volume to 50 mL.

The composition per 1 mL of the solution is as follows.

Active agent 61 Omg Low polymerization degree hydroxypropyl cellulose 30 mg

PEG—400

Whole ml Example 14

 1- (3-bromo-4-methoxybenzyl) 16-cyano-13- (trans-4-hydroxycyclohexyl) -2,3'-dihydro-1H-imidazo [4,5-b] pyridine-1 Dissolve 2-one (hereinafter referred to as the “drug 7”) (0.05 g) in propylene glycol (about 30 mL), add polyvinylpyrrolidone (1.5 g) to this solution, and dissolve. Further, propylene glycol was added to make a total volume of 50 mL.

The composition per 1 mL of the solution is as follows.

Active substance 7 lmg Polyvinylinpyrrolidone 30 mg Propylene glycolone __ *

Total 1 mL Example 15

 1- (3-chloro-1-4-benzyl) 16-cyano-3- (cis-14-hydroxycyclohexynole) 1,2,3-dihydro 1 H-imidazo [4,5-b] pyridine 2-one (hereinafter referred to as “Main Drug 8”) (0.1 g) is premixed with PEG-400 (about 30 mL), and polyethylene glycol 6000 (1.5 g) is added to this solution and dissolved. Then, PEG-400 was added. The total volume was adjusted to 50 mL.

The composition per 1 mL of the solution is as follows.

Active agent 8 2mg Polyethylene glycol 6000 3 Omg

PEG—400

Total lmL Industrial potential

 The liquid preparation of the present invention containing the anthranilic acid derivative (la) or the condensed imidazole derivative (Ib) or a salt thereof as the principal agent exists in a state where crystals do not precipitate up to a concentration approximately 100 times the solubility of the principal agent in water. It exhibits extremely good oral absorption.

Claims

Claims Formula (i)

[Where,  When X is CH, the following definition 1: R ¹ is a hydrogen atom or a halogen atom, R ² is an electron withdrawing group, R ³ has the formula: CONH—A—R ¹³ [where  A is a lower alkylene group, R ¹³ is a hydrogen atom; a hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group which may be substituted by lower alkyl. R ⁴ is a group of the formula: one NH—R ¹⁴ [where R ¹⁴ is a lower alkoxy group; a substituted or unsubstituted, saturated or unsaturated heterocyclic group, lower alkyl or halo (lower) amino group which may optionally be substitution by alkyl; wherein: A CH ₂ - R ¹⁵ wherein R ¹⁵ is a cycloalkyl group or an unsaturated heterocyclic group; or a group represented by the formula: CR ¹⁶ R ¹⁷ R ¹⁸ wherein R ¹⁶ and R ¹⁷ are each Independently, a carboxy group, a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a halogen, hydroxy, cyano, azide, lower alkoxy, lower alkylthio, protected carboxy, lower Alkanesulfonyl, acyloxy, lower alkanesulfonyloxy, aryl, aryloxy (which may be substituted by cyano), unsaturated heterocyclic group (lower alkyl May be substituted with Le), Guanijino (lower alkyl, is optionally substituted with Shiano and / "or halogen ), Isothioureido (optionally substituted with lower alkyl or cyano) and amino (substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxy). Or a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of R ¹⁶ and R ¹⁷ together with the carbon atom to which they are attached, may be a substituted or unsubstituted saturated carbocyclic group, or hydroxy-substituted, unsaturated carbocyclic And R ¹⁸ is a hydrogen atom; a lower alkoxy group; or a lower alkyl group which may be substituted with hydroxy or lower alkoxy). The force that is represented, or the following definition 2: R ¹ is a hydrogen atom, R ² is a halogen atom; a cyano group; a nitro group; a carpamoyl group; a lower alkyl group optionally substituted with a heterocyclic group; a carbamoyl group; a carboxy group; An alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group; R ³ and R ⁴ together form the formula:

