JPH08127540A - Antiulcerative medicine - Google Patents

Abstract

PURPOSE: To obtain an antiulcerative medicine effective for preventing/treating ulcers, esp. peptic ulcers in mammals, and having a rapid and high-quality therapeutic effect far superior to that of conventional therapies for ulcers. CONSTITUTION: This antiulcerative medicine is a combination of (A) a protein having cell growth factor activity, e.g. fibroblast growth factor activity, pref. a protein having acid-resistance basic fibroblast growth factor activity with (B) a proton pump inhibitor, pref. a benzimidazole-based compound (or a salt thereof) of the formula [ring A is substitutable; R<1> , R<3> and R<4> are each H, an alkyl or alkoxyl; R<2> is a (substituted) hydrocarbon group; (n) is 0 or 1]. The component A is pref. a recombinant-type bFGF muteine CS23 in which serines are substituted for the cysteines at 70th and 88th among the amino acids constituting basic fibroblast growth factor(bFGF). The daily dose of this medicine per kg body weight is as follows: A=0.01-1000 (esp. 0.1-10)μg and B=0.01-10 (esp. 0.1-1)mg.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicine comprising a protein having a cell growth factor activity and a proton pump inhibitor in combination. More specifically, the present invention relates to an anti-ulcer drug effective for the prevention / treatment of ulcers, particularly peptic ulcers in mammals.

[0002]

Ulcers are caused by various causes. In the case of peptic ulcer, the causes are gastric acid, pepsin, bile, food, and other factors that have an adverse effect on gastrointestinal mucosa and mucosal blood flow.
It is thought to be caused by a failure of the balance of factors that act protectively such as mucus secretion and bicarbonate secretion. Based on this idea, the treatment of peptic ulcer also suppresses attack factors,
Alternatively, treatment by enhancing defense factors has been desired, and many drugs having these actions have been developed and are now widely used. Histamine H ₂ as an attack factor inhibitor
Acid secretion inhibitors such as receptor blockers (cimetidine, ranitidine, famotidine, roxatidine, etc.), muscarinic receptor blockers (pirenzepine, etc.) and proton pump inhibitors (omeprazole, lansoprazole, etc.) are well known. On the other hand, prostaglandin derivatives (mizoprostol, ornoprosteel, etc.), sucralfate and the like are well known as protective factor enhancers. With the development of these drugs, the prevention and treatment of ulcerative and inflammatory lesions observed in the upper gastrointestinal tract such as reflux esophagitis, gastritis, gastric ulcer, duodenal ulcer, anastomotic ulcer, etc. have been clearly improved in recent years.

[0003]

However, there are still refractory ulcers that cannot be treated with these drugs, and ulcerative lesions caused by taking non-steroidal anti-inflammatory drugs such as indomethacin and aspirin are also present. It is a serious problem as a disease that is difficult to treat. Furthermore, it is known that ulcers cured by these drugs often recur after drug withdrawal, and there is a demand for the development of drugs capable of solving such remaining problems and advances in therapeutic methods.
It is considered that the above-mentioned attack factor inhibitor and defense factor enhancer do not directly promote the growth of mucosal cells for the healing of ulcer, but rather indirectly promote the healing by adjusting the healing environment. Recently, it has become clear that various growth factors play an important role in wound healing including gastrointestinal mucosa. For example, acidic and basic fibroblast growth factors and muteins thereof promote the healing of peptic ulcers. Have been revealed (Folkman J. et
al .: Annals of Surgery214, 414-427 (1991), Fitzpat
rick LR et al .: Digestion 53, 17-27 (1992), Kont
urek SJ et al .: Gut 34, 881-887 (1993), Szabo
S. et al .: Gastroenterology 106, 1106-1111 (1994),
Satoh H. et al .: Gastroenterology 100, A155 (199
1), Satoh H. et al .: Gastroenterology 102, A159 (1
992)). Furthermore, as a mechanism of action of these factors, there is almost no inhibition of attacking factors and enhancement of defense factors, and positively promoting healing of ulcer such as promotion of angiogenesis at the ulcer floor, and as a result, recurrence of ulcer It may be decreased (Satoh H. et al .: Gastroenterology 102,
A159 (1992)).

[0004]

Means for Solving the Problems Using the rat aspirin-induced gastric ulcer model in the present inventor, the inventors of the present invention clearly demonstrated that when a proton pump inhibitor and a fibroblast growth factor were used in combination, the respective drugs were superior to each other alone. It was found that an ulcer effect was obtained, and further research was conducted to complete the present invention.
That is, the present invention provides: (1) a drug characterized in that a protein having cell growth factor activity and a proton pump inhibitor are used in combination, (2) a protein having cell growth factor activity exhibits fibroblast growth factor activity The pharmaceutical according to the above (1), which is a protein having, (3) The pharmaceutical according to (2), wherein the protein having a fibroblast growth factor activity is a protein having a basic fibroblast growth factor activity, and (4) a base. The protein according to (3) above, wherein the protein having a basic fibroblast growth factor activity is acid resistant, and (5) the protein having a basic fibroblast growth factor activity is a basic fibroblast growth factor (bF).
(6) The mutein according to the above (3), which is a bFGF mutein in which at least one of the cysteines constituting (GF) is substituted with another amino acid, and the stability under acidic conditions is more enhanced than that of bFGF; Recombinant bF in which cysteines at positions 70 and 88 of bFGF are replaced with serine
The drug according to (5) above, which is GF mutein CS23,
(7) The drug according to (1) above, wherein the proton pump inhibitor is a benzimidazole compound, and (8) the benzimidazole compound has the general formula (II):

