JPH1081621A - Medicinal composition for oral administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a stable medicinal composition resistant to gastric acid by preparing a fumagilol derivative, a neovascular inhibitor, as a composition for oral administration stable to the acid in stomach. SOLUTION: This composition contains a fumagilol derivative, particularly a compound of the formula (R<1> is H; R<2> is a halogen and the like; R<1> and R<2> are combined; R<3> is 2-methyl-1-propenyl and the like; A is O and the like; R<4> is H and a hydrocarbon), or its salt as an active ingredient and is prepared to make possible to orally administrate stably for an acid in stomach. The method is to contain an oily base (particularly an active ingredient may be dissolved or dispersed into the oily base). As the oily base, fatty acid esters of glycerol and a polyglycerol, especially fatty acid triglycerides, are suitable. Further, fine grains with a diameter of 0.1μm-10mm may be formed by coating the active ingredient with an enteric coating agent. This medicinal composition is useful as a preventive and treating agent for tumor.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a stable pharmaceutical composition which is not decomposed by gastric acid when a fumagillol derivative which is an angiogenesis inhibitor useful as a pharmaceutical is administered orally.

[0002]

BACKGROUND OF THE INVENTION Angiogenesis is the development or growth of blood vessels and has been shown to be deeply involved in diseases such as cancer, diabetic retinopathy and rheumatoid arthritis. Angiogenesis inhibitors do not directly affect disease but inhibit blood supply to diseased sites by the development or growth of blood vessels, and are involved in the development or growth of these blood vessels based on a new mechanism of action that is different from conventional drugs It becomes a therapeutic agent for the disease. In particular, since angiogenesis for nutritional supplementation is indispensable for the growth of solid tumors, angiogenesis inhibitors are expected to have great potential as cancer therapeutics. Further, as a result of searching for an angiogenesis inhibitor, a fumagillol derivative was found. For example, EP-A-359,036 (JP-A-3-7270),
EP-A-357,061 (JP-A-3-7222), EP
-A-354,787, EP-A-386,667 (JP-A-3-14571), EP-A-387,650 (JP-A-3-7271) and EP-A-415,294 (JP-A-3-41571)
279376). EP-A-4614
No. 27 describes a complex comprising a fumagillol derivative or a salt thereof and a cyclodextrin which may be esterified, and a diuretic containing the complex. EP
-A-470,569 (JP-A-5-969) discloses a vaso-embolic agent containing both a fumagillol derivative and a vaso-embolic material such as a wax such as a glycerol ester of a fatty acid. Also, EP-A-602586
(JP-A-6-246331) discloses a stable pharmaceutical composition comprising a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin. Inhibition of angiogenesis is a cell growth inhibitory action rather than cytotoxicity, and continuous administration is required for suppressing tumor growth and treating diseases involving angiogenesis. Therefore, development of an orally-administered drug is desired from the viewpoint of easy administration.

[0003]

The fumagillol derivative having an angiogenesis inhibitory activity is mainly developed as a parenteral drug such as an injection because it is unstable. Also, the reported oral preparations were not sufficient for clinical application, and therefore there is a need for the development of clinically useful orally administrable drugs.

[0004]

In view of this fact, the present inventors have conducted intensive studies and, surprisingly, have surprisingly produced a composition for oral administration which is stable against this angiogenesis inhibitor and gastric acid. As a result, they succeeded in finding for the first time what can be used clinically, and have completed the present invention.

That is, the present invention provides (1) a pharmaceutical composition for oral administration which is stable against stomach acid, containing a fumagillol derivative, (2) a composition according to the above (1), which contains an oily base, 3) The composition according to the above (1) coated with an enteric coating agent, (4) the composition according to the above (2), wherein the fumagillol derivative is dissolved or dispersed in an oily base, (5) an oily base. The agent is liquid at room temperature and the ratio of fumagillol derivative to oily base is from about 0.001 to about 50;
% (W / v), (6) the oily base is solid at room temperature, and the ratio of the fumagillol derivative to the oily base is about 0.01 to about 100% (w / w). The composition according to the above (2), wherein the oily base is an ester of a fatty acid and an alcohol,
(8) The composition according to (7), wherein the ester of fatty acid and alcohol is a fatty acid ester of glycerin or polyglycerin, (9) the composition according to (8), wherein the fatty acid ester of glycerin is fatty acid triglyceride, 1
0) The composition according to the above (9), wherein the fatty acid triglyceride is a triglyceride of a saturated fatty acid having 6 to 22 carbon atoms, and (11) the composition according to the above (2), which is fine particles having a particle size of about 0.1 μm to 10 mm. (12) a pharmaceutical composition for oral administration obtained by drying a suspension containing a fumagillol derivative, an oily base and an emulsifier, (13) a gastric acid secretion inhibitor or / and / or an antacid. 1) described composition,

(14) The fumagillol derivative has the general formula (I)

Embedded image Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
^{5 R 6, N + R 5} R 6 R 7 · X -, S (O) nR 5 or S ⁺ R ⁵ R ⁶
· X ^- a (R ^5, R ⁶ and R ⁷ each may have a substituent hydrocarbon group or heterocyclic group, X ^- is a counter anion, m a is 0 or 1, n is 0 to And represents an integer of 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or sulfur atom. The nitrogen-containing or sulfur-containing heterocyclic group which may be substituted may have a substituent.) Or R ¹ and R ² represent a bond, and R ³ has a substituent. A represents O or NR ⁸ (R ⁸ represents hydrogen or a lower alkyl group or an aryl group which may have a substituent, respectively). ) indicates, R ⁴ is hydrogen, also may hydrocarbon group optionally having a substituent An acyl group. And (15) R ¹ and R ^{2 each} represent a bond or R ¹ is hydrogen and R ² is N (O) mR. ^{5 R 6, N + R 5} R 6 R 7 · X -, S
(O) nR ⁵ or ^{S + R 5 R 6 · X} - ( each symbol is as defined above (14) wherein); A is O or NH; may have R ³ are each a substituent 2 (14) The composition according to the above (14), wherein R ⁴ is hydrogen or a carbamoyl group which may have a substituent, (16) a bond between R ¹ and R ^2. (17) The composition according to the above (15), wherein A is O; R ³ may be substituted with a hydroxyl group or a dialkylamino group, respectively.
The composition according to the above (14), wherein -methyl-1-propenyl or isobutyl group, wherein R ⁴ is a carbamoyl group substituted with C _1-6 alkyl or halogeno C _1-6 alkanoyl group,

(18) The fumagillol derivative is 6-O-
(19) The composition according to the above (1), which is (N-chloroacetylcarbamoyl) fumagillol, (19) the fumagillol derivative is 4- (N′-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl) -4-hexenyl) -1- (1,
The composition according to the above (1), which is 3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride; (20) 6-O- (N-chloroacetylcarbamoyl) fumagillol or a salt thereof And a triglyceride of a saturated fatty acid having 6 to 22 carbon atoms, and the composition according to the above (1), wherein (21) 6-O-
The composition according to the above (1), wherein (N-chloroacetylcarbamoyl) fumagillol or a salt thereof is blended at a ratio of about 5 to about 30% (w / v) with respect to a triglyceride of a saturated fatty acid having 6 to 22 carbon atoms. , (22) 6-O- (N-
The above-mentioned (1) obtained by drying a suspension containing chloroacetylcarbamoyl) fumagillol or a salt thereof, a triglyceride of a saturated fatty acid having 6 to 22 carbon atoms and an emulsifier.
2) The composition according to the above, which is (23) an angiogenesis inhibitor.
The composition according to (1) or (12), (24) the composition according to (1) or (12), which is a prophylactic / therapeutic agent for a tumor, (25)
Enteric-coated preparation for oral administration containing a fumagillol derivative,
(26) the preparation according to (25), further comprising an oily base, (27) the preparation according to (25), which is a capsule, (2)
8) a drug for oral administration comprising a combination of a fumagillol derivative and a gastric acid secretion inhibitor or / and an antacid;
9) administering a fumagillol derivative after administering a gastric acid secretion inhibitor or / and an antacid;
The present invention relates to the drug described in (28).

