JP2709839B2 - Prevention and treatment of pancreatic disease - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel medicine and veterinary medicine.
More specifically, blood sugar lowering action, pancreatic insulitis inhibitory action,
Novel anti-obesity, anti-fatty action various diabetes, acute pancreatitis, chronic pancreatitis, obesity, hyperlipidemia, diabetic neuropathy, atherosclerosis novel preventive or therapeutic agent or gastritis, constipation, gastrointestinal tract Novel infections, flatulence, irritable large intestine, caries, hepatitis, nephritis and other diseases, and novel preventive and therapeutic agents for diseases of the adrenal gland.

(Background technology)

In Europe, the United States and Japan, the population is aging at present and adult diseases are increasing. Diabetes is one of the adult diseases, and diabetes includes insulin-dependent diabetes.
pendent diabetes mellitus; hereinafter abbreviated as IDDM) and independent diabetes mellitus (hereinafter abbreviated as NIDDM).

IDDM mainly occurs at a young age.
It is known to occur at a high rate of one in 300 to 500 people at the age of one. Many diabetics are forced to give lifelong insulin injections, which poses a number of personal and social problems.

In addition, diabetes is a terrible disease that causes various metabolic abnormalities based on abnormal metabolism of insulin and sugar, thereby causing damage to blood vessels and nerves, thereby causing almost all organs to be affected. Medical treatment is urgently needed.

Oral diabetes drugs such as insulin therapy or sulfonylurea drugs and biguanides are currently widely used as a means of treating diabetes, but all of them only reduce blood sugar levels symptomatically and become curative drugs for diabetes. I haven't.

Although the etiology and etiological factors of diabetes remain unresolved, the genetic background and environmental factors are also considered important. Regarding environmental factors, virus infection and chemical substances are known, and the detailed mechanism of the pathogenesis is unknown, but an autoimmune mechanism against pancreatic islets is considered.

In addition, pancreatitis includes acute pancreatitis and chronic pancreatitis, and is accompanied by necrosis of the pancreas.
Aprotinin preparations, recently gabexate mesilate preparations and the like have been applied.

The present inventors have intended to develop a new type of drug that can be expected to cure curatively such as diabetes and acute pancreatitis and reduce symptoms.

[Disclosure of the Invention]

The present inventors sought such a drug among various naturally occurring peptides having high safety and intensively studied them.

As a result, serum thymic factor (FTS: Facteur thy-mique s
It has been found for the first time that nonapeptide known as erique) and its derivatives or salts thereof have an effect of suppressing an increase in blood glucose in rats administered with alloxan or streptozotocin. The present invention has been made based on such findings, and provides a preventive / therapeutic agent for various diseases including diabetes, which comprises the nonapeptide or a derivative thereof as an active ingredient.

One of the present inventors has previously reported that FTS is a therapeutic agent for various diseases associated with immunodeficiency such as multiple sclerosis, Guillain-Barre syndrome, inflammatory neuritis, multiple neuritis and other immune demyelinating diseases. Although such therapeutic agents have been provided (JP-A-58-52225), the nonapeptide known as FTS is useful for various diseases including diabetes.
The fact that it has a prophylactic and therapeutic effect is completely unexpected from the prior art and is first discovered by the present inventors. Thus, the present invention provides a nonapeptide having the following amino acid sequence: Alternatively, a prophylactic / therapeutic agent for diseases such as diabetes and pancreatitis, which comprises, as an active ingredient, an ester at the carboxyl group of asparagine at the C-terminus or a pharmaceutically acceptable salt thereof (excluding a Zn complex salt). Is provided.

The nonapeptide used in the present invention can be produced without difficulty by a peptide synthesis method in a liquid phase or a solid phase commonly used for peptide synthesis (these methods are described in JP-A-54-16425). No., U
SP.4301065). Alternatively, it can also be prepared by genetic engineering or cell engineering techniques.

The ester at the carboxyl group of asparagine at the C-terminus of the nonapeptide used in the present invention is a pharmaceutically acceptable ester of a carboxylic acid, and examples thereof include methyl ester, ethyl ester, propyl ester and isopropyl ester. Esters, n-butyl ester, isobutyl ester, tert-butyl ester, n-pentyl ester, isopentyl ester,
Neopentyl ester, tert-pentyl ester, n-
Hexyl ester, sec-hexyl ester, heptyl ester, octyl ester, sec-octyl ester, tert-octyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, hexadecyl ester, Octadecyl ester, nonadecyl ester, eicosyl ester, cyclopentyl ester,
Cyclohexyl ester, cycloheptyl ester, cyclooctyl ester, allyl ester, isopropenyl ester, benzyl ester, o-, m-, or p-
Chlorobenzyl ester, o-, m-, or p-fluorobenzyl ester, o-, m-, or p-bromobenzyl ester, o-, m-, or p-iodobenzyl ester, o-, m-, Or p-methylbenzyl ester, o-, m-, or p-ethylbenzyl ester, o
-, M- or p-isopropylbenzyl ester, cinnamyl ester, aminoethyl ester, o-, m
-Or p-aminobenzyl ester, o-, m- or p-nitrobenzyl ester, o-, m- or p-
Methoxybenzyl ester, o-, m-, or p-ethoxybenzyl ester, o-, m-, or p-aminophenethyl ester, α-furfuryl ester, α-thienylmethyl ester, α-pyridylmethyl ester, α
-Pyridylethyl ester, piperidinomethyl ester, α-piperidylmethyl ester, morpholinoethyl ester, α-morpholinylmethyl ester and the like.