Embedded image [In the formula, ring A may be substituted, R ¹ , R ³ and R ⁴ may be the same or different and each represents hydrogen, an alkyl group or an alkoxy group, and R ² may be an optionally substituted hydrocarbon group. Wherein n represents 0 or 1] or the salt thereof, wherein the pharmaceutical is (7).
(8) The pharmaceutical according to (8) above, wherein the compound represented by I) is lansoprazole, (10) recombinant bFGF mutein C
The pharmaceutical according to (1) above, which comprises a combination of S23 and lansoprazole, (11) the pharmaceutical according to (1) above, which is for preventing or treating ulcer, (12) the above (11) wherein the ulcer is a peptic ulcer. (13) The kit according to (1) above, which is a kit comprising a protein having cell growth factor activity and a proton pump inhibitor, and (14) comprising a protein having cell growth factor activity and a proton pump inhibitor. The present invention relates to a method for enhancing the cell growth factor activity of a protein having cell growth factor activity, which comprises using the pharmaceutical composition according to (1) above, which is a pharmaceutical composition, and (15) a proton pump inhibitor in combination.

The cell growth factor means in vivo.
o) or a substance that promotes the growth of animal cells in vitro and is not a nutrient,
In the present invention, the “protein having a cell growth factor activity” includes any protein having the activity of the present growth factor as long as it has low toxicity. Examples of such cell growth factors include fibroblast growth factor (FGF) and platelet-derived growth factor.
(PDGF), epidermal growth factor (EGF), α-type and β-type transforming growth factors (TGFα, TGFβ), insulin-like growth factor (IGF), platelet-derived angiogenic factor (PD-ECG)
F) and the like. These proteins having cell growth factor activity may be those isolated and purified from the animal body or those produced by genetic engineering, and the constituent amino acids of the natural protein may be appropriately selected as long as they have the cell growth factor activity. It may be a mutein modified to, for example, one in which a part of the constituent amino acids is deleted or substituted, or one in which another amino acid is added. Examples of the protein having a fibroblast growth factor (FGF) activity include a protein having an acidic fibroblast growth factor activity, a protein having a basic fibroblast growth factor activity, and the like, but preferably a basic fiber A protein having blast growth factor activity can be mentioned. The protein having a basic fibroblast growth factor activity is preferably an acid-resistant one. Proteins having fibroblast growth factor (FGF) activity include acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF), and muteins thereof. Examples of bFGF muteins include muteins described in JP-A-2-193 or JP-A-3-505736. Among them, (1) a mutein in which at least one bFGF-constituting amino acid is substituted with another amino acid, (2) the mutein in (1) above in which the bFGF-constituting amino acid is cysteine, and (3) another amino acid is a neutral amino acid. The mutein of (1) above, which is
(4) The mutein of (1) above in which cysteine, which is at least one constituent amino acid, is substituted with serine is preferably exemplified. For example, the mature protein 25,69,8
Such as purified recombinant human basic FGF (rhbFGF) protein in which a mutation has been introduced by changing one or more of the four cysteines present at the 7 and 92 amino acid positions to serine (mutein) Modified FGF is mentioned. In the numbering of the constituent amino acids of human bFGF, the N-terminal Pro constitutes the first amino acid. Among these, a mutein in which at least one of cysteines constituting bFGF is substituted with another amino acid and stability under acidic condition is enhanced more than that of basic fibroblast growth factor is preferable, and particularly human b
Of the four cysteine residues present in the amino acid sequence of FGF, the mutein in which the second and third cysteine residues from the N-terminal side (positions 70 and 88) are replaced by serine (hereinafter referred to as CS23) is the most It is preferably used. The structure of CS23 is described by Seno et al., Biochemicals.
Biochemical and Biophysical Research Commu
nications), 151, No. 2, 701-708 (1988) and EP
-281,822 publication.

The proton pump inhibitor referred to in the present invention is
It refers to a drug that suppresses acid secretion by directly or indirectly inhibiting H / K-ATPase that functions as a proton pump in acid-secreting cells (parietal cells) of the gastric mucosa. Examples thereof include omeprazole, lansoprazole, pantoprazole, paliprazole sodium, reminoprazole, TY-11345, TU-199, F.
PL-65372, BY-686, Tannic Acid
acid), Ellagic acid, Ebselen (E
bselen), AHR-9294, Casigalol-A (Cassi
garol-A), bafilomycin, Y-25
942, Xanthoangelol E, SKF-96356, Epig
allocatechin gallate, WY-27198, T-330
Alternatively, SK & F-20054 and the like can be mentioned.

In particular, examples of the proton pump inhibitory active substance include benzimidazole compounds and the like. The benzimidazole compounds have a proton pump inhibitory action and have low toxicity. As the benzimidazole compound, for example, 2-[(pyridyl) -methylsulfinyl or -methylthio] benzimidazole or a derivative thereof and a salt thereof are preferable. More preferred are compounds represented by the following general formula (I) and salts thereof.