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The fumagillol derivative used in the present invention has a general formula

Embedded image

Wherein R ¹ is hydrogen, R ² is halogen, N
(O) mR ⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ .X ⁻ , S (O) nR ⁵ or S
^{+ R 5 R 6 · X -} ( wherein, the R ^5, R ⁶ and R ⁷ hydrocarbon may have a substituent hydrogen group or a heterocyclic group, X
^- is a counter anion, m is an integer of 0 or 1, n
Represents an integer of 0 to 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or sulfur atom. The nitrogen or sulfur-containing heterocyclic group may have a substituent. ) Or R ¹ and R
^{And 2} represent a bond, R ³ represents an optionally substituted 2-methyl-1-propenyl group or an isobutyl group, and A represents O or NR ⁸ (wherein, R ⁸ represents hydrogen or R ⁴ represents hydrogen, a hydrocarbon group optionally having a substituent, or an acyl group, each of which represents a lower alkyl group or an aryl group which may have a substituent. And fumagillol derivatives or salts thereof. In the general formula (I), examples of the halogen represented by R ² include fluorine, chlorine, bromine, and iodine. When R ¹ and R ² represent a bond, they form an epoxy ring.

As the hydrocarbon group of the optionally substituted hydrocarbon group represented by R ⁵ , R ⁶ or R ⁷ , a linear or branched alkyl group having 1 to 6 carbon atoms ( For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl and the like, an alkenyl group having 2 to 6 carbon atoms (for example, vinyl, allyl, 2-butenyl, methylallyl, 3
-Butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like), an alkynyl group having 2 to 6 carbon atoms (for example,
Ethynyl, propargyl, 2-butyn-1-yl, 3-
Butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), a cycloalkyl group having 3 to 6 carbon atoms.
(E.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), a cycloalkenyl group having 3 to 6 carbon atoms (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.),
An aralkyl group having 7 to 13 carbon atoms (for example, benzyl, 1
-Phenethyl, 2-phenethyl, etc.), having 6 to 10 carbon atoms
(For example, phenyl, naphthyl, etc.).

The heterocyclic group of the optionally substituted heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ includes 1 to 4 hetero atoms (for example, nitrogen, oxygen, sulfur, etc.). 5- or 6-membered heterocyclic group (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, tetrazolyl, etc.) and the like. . The heterocyclic group has a 5- or 6-membered ring (eg, benzene, pyridine, cyclohexane, etc.) which may contain 1 to 3 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to carbon atoms. Condensing 2
A cyclic fused ring group (for example, 8-quinolyl, 8-purinyl, etc.) may be formed.

The nitrogen-containing heterocyclic ring which may be formed by R ⁵ and R ⁶ together with an adjacent nitrogen atom includes 1 to 3 hetero atoms (for example, nitrogen, oxygen, sulfur, etc.) in addition to the nitrogen atom. And a 4- to 7-membered nitrogen-containing heterocyclic ring (e.g., pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, etc.) which may be included. R ⁵
And R ⁶ may form a sulfur-containing heterocyclic ring which may be formed together with an adjacent sulfur atom, even if it contains 1 to 3 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to the sulfur atom. A good 4- to 7-membered sulfur-containing heterocycle (for example, tetrahydrothiophen-1-yl, 1,4-thioxan-1-yl and the like) and the like can be mentioned.

The nitrogen-containing or sulfur-containing heterocyclic ring which R ⁵ and R ⁶ may form together with an adjacent nitrogen atom or sulfur atom is a 5- or 6-membered ring (for example, benzene, pyridine, pyrazine, pyrimidine, pyridazine, Condensed (condensed) with cyclohexane and the like to form a bicyclic fused ring group (eg, isoindoline-2-yl, 2-isoquinolyl, 1,3-dihydrobenzo [c] thiophen-2-yl, 2,3- Dihydrobenzo [b] thiophen-1-yl, 3,4-dihydro-1H
-2-benzopyran-2-yl, 3,4-dihydro-2
H-1-benzopyran-1-yl, 1,2,4,5-tetrahydro-3-benzothiepin-3-yl, 1,3-dihydrothieno [3,4-c] pyridin-2-yl, 5,7-
Dihydrothieno [3,4-b] pyrazin-6-yl, 5,7
-Dihydrothieno [3,4-d] pyridazin-6-yl) and the like.

The lower alkyl group of the lower alkyl group which may have a substituent represented by R ⁸ has 1 to 1 carbon atoms.
And 6 linear or branched alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.). Examples of the aryl group of the aryl group which may have a substituent represented by R ⁸ include an aryl group having 6 to 10 carbon atoms (for example, phenyl, naphthyl and the like).

The optionally substituted hydrocarbon group represented by R ⁴ is the above-mentioned optionally substituted hydrocarbon group represented by R ⁵ , R ⁶ or R ^7. And the like described above. When the hydrocarbon group represented by R ⁴ is an alkenyl group, an unsubstituted one is preferred. R ⁴
Examples of the acyl group optionally having a substituent represented by an acid residue such as acyl carboxylate, acyl sulfonate, carbamoyl, thiocarbamoyl, sulfamoyl, etc. Acyl group derived from an acid) and the like, for example, alkanoyl, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl, aryloxy which may each have a substituent Carbonyl and the like. Preferable is carbamoyl which may have a substituent.

The alkanoyl group of the alkanoyl group which may have a substituent described above includes an alkanoyl group having 1 to 6 carbon atoms (for example, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl and the like). Is mentioned. The aroyl group of the aroyl group which may have a substituent has 7 to 7 carbon atoms.
11 aroyl groups (for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like) and the like. As the heterocyclic carbonyl group in the heterocyclic carbonyl group which may have a substituent, a 5- or 6-membered heterocyclic carbonyl group containing 1 to 4 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl and the like). Examples of the arylsulfonyl group of the arylsulfonyl group which may have a substituent include an arylsulfonyl group having 6 to 10 carbon atoms (for example, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like).

The alkylsulfonyl group of the alkylsulfonyl group which may have a substituent has 1 to 6 carbon atoms.
Alkylsulfonyl group (e.g., methylsulfonyl,
Ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like). Examples of the alkoxycarbonyl group of the alkoxycarbonyl group which may have a substituent include an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl and the like). As the aryloxycarbonyl group of the aryloxycarbonyl group which may have a substituent, an aryloxycarbonyl group having 7 to 11 carbon atoms (for example,
Phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.). Examples of the substituent of 2-methyl-1-propenyl or isobutyl group which may have a substituent represented by R ³ include, for example, a hydroxyl group, an amino group and a lower (C _1-3 ) alkylamino group ( Examples thereof include methylamino, ethylamino, isopropylamino, and the like, and di-lower (C _1-3 ) alkylamino groups (eg, dimethylamino, diethylamino, and the like). Of these, a hydroxyl group and a di-lower (C _1-3 ) alkylamino group, particularly a dimethylamino group, are preferred.

A hydrocarbon group or a heterocyclic group which may have a substituent represented by R ⁵ , R ⁶ or R ⁷ ;
A nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with ⁵ or R ⁶ together with an adjacent nitrogen atom or sulfur atom, a lower alkyl group or aryl which may have a substituent represented by R ^8; And a hydrocarbon group or an acyl group each of which may have a substituent represented by R ⁴ (for example, an alkanoyl group, an aroyl group, a heterocyclic carbonyl group, a carbamoyl group, a thiocarbamoyl group, an arylsulfonyl group, an alkyl group) A sulfonyl group, a sulfamoyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group) may have 1 to 3 substituents at these possible positions.