 [here,  Y is an oxygen atom or a sulfur atom, R ^{2 3} is a lower alkyl group, a cycloalkyl group or heterocyclic瓌式groups, among these lower alkyl groups are hydroxy, protected hydroxy, • Ashiru, lower alkoxy-substituted Ararukiruokishi, Amino, lower alkyl Noleamino, asinoleamino, lower anorecoxy canoleponinoleamino, lower alkanesulfonylamino, peridode, lower alkylurede, sulfamoylamino, protected phoroxy, carboxy, lower alkane sulfonyl, lower alkylenedioxy, lower valvamoyl A lower alkyl group selected from the group consisting of rubamoyl and sulfamoyl. Cycloalkyl group and heterocyclic group may be hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkane Sulfonylamino, peridode, lower quinolelide, su / refamoylamino, protected carboxy, lower alkane sulfonyl, lower alkyl, hydroxy (lower) alkyl, protected hydroxy '(lower) alkyl May have 1 to 3 substituents selected from the group consisting of lower alkylenedioxy, rubamoyl and sulfamoyl, R ^{2 4,} R ^{2 5} and R ^{2 6} are the same or different, a hydrogen atom, a halogen atom, a lower Arukanoiru group, Kanorepokishi group, protected carboxy groups, Karupamoiru group, a nitro group, Shiano group, a lower alkyl group, A hydroxy-substituted lower alkyl group, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or any ^{two of} R 24, R ²⁵ and R ²⁶ together form a lower alkylenedioxy group. M may be an integer of 1 or 2]. When X is a nitrogen atom, R ¹ R ² , R ³ and R ⁴ all have the same meaning as in definition 2 above] Or a salt thereof, a non-toxic solvent capable of dissolving the compound or salt thereof, and a τΚ-soluble polymer. 2. The compound represented by the formula (I) is a compound represented by the formula (Ia):

[Where, R ¹¹ is a hydrogen atom or a Hagen atom, R ¹² is an electron withdrawing group, R ¹³ is a hydrogen atom; a hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;  A is a lower alkylene group, R ¹⁴ is a lower alkoxy group; a substituted or unsubstituted heterocyclic group, saturated or unsaturated, lower alkyl or halo (lower) amino group which may be substituted by alkyl; wherein: A CH ₂ - R ¹⁵ Wherein R ¹⁵ is a cycloalkynole group or an unsaturated heterocyclic group; or a group represented by the formula: _R 16 _R 17 _R 18 (where R ¹⁶ and R 17 are each independently a carboxyl group, a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a halogen, hydroxy, cyano , Azide, lower alkoxy, lower alkylthio, protected carboxy, lower alkane snorephonyl, acinoleoxy, lower anorecanth norephonyloxy, aryl, aryloxy (optionally substituted by cyano), unsaturated heterocyclic group (Optionally substituted with lower alkyl), guanidino (optionally substituted with lower alkyl, cyano and / or halogen), isothiopureido (optionally substituted with lower alkyl and / or cyano) and amino (Optionally selected from the group consisting of: acyl, protected alkoxy, lower alkanesulfonyl, optionally substituted by lower alkanesulfonyloxy or aryloxycarbonyl) May be substituted with the above substituent ヽ a lower alkyl group, or R ¹⁶ and R ¹⁷ are taken together with the carbon atom to which they are attached, to a substituted or unsubstituted saturated carbocyclic group or an unsaturated carbocyclic group which may be substituted by hydroxy. May be formed, and R ¹⁸ is a hydrogen atom; a lower alkoxy group; or a lower alkyl group which may be substituted with hydroxy or lower alkoxy). 2. The liquid preparation according to claim 1, which is an anthranilic acid derivative (la) represented by the following formula: 3. The compound represented by the formula (I) is Formula (I b):