The amide at the carboxyl group of asparagine at the C-terminus of the nonapeptide used in the present invention is an amide of a pharmaceutically acceptable carboxylic acid, and examples thereof include amide, methylamide, ethylamide, and propylamide. , Isopropylamide, n-butylamide, isobutylamide, tert-butylamide, n
-Pentylamide, isopentylamide, neopentylamide, tert-pentylamide, n-hexylamide,
sec-hexylamide, heptylamide, octylamide, sec-octylamide, tert-octylamide, nonylamide, decylamide, undecylamide, dodecylamide, tridecylamide, tetradecylamide, hexadecylamide, octadecylamide, nonadecylamide, eico Silamide, cyclopentylamide, cyclohexylamide, cycloheptylamide, cyclooctylamide, allylamide, isopropenylamide, benzylamide, o-, m-, or p-chlorobenzylamide, o-, m-, or p-fluoro Benzylamide,
o-, m-, or p-bromobenzylamide, o-, m
-Or p-iodobenzylamide, o-, m- or p-methylbenzylamide, o-, m- or p-ethylbenzylamide, o-, m- or p-isopropylbenzylamide, cinnamyl Amide, aminoethylamide, o-, m-, or p-aminobenzylamide, o
-, M-, or p-nitrobenzylamide, o-, m
-Or p-methoxybenzylamide, o-, m- or p-ethoxybenzylamide, o-, m- or p-
Aminophenethylamide, α-furfurylamide, α-
Thienylmethylamide, α-pyridylmethylamide, α
-Pyridylethylamide, piperidinomethylamide, α
-Piperidylmethylamide, morpholinoethylamide,
α-morpholinylmethylamide, methoxycarbonyl-
(Α-mercaptomethyl) methylamide, ethoxycarbonyl- (α-mercaptomethyl) methylamide and the like.

Examples of the above-mentioned pharmaceutically acceptable salts include acid addition salts at the amino group and base salts at the carboxyl group of the nonapeptide. Examples of the acid addition salts include salts with organic acids or inorganic acids, and examples thereof include formic acid, acetic acid, propionic acid, trifluoroacetic acid, tartaric acid, fumaric acid, malic acid, maleic acid, and oxalic acid. Acid, salts with carboxylic acids such as naphthoic acid, salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, and salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. can give.

As the above-mentioned base salt, a salt with an inorganic base, that is, an alkali metal salt, an alkaline earth metal salt, an ammonium salt,
Alternatively, a salt with an organic base, that is, a salt with an amine is mentioned, and examples thereof include a lithium salt, a sodium salt, a potassium salt, a calcium salt, an ammonium salt, a triethylamine salt, an ethanolamine salt, a tris salt, and a dicyclohexylamine salt. And so on.

The prophylactic / therapeutic agent for diseases such as diabetes and pancreatitis according to the present invention is prepared using a commonly used formulation means according to the dosage form. That is, an active ingredient substance selected from the above nonapeptides (hereinafter abbreviated as FTS) and derivatives thereof such as esters or amides or salts thereof,
It is prepared in an appropriate dosage form using a pharmaceutically acceptable carrier, excipient, diluent and the like as appropriate. The dosage form can be various dosage forms suitable for administration routes such as external use, oral administration, parenteral administration and the like.

The effects of the prophylactic and therapeutic agents according to the present invention have been confirmed by the following experiments. That is, 24 hours after the rats were fasted, alloxan (manufactured by Kanto Co.) or streptozotocin (hereinafter abbreviated as STZ: manufactured by SIGMA) was injected intravenously into the tail vein under anesthesia (iv). Was administered intravenously (single dose). Blood was collected from the jugular vein of this rat over time, and the blood glucose (glucose) value and the plasma anhydroglusheet value (hereinafter referred to as AG) were measured. Urine sugar was continuously collected from the bladder and stored for a predetermined period of time, and then measured as total urine sugar (hereinafter referred to as US). AG
Is a value that reflects the US well, the AG is small when the US value is large, and the AG increases when the US value decreases, and the US data is accurately grasped due to accidents in experimental procedures etc. This is a useful index that can be used as a guide when it is difficult (T.Yama
nouchi et al: Diabetes, 35 , 204-209, 1986).