Examples of the substituent include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.) and a C _2-6 alkenyl group ( For example, vinyl, allyl, 2-butenyl, methylallyl, 3
-Butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like, a _C2-6 alkynyl group (for example, ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyn- 3-yl, 3-pentyne-
1-yl, 4-pentyn-2-yl, 3-hexyne-1
-Yl), a _C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), a _C3-6 cycloalkenyl group (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C _6-10 aryl group (for example, phenyl, naphthyl and the like), amino group, mono C _1-6 alkylamino group (for example, methylamino, ethylamino, isopropylamino and the like), diC _1-6 alkylamino group (for example, , Dimethylamino, diethylamino, etc.), azide group, nitro group, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, C _1-4 alkoxy group
(E.g., methoxy, ethoxy, etc.), _C6-10 aryloxy group (e.g., phenoxy, naphthyloxy, etc.), C6-10
_1-6 alkylthio group (e.g., methylthio, ethylthio,
Propylthio, etc.), C _6-10 arylthio group (eg, phenylthio, naphthylthio, etc.), cyano group, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11 Aryloxycarbonyl group (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl,
2-naphthyloxycarbonyl, etc.), carboxy-C
_1-4 alkoxy group (e.g., carboxymethoxy, 2-carboxyethoxy and the like), _C1-6 alkanoyl group (e.g., formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl and the like),
C _7-11 aroyl group (for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C _1-6 alkylsulfonyl group
(E.g., methylsulfonyl, ethylsulfonyl, etc.),
C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (E.g., benzenesulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., 2-
Furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazole-2-
Yl, 1-methyl-5-tetrazolyl, etc.), a 5- or 6-membered heterocyclic carbonyl group containing 1-4 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., 2-furoyl,
2-thenoyl, nicotinoyl, isonicotinoyl, etc.) and 1 heteroatom (eg, nitrogen, oxygen, sulfur, etc.)
And a 5- or 6-membered heterocyclic thio group containing up to 4 (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, etc.), and the like. The heterocyclic thio group may form a bicyclic fused ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio, etc.) by condensing a benzene ring. Among these substituents, a C _1-6 alkyl group and a C _1-6 alkanoyl group are preferred. When R ⁴ represents a disubstituted carbamoyl group, a thiocarbamoyl group, or a sulfamoyl group, a carbamoyl group;
A thiocarbamoyl group or a sulfamoyl group is a nitrogen-containing heterocyclic ring together with its nitrogen atom [eg, pyrrolidine-
1-yl, piperidino, morpholino, piperazine-1
Containing 1 to 3 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) in addition to the nitrogen atom, such as -yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl and the like. 4- to 7-membered nitrogen-containing heterocycle, etc.
May be formed.

R ⁵ , R ⁶ or R ⁷ may have a substituent in a hydrocarbon group or a heterocyclic group which may have a substituent, and R ⁵ and R ⁶ may be adjacent to each other by a nitrogen atom or sulfur. A substituent in a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an atom, a substituent in a lower alkyl group or an aryl group which may have a substituent represented by R ⁸ , and R ⁴ A hydrocarbon group or an acyl group each of which may have a substituent (e.g., an alkanoyl group, an aroyl group, a heterocyclic carbonyl group, a carbamoyl group, a thiocarbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, a sulfamoyl group, Substituents in an alkoxycarbonyl group or an aryloxycarbonyl group) may have 1 to 3 substituents at further substitutable positions. It may be in.

Examples of the substituent include the above-mentioned C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _2-6 alkynyl group.
_3-6 cycloalkyl group, C _3-6 cycloalkenyl group, C
_6-10 aryl group, amino group, mono C _1-6 alkylamino group, di C _1-6 alkylamino group, azide group, nitro group,
Halogen, hydroxyl group, C _1-4 alkoxy group, C
_6-10 aryloxy group, C _1-6 alkylthio group,
C _6-10 arylthio group, cyano group, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group, C _7-11
Aryloxycarbonyl group, carboxy C _1-4 alkoxy group, C _1-6 alkanoyl group, halogeno C _1-6 alkanoyl group, C _7-11 aroyl group, C _1-6 alkylsulfonyl group, C _6-10 arylsulfonyl group , A C _1-6 alkylsulfinyl group, a C _6-10 arylsulfinyl group, a 5- or 6-membered heterocyclic group, a 5- or 6-membered heterocyclic carbonyl group, a 5- or 6-membered heterocyclic thio group, and the like.

[0022] X ^- include counter anion represented by, for example halogen ions (e.g., iodide ion, bromine ion, chloride ion), sulfur ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, Methane sulfate ion, p-tolyl sulfate ion, benzene sulfate ion,
Hydroxyl ions, carboxylate ions of organic acids (e.g., oxalate ions, maleate ions, fumarate ions, succinate ions, citrate ions, lactate ions, trifluoroacetate ions, lactobionate ions, acetate ions, Propionate ion, tartrate ion, ethyl succinate ion, etc.). Of these, halogen ions are preferred.

The compound represented by the above general formula (I) (hereinafter sometimes referred to as compound (I)) has an asymmetric center in the molecule and has optical activity, but its absolute structure is based on the raw material fumagillol Unless otherwise specified, it means the one that matches the absolute structure of fumagillol. The bonding mode of the substituent on the cyclohexane ring is

[0024]

Embedded image

A case is shown. In the compound (I), R ¹
And R ² represent a bond, or R ¹ is hydrogen and R ² is N (O) mR
^{5 R 6, N + R 5} R 6 R 7 · X -, S (O) nR 5 or S ⁺ R ⁵ R ⁶
· X ^-, more preferably ^{S + R 5 R 6 · X} - in which compounds are preferred. Further, it is preferable that R ⁵ and R ⁶ form a sulfur-containing heterocyclic ring together with an adjacent sulfur atom, and such a sulfur-containing heterocyclic ring is condensed with a 5- or 6-membered ring to form a bicyclic fused ring. May be. As the compound (I), a compound showing a bond between R ¹ and R ² is more preferable. A is preferably O or NH. Particularly, O is preferable. R ³ is preferably a 2-methyl-1-propenyl group or an isobutyl group which may be substituted with a hydroxyl group or a dialkylamino group, respectively. Particularly, a 2-methyl-1-propenyl group is more preferred. R ⁴ is preferably hydrogen or carbamoyl which may have a substituent. In particular, a C _1-6 alkanoyl group in which the substituent may be substituted with a C _1-6 alkyl group or halogen is preferable. Compound
Preferred specific examples of (I) include 6-O- (N-chloroacetylcarbamoyl) fumagillol, 6α- (N′-chloroacetylureido) -6-desoxyfumagillol,
4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,
3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride, 6
—O- (N-methylcarbamoyl) fumagillol and the like.

Compound (I) has an acidic substituent (for example, carboxyl) or a basic substituent (for example, carboxyl) in the molecule.
When it has amino, mono-lower alkylamino, di-lower alkylamino, nitrogen-containing heterocyclic group, etc., it may form a physiologically acceptable salt. Examples of the salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. Inorganic bases capable of forming these salts include alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline,
N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids as Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like, and as a basic or acidic amino acid, for example, arginine, lysine, ornithine, asparagine acid,
Glutamic acid is used. Among these salts, salts with bases (i.e., salts with inorganic bases, salts with organic bases, salts with basic amino acids) include carboxyl groups in the substituents of compound (I) and salts with acids ( That is, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid) is an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a nitrogen-containing heterocyclic group, or the like in the substituents of compound (I). And a salt that can be formed.