Embedded image [In the formula, ring A may be substituted, R ^b represents a hydrogen atom, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkylsulfonyl group, and R ^c and R ^e
And R ^g are the same or different and each represent a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkoxy group,
^d is a hydrogen atom, an alkyl group or a formula —OR ^f (wherein
R ^f represents a hydrocarbon group which may have a substituent), and q represents 0 or 1. The benzimidazole compounds are described in, for example, JP-A-52-6.
2275, JP-A-54-141783, JP-A-57-53406, JP-A-58-13588.
1, JP-A-58-192880, JP-A-5
9-181277, JP 61-50978, JP 62-116576, and JP 62-2.
77322, JP-A-62-258320,
JP-A-62-258316, JP-A-64-627
No. 0, JP-A-64-79177 and JP-A-5-
59043, JP-A-62-111980,
JP-A-5-117268, European Patent Publication No. 166287, European Patent Publication No. 51936.
No. 5, for example.

In the above general formula (I), when the ring A is substituted, examples of the substituent include a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, and a substituted group. Optionally substituted alkenyl group, optionally substituted alkoxy group, cyano group, carboxy group, carboalkoxy group, carboalkoxyalkyl group, carbamoyl group, carbamoylalkyl group, hydroxy group, hydroxyalkyl group, acyl group, carbamoyl Examples thereof include an oxy group, a nitro group, an acyloxy group, an aryl group, an aryloxy group, an alkylthio group and an alkylsulfinyl group. Hereinafter, each of the above substituents will be described. As a halogen atom,
Examples thereof include fluorine, chlorine, bromine and iodine. Of these, fluorine and chlorine are preferable. Further, fluorine is particularly preferable. The alkyl group in the optionally substituted alkyl group is a linear or branched alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl). , Tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like). Of these, straight or branched ones having 1 to 6 carbon atoms are preferable. Further, a straight or branched one having 1 to 3 carbon atoms is preferable. Examples of the substituent of the alkyl group include halogen, nitro, amino group (which may have 1 or 2 alkyl groups, acyl groups and the like as substituents), cyano group, hydroxy group, carboxy group, amidino. Group, guanidino group, carbamoyl group and the like.

The cycloalkyl group in the optionally substituted cycloalkyl group has, for example, 3 to 7 carbon atoms.
The cyclicle alkyl group of Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl group may have a substituent, and examples of the substituent include halogen, nitro,
Amino group (which may have 1 or 2 substituents such as alkyl group and acyl group), cyano group, hydroxy group,
Examples thereof include a carboxy group, an amidino group, a guanidino group, and a carbamoyl group. The alkenyl group in the optionally substituted alkenyl group has, for example, 2 to 2 carbon atoms.
Sixteen straight or branched alkenyl groups are preferred. Specific examples of the alkenyl group include allyl, vinyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexene-.
1-yl, 2-methyl-2-propen-1-yl, 3-
Methyl-2-buten-1-yl and the like can be mentioned. Of these, a linear or branched alkenyl group having 2 to 6 carbon atoms is preferable. Further, a linear or branched alkenyl group having 2 to 4 carbon atoms is preferable. The alkenyl group may have a substituent, and examples of the substituent include halogen, nitro, and amino groups (which may have 1 to 2 substituents such as an alkyl group and an acyl group). And groups such as cyano group, amidino group and guanidino group. The alkenyl group includes isomers (E, Z isomers) related to the double bond.
Examples of the alkoxy group in the optionally substituted alkoxy group include an alkoxy group having 1 to 10 carbon atoms. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy and n.
-Butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like can be mentioned. Of these, an alkoxy group having 1 to 6 carbon atoms is preferable. 1 more carbon
Alkoxy groups of 3 are particularly preferred. The alkoxy group may have a substituent, and examples of the substituent include halogen, nitro, and amino groups (which may have 1 or 2 alkyl groups, acyl groups and the like). , Amidino group, guanidino group and the like.

Examples of the halogen of the substituent on the above alkyl group, cycloalkyl group, alkenyl group and alkoxy group include chlorine, bromine, fluorine and iodine. As the alkyl group in the alkylamino group, which is a substituent on the above alkyl group, cycloalkyl group, alkenyl group and alkoxy group, for example, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-
Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like can be mentioned. Among them, a linear or branched alkyl group having 1 to 4 carbon atoms is particularly preferable. Examples of the acyl group in the acylamino group that is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group include an acyl group derived from an organic carboxylic acid. Of these, an alkanoyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Among them, an alkanoyl group having 1 to 4 carbon atoms is particularly preferable. The number of substituents on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group is 1 to 6, preferably 1 to 3.

Specific examples of the substituted alkyl group include:
For example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2-
Methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-diethylphosphorylethyl and the like can be mentioned. Of these, difluoromethyl, trifluoromethyl and hydroxymethyl are preferable. Furthermore, trifluoromethyl is particularly preferable. Specific examples of the substituted cycloalkyl group include, for example, 2-aminocyclopropan-1-yl and 4-hydroxycyclopentane-1.
-Yl, 2,2-difluorocyclopentan-1-yl and the like. Specific examples of the substituted alkenyl group include 2,2-dichlorovinyl, 3-hydroxy-2-propen-1-yl, 2-methoxyvinyl and the like. Specific examples of the substituted alkoxy group include, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl).
Examples include ethoxy and the like. Of these, difluoromethoxy is preferred.