[Where,  X is CH or a nitrogen atom, R ²¹ is a hydrogen atom,  R 22 is a halogen atom; a cyano group; a nitro group; a carbamoyl group; a lower alkyl carbamoyl group optionally substituted with a heterocyclic group; a carboxy group; a protected carboxy group; a lower alkyl group; A lower) alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group;  Y is an oxygen atom or a sulfur atom, R ^{2 3} is a lower alkyl group, a consequent opening alkyl or heterocyclic group, these of the lower alkyl group is hydroxy, protected hydroxy, § shea Le, lower alkoxy-substituted Ararukiruokishi, Amino, lower alkylamino , Asilamino, lower alkoxycarbonylamino, lower alkane sulfonylamino, ureido, lower alkyl ureide, sulfamoyl amino, protected carboxy, carbonyl, lower alkane sulfonyl, lower alkylenedioxy, lower rubamoyl, lower alkyl rubamoyl Cycloalkyl and heterocyclic groups may have from 1 to 3 substituents selected from the group consisting of sulfosmoyl; hydroxy, protected hydroxy, acyl, lower alkoxy substituted aralkyloxy, Amino, acylamino, lower alkoxycarbonylamino, lower alkane sulfonylamino, ureido, lower alkyl ureide, sulfamoylamino, protected carboxy, lower alkane sulfonyl, lower alkino And has 1 to 3 substituents selected from the group consisting of hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, lower alkylenedioxy, carpamoyl and sulfamoyl. Well, R ^{2 4,} R ^{2 5} and R ^{2 6} are the same or different, a hydrogen atom, a halogen atom, a lower Arukanoiru group, a carboxy group, a protected Karupokishi group, Karupamo I group, a nitro group, Shiano group, a lower alkyl A hydroxy-substituted lower alkyl group, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or any ^{two of} R 24, R ²⁵ and R ²⁶ together form a lower alkylenedioxy group May be  m is an integer of 1 or 2] The liquid preparation according to claim 1, which is a condensed imidazole derivative (lb) represented by the following formula: 4. The solution according to any one of claims 1 to 3, wherein the solvent is a polyhydric alcohol. 5. The liquid preparation according to claim 4, wherein the polyhydric alcohol is polyethylene glycol having an average molecular weight of less than 4,000 or propylene dalicol. 6. The method according to claim 4, wherein the polyhydric alcohol is polyethylene glycol 400. 液 solution. 7. The liquid preparation according to any one of claims 1 to 6, wherein the water-soluble polymer is a cellulose derivative. 8. The liquid preparation according to claim 7, wherein the cellulose derivative is hydroxypropyl cellulose. 9. The liquid preparation according to claim 8, which is a hydroxypropynolecellulose having a low polymerization degree. 10. In equation (Ia), R ¹¹ is a hydrogen atom,  R 12 is a nitro group, a cyano group or a halo (lower) alkyl group; R ¹³ is a phenyl group substituted by lower alkoxy and phenyl or halogen; R ¹⁴ has the formula: —CR ¹⁶ R ¹⁷ R ¹⁸ wherein R ¹⁶ and R ¹⁷ are each independently hydroxy-substituted, lower alkyl, or R ¹⁶ and R ^{17 17} is a saturated carbocyclic group substituted with an acyl-substituted amino group, together with the carbon atom to which they are attached, and R ¹⁸ is a hydrogen atom. Represented group,  10. The liquid preparation according to claim 2 or A, wherein A is a lower alkylene group. 11. The anthranilic acid derivative (la) is  (R) -N- (3,4-dimethoxybenzyl) 1-2- (2-hydroxy-1-methylethylamino) 1-5-nitrobenzamide, N— (4-chloro-3-methoxybenzyl) 1-2— [2-hydroxy-1- (hydroxymethyl) ethylamino] —5-nitrobenzamide, N- (3,4-Dimethoxybenzyl) -2-[(trans-4-honolemamide cyclohexyl) amino] -5-nitrobenzamide 'dihydrate,  (S) 15-cyano-N- (3,4-dimethoxybenzyl) 1-2- (2-hydroxy-1-methylethylamino) benzamide or  11. The compound according to claim 10, which is N— (3-chloro-1-4-methoxybenzylinole) -1-2- [2-hydroxy-11- (hydroxymethyl) ethylamino] -15- (trifluoromethyl) benzamide. Liquid. 2. In equation (I b),  X is a nitrogen atom, R ²¹ is a hydrogen atom, R ²² is a cyano group,  Y is an oxygen atom, R ^{23 is a} cyclohexyl group substituted with hydroxy or lower alkanoyloxy, R ²⁴ is a hydrogen atom,  R 25 is a halogen atom, Liquid according to any one of claims. 3 to 9 R ²⁶ is a lower alkoxy group. 3. Condensed imidazole derivative (Ib) force  1-(3-chloro-4-methoxybenzinole) 1 6-cyano 1-3-(trans 1 4-Hydroxycyclohexyl) -2,3-dihydro-1H-imidazo [4, 5-b] pyridine-1-2-,  1- (3-Promo 4-Methoxybenzyl) _ 6-Cyanol 3- (Trans-1-Hydroxycyclohexyl) 1,2,3-Dihydro-1H-Imidazo [4,5-b] pyridine-1 2— On or 1- (3-Chloro-4-methoxypentinole) 16-cyano-13- (cis-1-hydroxycyclohexyl) -1,2,3-dihydro_1H-imidazo [4,5-b] pyridine-1 2- on The liquid preparation according to claim 12, which is: 14. A capsule prepared by filling the liquid preparation according to any one of claims 1 to 13 into a capsule. 15. The capsule according to claim 14, wherein the capsule is a soft capsule or a sealed hard capsule.