When the compound (I) has a di-lower alkylamino group, a nitrogen-containing heterocyclic group or a nitrogen-containing aromatic heterocyclic group in the molecule, the nitrogen atom in these groups is further alkylated. To form a quaternary ammonium group (e.g., trimethylammonio, N-methylpyridinyl, N-methylpyrrolidine-1-ylium, etc.),
Examples of the counter anion include the same counter anions as those described above for X ⁻ . The compound represented by the general formula (I) or a salt thereof can be obtained by hydrolysis of fumagillin produced by a microorganism, fumagillol [Fumagillol] [Tabel, D.S.
bell. D. S. ), Journal of American
Chemical Society (J. Am. Chem. Soc.) 8
3 , 3096 (1961)] as a starting material, and can be produced by the method described in the aforementioned EP publication or a method analogous thereto. The physicochemical and biological properties of the compounds are described in detail in the previously mentioned EP publications.

In the "pharmaceutical composition or preparation thereof containing a fumagillol derivative which is stable against gastric acid" according to the present invention, at least one of the following means is required for stabilizing the fumagillol derivative against gastric acid. One is used. (1) An oily base is blended, (2) an enteric pharmaceutical preparation, and (3) a gastric acid secretion inhibitor or / and an antacid are blended. The oily base used in the present invention includes, for example, esters of fatty acids and alcohols, oils and fats or their hardened oils, waxes, saturated fatty acids, and higher alcohols from the viewpoints of stabilization and oral absorption of fumagillol derivatives. Kind,
Phospholipids or hydrocarbons are preferred. Particularly, esters of fatty acids and alcohols are widely used. The "fatty acids" in the "esters of fatty acids and alcohols" may be, for example, monocarboxylic acids or dicarboxylic acids. Specifically, examples of the dicarboxylic acids include oxalic acid, malonic acid, succinic acid, and glutaric acid. Acid, adipic acid, maleic acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, sebacic acid and the like. Also,
Monocarboxylic acids include C ₆ -C ₂₂ aliphatic carboxylic acids such as caproic acid (C ₆ ), caprylic acid (C ₈ ), capric acid (C ₁₀ ), lauric acid (C ₁₂ ), myristic acid (C ₁₄ ), palmitic acid (C ₁₆ ), stearic acid (C ₁₈ ), arachiic acid (C ₂₀ ), behenic acid (C ₂₂ ), and the like, and particularly preferred are medium-chain (C ₆ -C ₁₄ ) fatty acids. Examples of "alcohols" in "esters of fatty acids and alcohols" include, for example, methyl alcohol,
Ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-pentyl alcohol, n-hexyl alcohol, n-heptyl alcohol, n-octyl alcohol, n-decyl alcohol, n-lauryl alcohol, n-myristyl alcohol, n- Monoalcohols such as cetyl alcohol, n-octadecyl alcohol, isopropyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isopentyl alcohol, tert-pentyl alcohol; ethylene glycol, propylene glycol, 1,3-propanediol, etc. glycols; alcohols C ₁ -C ₂₀ triols such as glycerin and the like. The ester of the fatty acid and the alcohol may be any ester of the above-mentioned fatty acid and the alcohol as long as it can be used in pharmacology. Further, the ester with the same or different fatty acid may be used as the ester with the polyalcohol. Of these, fatty acid esters of glycerin or polyglycerin are preferred. In the “fatty acid ester of glycerin or polyglycerin”, the proportion of esterified hydroxyl groups to all hydroxyl groups (degree of esterification) is preferably about 60% or more, more preferably about 80% or more. Further, the degree of polymerization of polyglycerin is preferably from 2 to 16. The fatty acid esters of glycerin or polyglycerin are used alone or in combination of two or more. Preferably, it is appropriately selected and used so that the degree of esterification is about 60% or more, more preferably about 80% or more.

The fatty acid ester of glycerin is preferably a fatty acid triglyceride (triacylglycerol) in which three molecules of fatty acid are ester-bonded to one molecule of glycerol. Even if these fatty acids that form ester bonds are of the same type,
It may be a different type, preferably having 6 to 22 carbon atoms.
Saturated fatty acids. More preferably, the carbon number is 8 to
There are 18 saturated fatty acids. In particular, C 8 -C 12
Saturated fatty acids are commonly used.

Examples of the “glycerol fatty acid ester” include Miglyol 810 (MIGLYOL81).
0, caprylic / capric triglyceride, fatty acid composition 65-75% of caprylic acid, 25-3 of capric acid
5%), Miglyol 812 (MIGLYOL 812, caprylic / capric triglyceride, fatty acid composition: 50-65% of caprylic acid, 30-45 of capric acid)
%), Miglyol 829 (MIGLYOL829, glyceryl di (succinate / caprate) succinate), and the fatty acid composition was 35-45% for caprylic acid and 2% for capric acid.
0-30%, succinic acid 12-16%), Miglyol 840 (MIGLYOL 840, propylene glycol dicaprylate), fatty acid composition is 65-80 for caprylic acid
%, Capric acid 15-30%), Dynasan 110
(DYNASAN110, capric triglyceride),
Dynasan 112 (DYNASAN 112, lauric triglyceride), Dynasan 114 (DYNASAN 1
14, myristic triglyceride), dynasan 11
6 (DYNASAN116, palmitic acid triglyceride), Dynasan 118 (DYNASAN118, stearic acid triglyceride) and the like are available from Hils AKT (HULS AKT).
IENGESELLSCHAFT, Germany) and Triester F-810 (caprylic / capric triglyceride) are sold by Nikko Chemicals (Tokyo). These may be used as a mixture of two or more.

As described above, the fatty acid ester of polyglycerin is preferably one of various glycerin polymers having a degree of polymerization of glycerin of 2 to 16. Particularly, 2 to 10 are preferable. Also, at least one of the (degree of polymerization + 2) hydroxyl groups, preferably about 60% or more, preferably about 80% or more.
% Or more of the fatty acids are ester-bonded. The fatty acid is preferably a saturated type. It is a saturated fatty acid having 6 to 22 carbon atoms, more preferably 8 to 18 carbon atoms. The fatty acids to be esterified may be of the same type or of different types.

Many kinds of fatty acid esters of polyglycerin having different combinations of the degree of polymerization of glycerin, the kind of fatty acid and the degree of esterification thereof are sold as commercial products, and all of them can be used in the present invention. For example, PS-3
10 (tetraglycerin pentastearate), MS-3
10 (tetraglycerin monostearate), HB-3
10 (tetraglycerin hexabehenate), PO-3
10 (tetraglycerin pentaoleate), PO-5
00 (hexaglycerin monostearate), DAO-
750 (decaglycerin decaoleate), DAS-7
Tetrag 50 (decaglycerin decasterate) from Sakamoto Yakuhin (Osaka), Poem J46B (tetraglycerin hexabehenate) etc. from RIKEN Vitamin (Tokyo)
lyn5-S (tetraglycerin pentastearate), De
caglyn 10-S (decaglycerin decastearate) and the like are sold by Nikko Chemicals (Tokyo). These may be used alone or in combination of two or more. Also,
It can be used in combination with other oily bases such as fatty acid esters of glycerin.