The alkoxy group of the carboalkoxy group has 1 to 7 carbon atoms (eg, methoxy, ethoxy, n-
Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy and the like). The alkoxy group of the carboalkoxyalkyl group has 1 to 4 carbon atoms.
(Eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), the alkyl group has 1 to 4 carbon atoms (eg, methyl, ethyl, n -Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te
rt-butyl etc.), and examples thereof include carbomethoxymethyl, 2-carbomethoxyethyl, 2-carbomethoxypropyl, carboethoxymethyl, 2-carboethoxyethyl, 1-carbomethoxypropyl, carbopropoxymethyl, Carbobutoxymethyl and the like can be mentioned. The alkyl group of the carbamoylalkyl group has 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl,
(tert-butyl etc.).

The alkyl group of the hydroxyalkyl group has 1 to 7 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl). , Neopentyl, hexyl, heptyl, etc.). Examples of the acyl group and the acyloxy group include an alkanoyl group having 1 to 4 carbon atoms, and examples thereof include formyl, acetyl, propionyl,
Examples include butyryl and isobutyryl. The aryl group and the aryl group of the aryloxy group have 6 carbon atoms.
To 12 (eg, phenyl, naphthyl, etc.). The alkyl groups of the alkylthio group and the alkylsulfinyl group each have 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, hexyl and the like). 1-4 are preferable and, as for the number of the substituents on the substituted A ring, further 1-2 are especially preferable. Examples of the position of the substituent on the benzene ring include 4-position and 5-position,
5th is preferable among them. As a preferred example of ring A,
A ring which may be substituted with a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group or an optionally substituted alkoxy group, etc. is there. The alkyl group represented by R ^b has 1 to 5 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.), the acyl group having 1 to 4 carbon atoms (eg, alkanoyl group having 1 to 4 carbon atoms) is a carboalkoxy group. Alkoxy has 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), and alkyl of the alkylcarbamoyl group and dialkylcarbamoyl group has 1 to 4 carbon atoms. Examples, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl, etc.), and examples of alkyl of the alkylsulfonyl group include those having 1 to 4 carbon atoms as described above. R ^b is preferably hydrogen.

The alkyl group represented by R ^c , R ^e or R ^g is a linear or branched one having 1 to 10 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like). Among these, straight-chain or branched ones having 1 to 6 carbon atoms, particularly straight-chain or branched ones having 1 to 3 carbon atoms are preferable. The alkoxy group represented by R ^c , R ^e or R ^g has 1 to 10 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-
Pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy and the like). Of these, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferable. The alkoxy of the alkoxyalkoxy group represented by R ^c , R ^e or R ^g has 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, tert-butoxy, etc.). R ^c
Of these, a hydrogen atom, an alkyl group and an alkoxy group are preferable. R ^e is preferably a hydrogen atom, an alkyl group or an alkoxy group. R ^g is preferably a hydrogen atom. Examples of the alkyl group represented by R ^d include those having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Examples of the hydrocarbon group of the hydrocarbon group which may have a substituent represented by R ^f include a hydrocarbon group having 1 to 13 carbon atoms, for example, a linear or branched C 1 hydrocarbon group.
~ 6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), alkenyl group having 2 to 6 carbon atoms (eg, vinyl, allyl, 2-butenyl) , Methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), alkynyl groups having 2 to 6 carbon atoms (eg, ethynyl, propargyl, 2-butyne-1).
-Yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), carbon number 3-6 A cycloalkyl group (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.), carbon number 3-6
A cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl,
1-phenethyl, 2-phenethyl, etc.), 6 to 1 carbon atoms
And aryl groups of 0 (eg, phenyl, naphthyl, etc.) and the like. Among them, a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,
Isopentyl, hexyl, etc.) are preferred. Furthermore, a linear or branched alkyl group having 1 to 4 carbon atoms is preferable.

Examples of the substituent in the hydrocarbon group having a substituent include a C _6-10 aryl group (eg, phenyl, naphthyl, etc.), amino, and a C _1-6 alkylamino group (eg,
Methylamino, ethylamino, isopropylamino, etc.), diC _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), N—C _7-14 aralkyl-N
—C _3-6 cycloalkylamino (eg, N-benzyl-N
-Cyclohexylamino), N-aralkyl-N-
Alkylamino (eg, N- (1-naphthylmethyl) -N
-Ethylamino etc.), azide, nitro, halogen (eg fluorine, chlorine, bromine, iodine etc.), hydroxyl, C _1-4 alkoxy group (eg methoxy, ethoxy, propoxy, butoxy etc.), C _6-10 aryl Oxy group (eg, phenoxy, naphthyloxy, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), C _6-10 arylthio group (eg, phenylthio,
Naphthylthio), cyano, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11 aryloxycarbonyl group (eg, phenoxycarbonyl,
1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl etc.), carboxy-C _1-4 alkoxy group (eg carboxymethoxy, 2-carboxyethoxy etc.), C _1-6 alkanoyl group (eg formyl, acetyl, propionyl, Isopropionyl, butyryl, pentanoyl, hexanoyl, etc., C _7-11 aroyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, 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 (eg, benzenesulfinyl, 1
-Naphthylsulfinyl, 2-naphthylsulfinyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), 5 or 6 containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) Membered heterocyclic groups (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), hetero 1 atom (eg nitrogen, oxygen, sulfur, etc.)
A 4- or 5-membered heterocyclic carbonyl group (eg, 2-
Furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.), heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) 1
A 5- or 6-membered heterocyclic thio group containing 4 to 4 (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, etc.) and the like, and The heterocyclic thio group may be condensed with a benzene ring to form a bicyclic condensed ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio, etc.). Among them, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, C _1-4 alkoxy group (eg,
(Methoxy, ethoxy, propoxy, butoxy etc.) are preferred. The number of the substituents is 1 to 5, preferably 1 to
It is 3.

R ^d is preferably an optionally substituted alkoxy group or an optionally substituted alkoxyalkoxy group. The alkoxy group which may be substituted has 1 to 8 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n
-Butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, etc.), each of which may have a carbon number as an alkoxy group. 1 to 4 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) can be mentioned. As R ^d ,
Particularly, an optionally halogenated alkoxy group having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, and an optionally halogenated alkoxyalkoxy group are preferable. Preferred examples of the optionally halogenated alkoxy group include, for example, 2,2,2-trifluoroethoxy, 2,2,
3,3,3-pentafluoropropoxy, 1- (trifluoromethyl) -2,2,2-trifluoroethoxy, 2,
2,3,3-tetrafluoropropoxy, 2,2,3,3,
4,4,4-heptafluorobutoxy, 2,2,3,3,4,
Examples include 4,5,5-octafluoropentoxy and methoxy. Preferred examples of the optionally alkoxylated alkoxyalkoxy group include 3-methoxypropoxy and the like. q is preferably 0.

More specifically, the benzimidazole compound used in the present invention is, for example, one represented by the general formula (I
I)

[Chemical 4] (In the formula, ring A may be substituted, R ¹ , R ³ and R ⁴ are the same or different and each is a hydrogen, an alkyl group or an alkoxy group, and R ² is a hydrocarbon which may have a substituent. Group, n is 0 or 1, respectively). In the above general formula (II), as the A ring,
The same as the ring A in the general formula (I) can be mentioned.

Examples of the alkyl group represented by R ¹ , R ³ or R ⁴ include linear or branched alkyl groups having 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, Decyl etc. are mentioned. Of these, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Further, a linear or branched alkyl group having 1 to 3 carbon atoms is particularly preferable.

Examples of the alkoxy group represented by R ¹ , R ³ or R ⁴ include alkoxy groups having 1 to 10 carbon atoms. Specific examples of the alkoxy group include, for example, methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, tert-
Examples thereof include butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Of these, an alkoxy group having 1 to 6 carbon atoms is preferable. 1 more carbon
Alkoxy groups of 3 are particularly preferred. The hydrocarbon group which may have a substituent represented by R ² is the above R ^f.
The same as that shown in. R ¹ is preferably an alkyl group having 1 to 6 carbon atoms or 1 to 6 carbon atoms.
Is an alkoxy group. More preferably, the carbon number is 1 to 3.
Is an alkyl group. R ³ is preferably hydrogen or an alkyl group having 1 to 6 carbon atoms. More preferably, it is hydrogen. R ² is preferably 1) halogen, 2) hydroxyl or 3) an alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms. More preferably, 1) a halogen or 2) an alkyl group having 1 to 3 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms. R ⁴ is preferably hydrogen.

Specific examples of the benzimidazole compound used in the present invention include 2- [2- [3-methyl-4-].
(2,2,3,3-Tetrafluoropropoxy) pyridyl]
Methylthio] benzimidazole (hereinafter referred to as compound A), 2- [2- [3-methyl-4- (2,2,2-trifluoroethoxy) pyridyl] methylsulfinyl]
Benzimidazole (lansoprazole), 2-[(2
-Pyridyl) methylsulfinyl] benzimidazole (timoprazole), 2- [2- (3,5-dimethyl-4)
-Methoxypyridyl) methylsulfinyl] -5-methoxy-1H-benzimidazole (omeprazole),
2- [2- [4- (3-Methoxypropoxy) -3-methylpyridyl] methylsulfinyl] -1H-benzimidazole sodium salt, 2- [2- (3,4-dimethoxy) pyridyl] methylsulfinyl] -5 -Difluoromethoxy-1H-benzimidazole (pantoprazole) and the like can be mentioned.

The benzimidazole compound or its salt used in the present invention can be produced, for example, by the methods described in the above-mentioned publicly known Japanese and European patent publications and methods analogous thereto. The salt of a benzimidazole compound is preferably used as a physiologically acceptable salt. Examples of physiologically acceptable salts include salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like. Examples of the inorganic base used include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.),
Examples of organic bases include trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine, and examples of basic amino acids include arginine and lysine. To be These salts are produced by a method known per se, for example, the method described in JP-A-64-79177 and JP-A-59-167587 or a method analogous thereto.