As the "oils and fats", for example, soybean oil,
Olive oil, rapeseed oil, peppermint oil, sesame oil, castor oil,
Camellia oil, wheat germ oil, fennel oil, corn oil, sunflower oil, cottonseed oil, coconut oil, peanut oil, and the like, and hardened oils thereof. Examples of the "waxes" include carnauba wax and whale wax.
The “saturated fatty acids” include, for example, caprylic acid, capric acid, palmitic acid, stearic acid, behenic acid and other C
Etc. ₈ fatty acid or its salt -C ₂₂ thereof. As the "higher alcohols", for example, cetyl alcohol, alcohols C ₁₀ -C _20, such as stearyl alcohol. Examples of the “phospholipid” include hydrogenated lecithin. Examples of the "hydrocarbons" include paraffin, microcrystalline wax and the like. The above oil bases can be used alone or in combination of two or more. As the oily base used in the present invention, fatty acid esters of glycerin or polyglycerin are generally used from the viewpoints of fumagillol stability and oral absorption. The pharmaceutical composition of the present invention is an oral pharmaceutical composition obtained by stabilizing a fumagillol derivative against gastric acid. The "pharmaceutical composition" may be in liquid or solid form. The "pharmaceutical composition" can be produced by a method known per se.
For example, the following method can be mentioned.

When an oily base liquid at room temperature (5 to 30 ° C.) is used, a fumagillol derivative is added thereto and dissolved or dispersed by a method such as stirring to obtain a composition.
When an oily base that is solid at room temperature (5 to 30 ° C.) is used, the fumagillol derivative is dissolved or dispersed and solidified after making the base liquid. By a method known per se, for example,
The fumagillol derivative is dissolved or dispersed in a liquefied state by heating the oil base to a temperature equal to or higher than its melting point, and then cooled to solidify. When solidifying, it may be formed into particles or pellets as necessary. As a molding method, a method known per se is used. For example, when particles are used, preferably, they are spherical fine particles having a particle size of about 0.1 to about 1000 μm. As a molding method, a method known per se (for example,
No. 23533). For example, there are a method in which the fumagillol derivative is dissolved or dispersed in an aqueous phase, a spray drying method, and a spray chilling method in which fine oil droplets are formed and rapidly cooled and solidified. The “aqueous phase” may optionally contain a dispersing agent (eg, Tween 8) to avoid agglomeration of the particles.
0, carboxymethylcellulose, polyvinyl alcohol, etc.). The ratio of the fumagillol derivative to the oily base in the composition can be appropriately selected depending on the physicochemical properties of these components, for example, solubility, dispersibility and the effective dose of the fumagillol derivative. When the oily base is a liquid, it is preferably about 0.001 to about 50.
% (W / v). More preferably, about 5 to about 30
% (W / v). When the oleaginous base is a solid, it is preferably from about 0.01 to about 900% (w / w). More preferably, it is about 0.01 to about 100% (w / w). The concentration and content of the fumagillol derivative in the composition can be appropriately selected according to the physicochemical properties of the composition. When the composition is a liquid, its concentration is between about 0.0005-30.
% (W / v), preferably about 0.005 to 25% (w / v).
v). When the composition is a solid, its content is about 0.01% to 90% (w / w), preferably about 0.1% to 50% (w / w). In addition to this, if necessary, further preservatives (eg, benzyl alcohol, ethyl alcohol, benzalkonium chloride,
Phenol, chlorobutanol, etc.), antioxidants (eg, butylhydroxyanisole, propyl gallate,
Ascorbic acid palmitate, α-tocopherol, etc.), thickeners (eg, lecithin, hydroxypropylcellulose, aluminum stearate, etc.) may be used.

The suspension of the present invention (generally called lipid microspheres or lipid nanospheres) containing a fumagillol derivative, an oily base and an emulsifier, and a composition obtained by drying this suspension (generally, a dry emulsion and ) Can be produced in a manner known per se. That is, an oily base in which a fumagillol derivative is dissolved or dispersed (for example, a fatty acid ester of glycerin, a fatty acid ester of polyglycerin, a fatty acid ester of fatty alcohol or vegetable oil, or a mixture of two or more of these) is used with various emulsifiers. The emulsion is emulsified in an aqueous phase to obtain fine particles having an average particle diameter of about 10 to 500 nm. As the emulsifier used in the present invention, any pharmaceutically acceptable emulsifier can be used, and particularly, pharmaceutically acceptable phospholipids and nonionic surfactants are suitably used. The emulsifier may be used alone, or a mixture of two or more kinds may be used. Examples of the phospholipid include naturally obtained phospholipids such as egg yolk lecithin and soybean lecithin, hydrogenated products thereof, and synthetically obtained phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Can be Among these, egg yolk lecithin, soybean lecithin and phosphatidylcholine derived from egg yolk and soybean are preferably used. Examples of the nonionic surfactant include high molecular weight surfactants having a molecular weight of about 800 to 20,000, such as polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, and cured castor. Oil polyoxyethylene derivatives, polyoxyethylene sorbitan derivatives, polyoxyethylene sorbitol derivatives, polyoxyethylene alkyl ether sulfates and the like can be mentioned. The amount of the emulsifier used is about 0.1 to 10%, preferably about 0.1%, in the suspension.
It is selected from the range of 5 to 5%.

In addition to the above components, if necessary, a stabilizer such as an antioxidant or a chelating agent for further improving the stability of the active ingredient, or a tonicity agent for adjusting the osmotic pressure may be used. Further, an emulsifying aid may be added to improve the emulsifying power, and an emulsifying stabilizer may be added to further improve the stability of the emulsifying agent. Specific examples of such tonicity agents include glycerin, sugar alcohols, monosaccharides, disaccharides,
Amino acids, dextran, albumin and the like can be mentioned, and these can be used alone or in combination of two or more.

Examples of the stabilizer for the main drug include antioxidants such as ascorbic acid, tocopherol, sorbic acid, and retinol. Examples of the chelating agent include:
Citric acid, tartaric acid and the like. The amount of stabilizer used is between about 0.0001 to about 10 in the final dosage form.
%, More preferably from about 0.0001 to about 5%. In addition, specific examples of the emulsifying aid include C6 to C30.
Fatty acids, salts or monoglycerides of these fatty acids,
For example, caproic acid, capric acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitooleic acid, oleic acid, linoleic acid, arachidonic acid, eicosapentanoic acid, docosahexaenoic acid, and these And salts of these carboxylic acids, for example, sodium salts, potassium salts, calcium salts, and monoglycerides of these carboxylic acids.

As the emulsion stabilizer, cholesterol, cholesterol ester, tocopherol, albumin, fatty acid amide derivative, polysaccharide, fatty acid ester derivative of polysaccharide and the like are used. To the pharmaceutical composition of the present invention, a viscous substance which exhibits adhesiveness to the gastrointestinal mucosa by exhibiting viscosity by water may be added. The viscous substance is not particularly limited as long as it is a pharmaceutically acceptable substance. For example, a polymer (for example, an acrylic acid-based polymer or a copolymer and a salt thereof), a natural viscous substance (for example, mucin, Agar, gelatin, pectin, carrageenan, sodium alginate, locust bingham, xanthan gum, tragacanth gum, gum arabic,
Chitosan, pullulan, waxy starch, sucralfate, curdlan, cellulose and derivatives thereof, and the like. In addition, conventional additives used in the manufacture of pharmaceutical preparations for oral administration may be added for controlling the release of the main drug and for formulating the preparation. Examples of the additives include excipients (eg, lactose, corn starch, talc, crystalline cellulose, powdered sugar, magnesium stearate, mannitol,
Light silicic anhydride, magnesium carbonate, calcium carbonate,
L-cysteine, etc.), binders (eg, starch, sucrose,
Gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone,
Pullulan, dextrin, etc.), disintegrant (eg, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.), anionic surfactant (eg, sodium alkyl sulfate, etc.), nonionic surfactant ( For example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene castor oil derivatives, etc.), antacids and mucosal protective agents (for example, magnesium hydroxide, magnesium oxide, aluminum hydroxide,
Aluminum sulfate, magnesium metasilicate aluminate, magnesium aluminate silicate, sucralfate, etc.), cyclodextrin and its carboxylic acid (eg, maltosyl-β-cyclodextrin, maltosyl-β-cyclodextrin carboxylic acid, etc.), flavoring agent ( For example, fennel oil, lavender oil, lemon oil, orange essence, rose oil, matcha powder, bergamot oil,
(D, l) Borneol, sugar, bitter essence, pine flavor, natural pearl extract AH
-10), coloring agents, adsorbents, preservatives, wetting agents, antistatic agents, disintegration extenders, and the like. The amounts of these additives to be added are appropriately selected within a range that does not impair the stability and absorption of the main drug.

The pharmaceutical preparation for oral administration of the present invention can be produced basically according to a known method or a method analogous thereto. In particular, emulsification can be performed by a known emulsification technique, but it is preferable that the drug is dissolved or dispersed in oil in advance. For example, a more preferable method includes the following method. That is, a predetermined amount of a main ingredient, an oil component, an emulsifier, and if necessary, an isotonic agent, a stabilizer of the main ingredient, an emulsifying aid, and an emulsion stabilizer are mixed, and the mixture is mixed at about 30 to about 90 ° C., preferably about 40 to 90 ° C. The mixture was heated to a temperature of about 80 ° C., mixed with a predetermined amount of water, and mixed with a conventional homogenizer or homomixer (for example,
Homogenizer using a pressurized injection homogenizer, ultrasonic homogenizer, high-speed mixer, etc.) to obtain a coarse emulsion, add water if necessary, homogenize with the above homogenizer, and filter with a filter of 5 μm or more. Obtained by removing large particles of Particle size is about 0.01 to about 5
The range of μm (10-5000 nm) is preferred, and about
The range is more preferably from 0.01 to about 0.5 μm (10 to 500 nm), and from about 0.02 to about 0.2 μm (20 to 200 n
The range of m) is more preferred.

Various additives (for example, trehalose, maltose, lactose, sucrose, saccharose, mannitol) are used during the production of the suspension in order to prevent the association of fine particles in the oil phase when the suspension is dried. Saccharides such as glucose, basic amino acids, neutral amino acids, acidic amino acids, sodium chloride, etc.). The suspension is dried by, for example, vacuum drying, spray drying, freeze drying, or the like. The composition of the present invention has an average particle size of about 0.01 μm to about 10 mm, preferably about 0.1 μm.
Microparticles from m to about 10 mm are preferred. When the composition is a solid, the particle size is preferably about 1 μm to about 10 mm,
For liquids, it is preferably between about 0.1 μm and about 1000 μm.

As described above, the composition of the present invention is preferably stabilized with gastric acid by blending it with an oily base or by performing an enteric coating, etc., but a drug for oral administration containing a fumagillol derivative is preferred. The composition may be used in the medicament of the present invention. In this case, the composition may contain a gastric acid secretion inhibitor and / or an antacid, or may be used in combination with these to stabilize gastric acid. Examples of the “gastric acid secretion inhibitor” include H ₂ blockers (eg, famotidine,
Cimetidine, ranitidine hydrochloride, etc.), proton pump inhibitors (eg, lansoprazole, omeprazole, etc.) and the like are used. As the "antacid", for example, compounds that increase the pH in the stomach, such as magnesium carbonate, sodium hydrogen carbonate, magnesium hydroxide, magnesium oxide and magnesium hydroxide, are used.

A medicament using the composition of the present invention may be obtained by administering the above "gastric acid secretion inhibitor" and / or the above "antacid" as a pretreatment, thereby increasing the gastric pH.
It is desirable to administer it after reducing the effects of gastric acid. The pharmaceutical composition of the present invention may be coated with an enteric coating agent to form an enteric preparation. The drug (fumagillol derivative) -containing core composition coated with the enteric coating may be produced by the above-mentioned method using an oily base, or may be produced by a known method without using an oily base. In the composition of the present invention, the form of the core containing the drug is not particularly limited, and examples thereof include naked tablets, pills, granules, and fine granules. The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, and the like, and is prepared by a wet extrusion granulation method, a fluidized bed granulation method, or the like. Examples of excipients contained in the core include sucrose, lactose, mannitol, sugars such as glucose,
Starch, crystalline cellulose, calcium phosphate and the like are used. As the binder, for example, polyvinyl alcohol,
Hydroxypropylcellulose, macrogol, Pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), polyvinylpyrrolidone, low-substituted hydroxypropylcellulose (L-HPC) and the like are used. As the lubricant and the aggregation preventing agent, for example, talc, magnesium stearate and the like are used.

The nucleus can be prepared by spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) onto the inert carrier particles serving as the center of the nucleus. Alternatively, it can be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a small amount of a drug or a mixture thereof with an excipient, a lubricant and the like is added. As the inert carrier particles, those produced from, for example, sucrose, lactose, starch, crystalline cellulose, and waxes can be used. The components contained in the nucleus are not particularly limited to the above-mentioned substances, and are not limited as long as they are pharmaceutically acceptable. The resulting core may then be coated on its surface with a protective agent to separate the drug from the coating. As the protective agent, for example, a polysaccharide which may have a sulfate group such as pullulan, dextrin, and alkali metal alginate; a hydroxyalkyl cellulose or a hydroxyalkyl group such as hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose having a carboxyalkyl group; Polysaccharides, hydrophilic substances such as methylcellulose, polypinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used. As the protective agent, a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group is preferably used, more preferably hydroxypropylmethylcellulose. The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.

The "enteric coating agent" is an enteric polymer which is substantially insoluble at acidic pH but at least partially soluble at basic pH due to weaker acidic. The “acid pH” is about 0.5 to
About 4.5, preferably from about 1.0 to about 2.0. The “weaker acidic to basic pH” is about 5.0
~ 9.0, preferably from about 6.0 to about 7.5. Specifically, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethyl acetate succinate (Shin-Etsu Chemical Co., Ltd.), methacrylic acid copolymer (trade name: Eudragit L-30D-55, manufactured by Rame Pharma Co., Ltd.) , L1
00-55, L100, S100, etc.). Even if these are used as they are as enteric preparations, they are effective in terms of stability and the like. For coating, conventional methods such as pan coating method, fluid coating method,
The rolling coating method can be adopted. When the coating agent is a solution or dispersion containing water or an organic solvent, a spray coating method can also be employed. The proportion of water or organic solvent used is, for example, about 25 to about 99% by weight. The type of the organic solvent is not particularly limited. For example, alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), ketones (eg, acetone, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, trichloromethane, etc.), etc. Is used. When no oil base is used, the solvent used for coating is desirably an organic solvent.

The pharmaceutical composition of the present invention has a low toxicity and a strong pharmacological action, for example, a mammal (eg, mouse, rat,
Diseases associated with angiogenesis in monkeys, cattle, dogs, humans, etc., such as (1) inflammatory diseases such as rheumatoid arthritis, (2) diabetic retinopathy or (2) benign and malignant tumors (eg gastric cancer, esophagus) Cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma, rectal cancer, colon cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, breast cancer, biliary tract cancer, pancreatic cancer, prostate cancer, Endometrial cancer, cervical cancer, ovarian cancer, bladder cancer,
Skin cancer, malignant melanoma, thyroid cancer, bone tumor, hemangiomas, angiofibromas, retinal sarcoma, penile cancer, pediatric solid carcinoma, Kaposi meat type caused by AIDS, etc.) and their recurrence or metastasis to other organs ) Are useful as preventive and therapeutic agents. In addition, it is particularly useful when the composition is a pharmaceutical composition in which the drug concentration in the blood in the drug-effect-producing region where side effects do not occur is long-lasting. It is also effective in terms of stability and the like to fill the pharmaceutical composition of the present invention into the capsule coated with the enteric coating agent as described above and use it as an enteric capsule. As capsules, for example, soft capsules (such as R.P.S. Pharmaceutical compositions of the present invention may be prepared in accordance with conventional methods using drugs other than oral preparations, for example, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg,
Rectal preparations, vaginal suppositories, etc.), injections (eg, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intraperitoneal, intralesional, etc.) Can also be used.