The medicament of the present invention is applied to the prevention and treatment of ulcers in animals, and is particularly effective in the prevention and treatment of peptic ulcers in mammals including humans. Examples of such peptic ulcer include gastric ulcer, duodenal ulcer, reflux esophagitis, rostral ulcer or acute and chronic gastritis. A feature of the pharmaceutical agent of the present invention is that a protein having a cell growth factor activity and a proton pump inhibitor are used in combination, and the use form thereof is not particularly limited. For example, a protein having a cell growth factor activity and a proton pump inhibitor may be provided as a formulation that is usually administered, or a composition in which both are combined in advance may be used. Examples of the pharmaceutical agent of the present invention include a protein having cell growth factor activity (sometimes referred to as active ingredient A) and a proton pump inhibitor (sometimes referred to as active ingredient B), which are well-known pharmaceutical preparations. According to the method, if necessary, a pharmaceutically acceptable diluent, excipient, etc. are used, and mixed to form one agent.
If desired, each formulation may be prepared using a pharmaceutically acceptable diluent, excipient, or the like, or each separately formulated into a set (kit). For example, the medicament of the present invention is (1) a kit comprising a protein having cell growth factor activity and a proton pump inhibitor, or (2) a composition containing a protein having cell growth factor activity and a proton pump inhibitor. Used as.

The route of administration of the medicament of the present invention is preferably oral administration, but parenteral administration (eg, intravenous administration, subcutaneous administration, intramuscular administration, etc.) is also possible. In particular, the proton pump inhibitor can be administered either orally or parenterally. Specifically, it is determined in consideration of the target ulcer site and the like. When the protein having cell growth factor activity and the proton pump composition are separately formulated, they may be administered to the same subject by the same route or different routes separately, at the same time, or at different times. . In administering the pharmaceutical agent of the present invention, the protein having a cell growth factor activity and the proton pump inhibitor can be administered in a dosage form prepared by a conventional method. In the case of a protein having cell growth factor activity, for example, Japanese Patent Publication No. 50573/1993
It can be prepared by the method described in JP-A-6. That is,
Tablets and capsules include pharmaceutically acceptable carriers (eg, lactose, corn starch, light silicic anhydride,
Microcrystalline cellulose, sucrose), binder (eg pregelatinized starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintegrant (eg carboxymethylcellulose, starch, low-substituted hydroxypropylcellulose) ), Surfactants [eg Tween80 (Kao-Atlas), Pluronic F6
8 (Asahi Denka, Japan), polyoxyethylene-polyoxypropylene copolymer], antioxidant (eg, L-cysteine, sodium sulfite, sodium ascorbate),
Prepared by employing a lubricant (eg, magnesium stearate, talc), and the like. When prepared as an injectable aqueous solution, this solution is prepared by a conventional method using a solvent such as an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution) or an oily solvent (eg, sesame oil, olive oil). . If necessary, 1
Alternatively, more additives can be used. Such additives include solubilizing agents (eg sodium salicylate, sodium acetate), buffering agents (eg sodium citrate, glycerin), isotonic agents (eg glucose,
Invert sugar), stabilizers (eg human serum albumin, polyethylene glycol), preservatives (eg benzyl alcohol, phenol) or analgesics (eg benzalkonium chloride, brocaine hydrochloride). Also, when prepared as a solid preparation for injections, this preparation may for example be a diluent (eg distilled water, saline, glucose),
It can be produced by an ordinary method using an activator (eg, carboxymethyl cellulose, sodium alginate), a preservative (eg, benzyl alcohol, phenol) or an analgesic (eg, benzalkonium chloride, brocaine hydrochloride).

On the other hand, in the case of a proton pump inhibitor, the same method as described above can be adopted in principle, but the method described in JP-A-63-301816 and the low-substituted hydroxypropylcellulose are used. Nucleated granules coated with a powder-like dusting agent or
It can be preferably administered as a solid composition stabilized by the method described in Japanese Patent No. 163018, that is, a stabilizer comprising a basic inorganic salt of magnesium and / or calcium. Examples of the composition for oral administration, which comprises the protein having cell growth factor activity and the proton pump inhibitor in the medicine of the present invention, include tablets, pills, granules, powders, capsules, syrups, and emulsions. , Suspension agents and the like. Such a composition is produced by a method known per se, and lactose, starch, sucrose, magnesium stearate or the like is used as a carrier or excipient. Examples of the composition for parenteral administration include suppositories,
It can be an external preparation or the like. As a suppository, for example,
Rectal suppositories, vaginal suppositories and the like can be mentioned, and examples of the external preparation include ointments (including cream), vaginal preparations, nasal preparations, transdermal preparations and the like. For example, in the case of a suppository, the composition of the present invention can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se.

The contents of the protein having a cell growth factor activity and the proton pump inhibitor in the drug of the present invention may be appropriately selected depending on the preparation. For example, the protein having a cell growth factor activity is about 0.0001 to 10 weight. %, Preferably about 0.001-1% by weight, more preferably about 0.1.
It is from 01 to 0.2% by weight. The proton pump inhibitor is about 0.1 to 90% by weight, preferably about 1 to 50% by weight, more preferably about 2 to 20% by weight. The protein having the cell growth factor activity to be used for the proton pump inhibitor varies depending on the individual combination.
For example, it is about 0.0001 to 1 times (weight ratio), preferably about 0.001 to 0.1 times (weight ratio) of the proton pump inhibitor. In the medicament of the present invention, a protein having a cell growth factor activity and a proton pump inhibitor separately formulated can be simultaneously administered to the same subject. In addition, the same subject can be administered with a time lag. The frequency of administration of each component may be different. For example, the number of administrations of the proton pump inhibitor is preferably 1
~ 2 times / day, more preferably once / day, and the number of administrations of the protein having cell growth factor activity is preferably 1 to 4 times / day, more preferably 3 to 4 times / day. .