The liquid or solid pharmaceutical composition obtained by the present invention can be orally administered according to a method known per se. In the case of a liquid, it can be directly administered to the digestive tract using a catheter or a probe for oral administration, or can be orally administered in a usual manner by preparing a dosage form filled in a hard capsule, a soft capsule, or the like. In the case of a solid, it can be orally administered in a usual manner as a powdery dosage form, a dosage form filled in capsules or a tablet, or it can be redispersed in an appropriate dispersion medium and administered in a liquid form. The preparation for oral administration of the present invention has a fumagillol derivative amount of about 1 mg to about 3 g, preferably about 10 mg to about 1 g per day for a breast cancer patient (body weight: 50 kg). The pharmaceutical composition of the present invention improves the stability and oral absorbability of the fumagillol derivative, provides stronger pharmacological activity, and provides more reliable therapeutic effects.

[0047]

The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Example 1 The concentration of 6-O- (N-chloroacetylcarbamoyl) fumagillol (hereinafter, referred to as compound A) is miglyol 8
12 (MIGLYOL812, caprylic / capric triglyceride, Hils Aktieng)
ESELLSCHAFT), 100m to Germany)
g / ml (10% w / v) to prepare a uniform solution. Example 2 When the concentration of Compound A was Miglyol 829 (MIGLYOL)
829, glyceryl succinate (caprylic / capric acid), Hirs) at 100 mg / ml (10% w
/ V) to prepare a uniform solution. Example 3 Miglyol 829 (MIGLYOL)
889, glyceryl di (caprylate / caprate) succinate, 20 mg / ml (2% w /
v) to prepare a homogeneous solution.

Example 4 The concentration of Compound A was 5 mg / ml (0.5% w / v) with respect to penta (tetra) glyceride oleate (trade name: PO-310, Sakamoto Yakuhin Co., Ltd., Osaka). And a homogeneous solution was prepared. Example 5 Hexa (tetra) glyceride behenate (trade name: HB-3)
10, Sakamoto Yakuhin Co., Ltd., Osaka) 7.2 g and stearic acid mono (tetra) glyceride (trade name MS-310,
0.8 g of the compound (Asakamoto Yakuhin, Osaka) is heated and melted at 85 ° C., and 1.0 g of the compound A, an acrylic acid polymer (trade name: Hibiswako 104, Wako Pure Chemical Industries, Ltd., Osaka)
0 g was added, and the mixture was stirred at a temperature of 80 ° C. for 15 minutes to be dispersed. By adding the molten mixture to a 15 cm diameter aluminum disc rotating at 2400 rpm at a rate of 10 g / min, a 42/80 mesh (size passing through a 42 mesh sieve and remaining on the 80 mesh sieve (about 180 To 350 μm), which is similarly abbreviated hereinafter.)

Example 6 Hexa (tetra) glyceride behenate (trade name: HB-3)
10) 5.6 g and 2.4 g of stearic acid mono (tetra) glyceride (trade name: MS-310) were heated and melted at 85 ° C., and 1.0 g of compound A and an acrylic acid polymer (trade name: Hibiswako 104) 0 g was added, and the mixture was stirred at a temperature of 80 ° C. for 15 minutes to be dispersed. 24 melt mixture
By adding at a rate of 10 g / min to a 15 cm diameter aluminum disc rotating at 00 rpm.
A 2/80 mesh spherical fine granule was obtained.

Example 7 Hexa (tetra) glyceride behenate (trade name: HB-3)
10) 4.8 g and 3.2 g of stearic acid mono (tetra) glyceride (trade name: MS-310) were heated and melted at 85 ° C., and 1.0 g of compound A and an acrylic acid polymer (trade name: Hibiswako 104) 0 g was added, and the mixture was stirred at a temperature of 80 ° C. for 15 minutes to be dispersed. 24 melt mixture
By adding at a rate of 10 g / min to a 15 cm diameter aluminum disc rotating at 00 rpm.
A 2/80 mesh spherical fine granule was obtained.

Example 8 0.6 ml of the solution obtained in Example 1 was filled in a No. 0 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0, Shin-Etsu Chemical Co., Ltd.) to give an enteric capsule preparation. Example 9 0.6 ml of the solution obtained in Example 2 was filled in a No. 0 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation.

Example 10 0.6 ml of the solution obtained in Example 3 was filled in a No. 0 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation. Example 11 0.6 ml of the solution obtained in Example 4 was filled in a No. 0 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation.

Example 12 0.8 ml of the solution obtained in Example 1 was filled in a soft capsule (5 Oval, R.P. The surface of the obtained capsule was coated with hydroxypropylmethylcellulose phthalate (trade name: HP-50) to obtain an enteric capsule preparation. Example 13 0.8 ml of the solution obtained in Example 2 was filled in a soft capsule (5 Oval, R.P. The surface of the obtained capsule was coated with hydroxypropylmethylcellulose phthalate (trade name: HP-50) to obtain an enteric capsule preparation.

Example 14 0.8 ml of the solution obtained in Example 3 was filled in a soft capsule (5 Oval, R.P. The surface of the obtained capsule was coated with hydroxypropylmethylcellulose phthalate (trade name: HP-50) to obtain an enteric capsule preparation. Example 15 0.8 ml of the solution obtained in Example 4 was filled in a soft capsule (5 Oval, R.P. The surface of the obtained capsule was coated with hydroxypropylmethylcellulose phthalate (trade name: HP-50) to obtain an enteric capsule preparation.

Example 16 300 mg of the fine granule obtained in Example 5 was filled in a No. 1 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation. Example 17 300 mg of the fine granule obtained in Example 6 was filled in a No. 1 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation.

Example 18 300 mg of the fine granule obtained in Example 7 was filled in a No. 1 gelatin capsule. The surface of the obtained capsule is coated with hydroxypropyl methylcellulose phthalate (trade name: HP-5).
0) to give an enteric capsule preparation. Example 19 The fine granules obtained in Example 5 were applied to a spiral flow type coating apparatus (Freund Corporation, SFC-Labo).
, Polyethylene glycol 6000, talc, titanium oxide and polysorbate 80 (Rheodol (Rheo)
dol) TW-0120) -containing enteric Eudragit (Eu
dragit) L30D-55 (methacrylic acid copolymer L
D, Laem Pharma) After spraying and coating the suspension,
The mixture was sieved and vacuum-dried at 42 ° C for about 18 hours to obtain an enteric fine granule.

Example 20 The fine granules obtained in Example 6 were treated in the same manner as in Example 19 to obtain enteric fine granules. Example 21 The fine granules obtained in Example 7 were treated in the same manner as in Example 19 to obtain enteric fine granules.

Example 22 Production of Enteric Coated Coating Formulation Containing Compound A (1) Preparation of Granules Containing Compound A Sugar granules were prepared using compound A, sucrose, starch and L-HPC.
Together with a centrifugal fluidized-bed granulator (CF-1000S, Freund), and coated with sugar particles while spraying an L-HPC ethanol solution. The obtained particles were dried in a vacuum dryer at 40 ° C. for 18 hours and then sieved to a particle size of 500 to 1
250 μm granules were obtained. The formulation used is shown below. Formulation: Sugar (spherical granulated product) 110.0 mg Compound A 52.4 Sucrose 59.8 Starch 36.4 Low-substituted hydroxypropylcellulose (L-HPC) 40.0 Hydroxypropylcellulose (HPC) 1.4 Ethanol 0 .07mg meter 300.0 mg (2) was coated with an ethanol solution of hydroxypropylmethyl cellulose phthalate in a spiral flow coating apparatus granules obtained in preparation above enteric coating granules (1), after drying, sieving Thereafter, the desired enteric-coated granules were obtained. The formulation used is shown below. Formulation: Compound A-containing granules 300.0 mg Hydroxypropyl methylcellulose phthalate 40.9 (HP-50) Ethanol 1.0 ml Total 340.9 mg

EXPERIMENTAL EXAMPLE 1 1 × 10 ⁵ Colon 26 per mouse was placed on the flanks of 10-week-old female BALB / c mice (Charles River Japan).
Tumor cells were implanted to produce tumor-bearing mice. These tumor-bearing mice were divided into four groups, and from day 7 to day 20 after tumor implantation, a migliol 812 solution of about 0.2 ml or a compound A miglyol 812 solution was orally administered once daily. Then, on the 21st day, the tumor at the implantation site was removed and weighed, and the weight ratio (T / C) to the untreated control group was determined [Table 1]. In addition, the number of colonies of tumors metastasized to the lung was counted, the median of each group was determined, and the ratio to the untreated control group (T /
C) was determined [Table 2]. As a result, a strong tumor growth inhibitory effect and a tumor metastasis inhibitory effect were observed depending on the dose of Compound A.

[0060]

Table 1 Dose (mg / kg) Number of subjects T / C (%) Non-treated control group 10 100 Miglyol 829 0 584 25 434 Miglyol 829 solution of Compound A 50 5 21

Table 2 Dose (mg / kg) Number of subjects T / C (%)
Untreated control group 10 100 Miglyol 829 0 5 124 25 47 Miglyol 829 solution of Compound A 50 5 52

Experimental Example 2 Famotidine (SIGMA) was administered to SD rats fasted overnight.
Was administered subcutaneously (dose 10 mg / kg). Administration 1
After an hour, the compound A-containing methylcellulose suspension was orally administered (dose: 100 mg / kg). Blood was collected from the tail vein with time, and the metabolite concentration in the plasma was measured. Further, as a control experiment, a suspension containing Compound A was administered to rats not administered with famotidine in the same manner. as a result. In the famotidine-treated group with increased gastric pH, a marked increase in absorption of Compound A was observed [Table 3].

[Table 3] Experimental Example 3 The compound A-containing migliol 812 solution obtained in Example 3 was orally administered to an SD rat that had been fasted overnight (dose: 100 mg / kg). Blood was collected from the tail vein with time, and the metabolite concentration in the plasma was measured. Also, as a control experiment,
A methylcellulose suspension containing Compound A was administered similarly. As a result, a marked increase in absorption of Compound A was observed in the miglyol solution administration group [Table 4].

[Table 4]

[0062]

EFFECT OF THE INVENTION The preparation of the present invention is stable even in oral administration and exhibits excellent tumor growth inhibitory effect and tumor metastasis inhibitory effect based on angiogenesis inhibitory effect. Can be.

Claims (29)

[Claims] 1. A pharmaceutical composition for oral administration which is stable against gastric acid and contains a fumagillol derivative. 2. The composition according to claim 1, which contains an oily base. 3. The composition according to claim 1, which is coated with an enteric coating agent. 4. The composition according to claim 2, wherein the fumagillol derivative is dissolved or dispersed in an oily base. 5. The oily base is liquid at room temperature, and the ratio of the fumagillol derivative to the oily base is from about 0.001 to about 5
The composition according to claim 2, which is 0% (w / v). 6. The oily base is solid at room temperature, and the ratio of the fumagillol derivative to the oily base is about 0.01 to about 10%.
The composition according to claim 2, which is 0% (w / w). 7. The composition according to claim 2, wherein the oily base is an ester of a fatty acid and an alcohol. 8. The composition according to claim 7, wherein the ester of the fatty acid and the alcohol is a fatty acid ester of glycerin or polyglycerin. 9. The composition according to claim 8, wherein the fatty acid ester of glycerin is a fatty acid triglyceride. 10. The composition according to claim 9, wherein the fatty acid triglyceride is a triglyceride of a saturated fatty acid having 6 to 22 carbon atoms. 11. The composition according to claim 2, which is fine particles having a particle size of about 0.1 μm to 10 mm. 12. A pharmaceutical composition for oral administration obtained by drying a suspension containing a fumagillol derivative, an oily base and an emulsifier. 13. The composition according to claim 1, further comprising a gastric acid secretion inhibitor or / and an antacid. 14. The fumagillol derivative represented by the general formula (I): ## STR1 ## Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
^{5 R 6, N + R 5} R 6 R 7 · X -, S (O) nR 5 or S ⁺ R ⁵ R ⁶
· X ^- a (R ^5, R ⁶ and R ⁷ each may have a substituent hydrocarbon group or heterocyclic group, X ^- is a counter anion, m a is 0 or 1, n is 0 to And represents an integer of 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or sulfur atom. The nitrogen-containing or sulfur-containing heterocyclic group which may be substituted may have a substituent.) Or R ¹ and R ² represent a bond, and R ³ has a substituent. A represents O or NR ⁸ (R ⁸ represents hydrogen or a lower alkyl group or an aryl group which may have a substituent, respectively). ) indicates, R ⁴ is hydrogen, also may hydrocarbon group optionally having a substituent An acyl group. ] The fumagillol derivative represented by these, or its salt, The composition of Claim 1. 15. R ¹ and R ² represent a bond, or R ¹ is hydrogen and R ² is N (O) mR ⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ .X ⁻ , S (O ) n
R ⁵ or ^{S + R 5 R 6 · X} - ( each symbol is as defined claim 14); A is O or NH; R ³ may have a substituent 2-methyl-1 - propenyl or isobutyl group; and R ⁴ is the composition of claim 14 wherein the carbamoyl group which may have hydrogen or a substituent. 16. The composition according to claim 15, wherein R ¹ and R ² represent a bond. 17. A is O, and R ³ is each optionally substituted with a hydroxyl group or a dialkylamino group.
A methyl-1-propenyl or isobutyl group, wherein R ⁴ is C
_1-6 alkyl or halogeno C _1-6 The composition of claim 14 alkanoyl group is a carbamoyl group substituted. 18. The composition according to claim 1, wherein the fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol. (19) the fumagillol derivative is 4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c ] The composition according to claim 1, which is thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride. 20. 6-O- (N-chloroacetylcarbamoyl) fumagillol or a salt thereof and C6-C22.
2. The composition according to claim 1, wherein the composition is mixed with triglycerides of saturated fatty acids. 21. 6-O- (N-chloroacetylcarbamoyl) fumagillol or a salt thereof having 6 to 22 carbon atoms.
The composition according to claim 1, wherein the composition is blended at a ratio of about 5 to about 30% (w / v) with respect to the triglyceride of the saturated fatty acid. 22. 6-O- (N-chloroacetylcarbamoyl) fumagillol or a salt thereof, having 6 to 22 carbon atoms.
13. The composition according to claim 12, which is obtained by drying a suspension containing triglycerides of saturated fatty acids and an emulsifier. 23. The method according to claim 1, which is an angiogenesis inhibitor.
2. The composition according to 2. 24. The composition according to claim 1, which is a prophylactic / therapeutic agent for a tumor. (25) An enteric preparation for oral administration containing a fumagillol derivative. 26. The preparation according to claim 25, further comprising an oily base. (27) the preparation according to the above (25), which is a capsule; 28. A medicament for oral administration comprising a combination of a fumagillol derivative and a gastric acid secretion inhibitor or / and antacid. 29. The medicament according to claim 28, wherein the fumagillol derivative is administered after administering the gastric acid secretion inhibitor and / or the antacid.