When the drug of the present invention is administered, for example, a protein having a cell growth factor activity is usually in a state where acid secretion is suppressed by administration of a proton pump inhibitor (usually about 30 to 60 after oral administration of a proton pump inhibitor). It is preferable to administer the drug after 1 minute. When acid secretion is continuously suppressed by daily administration of a proton pump inhibitor, it can be co-administered with a proton pump inhibitor. The dose of the drug of the present invention is appropriately selected depending on the type and symptom of the ulcer, but the protein having a cell growth factor activity is 0.01 to
1000 μg / kg / day, preferably 0.1-300 μ
g / kg / day, more preferably 0.1 to 10 μg / k
g / day, while the proton pump inhibitor was 0.0
1 mg / kg / day to 10 mg / kg / day, preferably 0.1 to 3 mg / kg / day, more preferably 0.1 m
g / kg / day to 1 mg / kg / day is administered. The dose for one dose is determined in consideration of such daily dose and dosage form. In addition to the protein having a cell growth factor activity and a proton pump inhibitor, the medicine of the present invention also comprises
It may contain active ingredients such as anti-ulcer substances (eg H ₂ blockers).

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION

Experimental Example 7-week-old Jcl: SD male rats (body weight: 220 g) were used for 24
It was used for the experiment after fasting for an hour. Rats with 1% NaHCO ₃ and 0.5%
Lansoprazole or vehicle suspended in a vehicle containing methylcellulose was orally administered, and 0.5% after 30 minutes
Aspirin suspended in methylcellulose (vehicle-) was orally administered at 200 mg / kg. One hour after the administration of aspirin, a normal solid diet was given for 2 hours. Three hours later, in Experiment 1, vehicle 23 containing no NaHCO ₃ and in Experiment 2 vehicle-containing CS23, which is a human basic fibroblast growth factor mutein, or each vehicle, was dissolved in a vehicle containing 1% NaHCO _3. It was orally administered. Twenty-four hours after the administration of aspirin, the animals were killed with carbon dioxide, and the stomach was removed together with the lower esophagus and duodenum. The excised stomach was occluded with an esophagus with a clip, 10 ml of 1% formalin was injected into the stomach from the duodenum, and the whole stomach was immersed in a 1% formalin solution. About 15
After a minute, the stomach is incised along the greater curvature and the contents are removed.
Under a stereoscopic microscope (x10), the length (mm) of each lesion formed in the body of the stomach was measured. The sum of the individual injuries in each rat was calculated and used as the gastric mucosal injury index. The results of Experiment 1 and Experiment 2 are shown in [Table 1] and [Table 2], respectively.

[0028]

[Table 1] Drug (1) was orally administered 30 minutes before aspirin administration, and drug (2) was orally administered 6 hours after aspirin administration. Veh-: Solution containing 1% NaHCO ₃ and 0.5% methylcellulose Veh-: Solution containing 0.5% methylcellulose LPZ: Lansoprazole (): Dose (mg / kg, po) a: p <0.05 vs 1 group, b: p <0.05 vs 2 groups, c: p <0.05 vs
4 groups

[0029]

[Table 2] Drug (1) was orally administered 30 minutes before aspirin administration, and drug (2) was orally administered 6 hours after aspirin administration. Veh-: Solution containing 1% NaHCO ₃ and 0.5% methylcellulose LPZ: Lansoprazole (): Dose (mg / kg, po) a: p <0.01 vs 1 group, b: p <0.05 vs 2 group, c: p <0.05
vs 4 groups As shown in [Table 1] and [Table 2], lansoprazole (1 and 3 mg / kg) decreased the gastric damage index depending on the dose in both experiments, and the index of the 3 mg / kg administration group Is vehi
It was significantly smaller than the control group treated with cle. CS23 (0.1 mg
/ kg) was dissolved in a vehicle containing no 1% NaHCO ₃ and administered, but no effect was observed in Experiment 1, but 1% NaHCO 3
40% in Experiment 2 which was administered by dissolving in vehicle-containing ₃
Showed a decreasing effect on. The co-administration of lansoprazole and CS23 significantly decreased the damage index, and the damage index of the 6th group treated with lansoprazole 3 mg / kg and CS23 0.1 mg / kg was significantly lower than that of each single group. The above results indicate the usefulness of the combined use of both drugs in the prevention and treatment of ulcers.

[0030]

【Example】

Formulation Example The drug of the present invention can be produced, for example, by the following formulation. 1. Capsules (1) Lansoprazole 10 mg (2) CS23 0.1 mg (3) Lactose 90 mg (4) Microcrystalline cellulose 70 mg (5) Magnesium stearate 10 mg 1 capsule 180.1 mg (1), (2), (3) After mixing 1/2 of (4) and (5), granulate. The rest (5) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablets (1) Lansoprazole 10 mg (2) CS23 0.1 mg (3) Lactose 35 mg (4) Corn starch 150 mg (5) Microcrystalline cellulose 30 mg (6) Magnesium stearate 5 mg 1 tablet 230.1 mg (1), (2), 2/3 of (3), (4) and (5) and (6)
Mix 1/2 of the mixture and granulate. The rest of (5) and (6) is added to this and the mixture is pressed into tablets.

3. Kit A kit in which each component is separately formulated is prepared using Capsule A and Capsule B. (A) Capsule A (1) Lansoprazole 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3), and 1 of (4) After mixing / 2, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. (B) Capsule B (1) CS23 0.1 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 170.1 mg (1), (2) and (3), and ( Mix 1/2 of 4) and granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

4. Kit A kit in which each component is separately formulated is prepared using Capsule B and Capsule C. (A) Capsule B (1) CS23 0.1 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 170.1 mg (1), (2) and (3), and ( Mix 1/2 of 4) and granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. (B) Capsule C Nonpareil (Sugar core coated with 75 parts by weight of sucrose by 25 parts by weight of corn starch by a method known per se)
28 mesh) 1650 g, CF device (CF-360,
Rotor speed is 25, put in Freund Co., Japan)
Spraying agent 1 of the following composition obtained by premixing 1050 ml of hydroxypropylcellulose solution (2% (W / V)) at 30 ml / min at room temperature at 0 rpm, and then spraying agent 2 at 60 g / min Coating, vacuum drying at 40 ° C for 16 hours, and 1 using a round sieve
4-32 mesh spherical nucleated granules are obtained.

[Spraying Agent 1] Lansoprazole 450 g Magnesium carbonate 336 g Graniu sugar 297 g Corn starch 300 g L-HPC 354 g (Hydroxypropoxyl group substitution degree: 10.0 to 13.0)
% (W / W), average particle size 30 μm or less) [Spraying agent 2] Graniu sugar 300 g Corn starch 246 g L-HPC (the same as above) 246 g The obtained granules 3800 g were put in a fluidized bed coating machine (Ogawara Co., Ltd.). , Blast 65 ° C, product temperature 40 ° C, 50 ml / min of enteric film solution of the following composition
And enteric coated to obtain enteric coated granules. Talc and light silicic acid anhydride are mixed with the granules and filled into No. 1 hard capsules using a capsule filling machine (Park Davis, USA) to produce capsules. [Enteric film liquid] Eudragit L30D-55 2018 g (solid content 650 g) Talc 182 g Polyethylene glycol 6000 60 g Titanium oxide 60 g Tween 80 27 g Water 4230 ml [Composition in one capsule] Enteric coated granules 368.8 mg Lansoprazole 30.0 mg Magnesium carbonate 22 4 mg Nonpareil 110.0 mg Graniu sugar 59.8 mg Corn starch 36.4 mg L-HPC 40.0 mg Hydroxypropyl cellulose 1.4 mg Eudragit L30D-55 44.6 mg Talc 13.4 mg Polyethylene glycol 6000 4.4 mg Titanium oxide 4.4 mg Tween 80 2.0 mg Talc 0.6 mg Light anhydrous silicic acid 0.6 mg No. 1 hard capsule 79.0 mg Total 449.0 mg

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, when a protein having a cell growth factor activity and a proton pump inhibitor are used together for the treatment of ulcer, a fast and high-quality therapeutic effect far exceeding conventional treatment can be obtained. In addition, the dose can be reduced as compared with the case where each is administered alone.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area A61K 31:44) A61K 31:44)

Claims (15)

[Claims] 1. A medicine comprising a protein having a cell growth factor activity in combination with a proton pump inhibitor. 2. The medicine according to claim 1, wherein the protein having cell growth factor activity is a protein having fibroblast growth factor activity. 3. The medicine according to claim 2, wherein the protein having fibroblast growth factor activity is a protein having basic fibroblast growth factor activity. 4. The medicine according to claim 3, wherein the protein having basic fibroblast growth factor activity is acid resistant. 5. A protein having basic fibroblast growth factor activity, wherein at least one of the cysteines constituting basic fibroblast growth factor (bFGF) is replaced with another amino acid, and the stability under acidic conditions is improved. The medicament according to claim 3, which is a bFGF mutein that is more potent than bFGF. 6. A recombinant bFG in which the cysteines at positions 70 and 88 of human bFGF are replaced with serines.
The medicine according to claim 5, which is F mutein CS23. 7. The medicine according to claim 1, wherein the proton pump inhibitor is a benzimidazole compound. 8. A benzimidazole compound is represented by the general formula (II): [In the formula, ring A may be substituted, R ¹ , R ³ and R ⁴ may be the same or different and each represents hydrogen, an alkyl group or an alkoxy group, and R ² may be an optionally substituted hydrocarbon group. And n is 0 or 1], or a salt thereof. 9. The medicine according to claim 8, wherein the compound represented by the general formula (II) is lansoprazole. 10. The medicine according to claim 1, which comprises a combination of recombinant bFGF mutein CS23 and lansoprazole. 11. A method for preventing or treating an ulcer.
The described medicine. 12. The medicine according to claim 11, wherein the ulcer is a peptic ulcer. 13. The pharmaceutical according to claim 1, which is a kit comprising a protein having a cell growth factor activity and a proton pump inhibitor. 14. A pharmaceutical composition comprising a protein having cell growth factor activity and a proton pump inhibitor.
The described medicine. 15. A method for enhancing cell growth factor activity of a protein having cell growth factor activity, which comprises using a proton pump inhibitor together.