Representative results are shown in Tables 1, 2, 3 and 4 below.
Shown in As shown in Tables 1 and 2, both in the alloxan diabetic rats and in the STZ diabetic rats,
In the blood glucose level of each of the FTS-administered groups up to 7 hours, the suppression of the increase in the blood glucose in the acute phase was apparent as compared with the control group. Furthermore, as shown in Table 4, in alloxan diabetic rats to which FTS was subcutaneously administered 20 hours and 44 hours after the first nonapeptide administration (frequent administration), the blood glucose level in the subacute phase 71 hours after administration was similar to the control group. Compared to
It was clearly suppressed. Also, after injecting the diabetes inducer first,
One hour later, even if FTS was intravenously injected, the increase in blood glucose at each time was suppressed.

Next, as shown in Table 3, in both diabetic rats,
In the control group, the US was as high as around 150 mg, and the AG was reduced to around 2.0 μg, whereas in the FTS-administered group, the US remained in a smaller amount. Correspondingly, a smaller decrease in AG was also confirmed. Furthermore, even in the case of frequent administration of FTS in Table 4, AG was higher than that in the control group. From the above
It is considered that FTS has a clear action of inhibiting the onset of hyperglycemia, that is, the action of suppressing the onset of diabetes.

Also, when the route of injection administration of FTS was changed to subcutaneous, intramuscular, or intraperitoneal, elevation of blood glucose and urine glucose was suppressed, respectively, as described above.

In addition, FTS was administered to spontaneously diabetic genetically diabetic mice and rats. FTS is used in NOD mice or BB rats, which are model animals of type I diabetes, or KK mice, which are well-known as spontaneously diabetic animals.
When intravenous injection, subcutaneous injection, intramuscular injection, and intraperitoneal injection were performed 1 to 3 times a week from 2 months, suppression of the onset of diabetes and a significant delay were observed. This was supported by changes in blood biochemical data, leukocyte counts and lymphocyte subsets, as well as histopathological findings of the pancreas.

In the BB rat experiment, 7 control groups and 7 FTS-administered groups were prepared, and phosphate buffered saline (PB
S), to the FTS administration group, PBS-dissolved FTS 500 μg / kg was intraperitoneally administered once a week, respectively, and the body weight was measured once a week. From around the age of 10 weeks, the increase in body weight of the control group slowed down and further decreased with time, whereas the body weight of the FTS-administered group showed an increase curve similar to that of a normal rat. The results are shown in FIG. Judging from blood AG, the final incidence of diabetes was 6/7 (86
%) And 2/7 (29%) in the FTS-administered group, a significant effect of FTS on suppressing the onset of diabetes was observed. In addition, even in the case of diabetes onset in the FTS administration group, the symptoms were milder than those in the control group, and the onset tended to be delayed.

These results demonstrated that FTS is useful not only as a hypoglycemic agent in diabetes but also as a therapeutic agent for roots and as a preventive agent. The effect is clearly apparent even when FTS is administered alone, but it is also possible to use insulin, oral diabetes drugs, etc. at the same time.

Furthermore, when the effects of FTS were examined in a dog model of acute pancreatitis and chronic pancreatitis, pancreatitis was found to be relaxed and treated.
Blood biochemical examination and histopathological examination revealed this. In other words, FTS can be a valuable medicine as a preventive / therapeutic agent for pancreatitis, and it can also be used to prevent diabetes associated with pancreatitis.
Is considered to be a desirable medicine in that it can be prevented and treated.

In addition, other experiments indicate that FTS has been used as a novel prophylactic / therapeutic agent for obesity, hyperlipidemia, atherosclerosis, diabetic, alcoholic, etc., as well as gastritis, constipation, gastrointestinal infection, flatulence. It has been clarified that it is also expected to be effective as a prophylactic / therapeutic agent for diseases such as irritable colon, caries, hepatitis and nephritis, and diseases of the adrenal gland.

In order to examine the toxicity of the active ingredient in the drug according to the present invention, 100 mg / kg of the active ingredient was administered daily to mice.
Although administered subcutaneously for 14 days, no abnormalities were observed in appearance. In addition, the active ingredient substance 30 mg / kg
Administered subcutaneously for days, both in appearance and in serum biochemistry,
No abnormalities were found in the results of the pathological dissection. Thus, the drug according to the present invention is a safe drug with extremely low toxicity, and can be administered for a long period of time.

Target animals to which the agent according to the present invention can be administered include, for example, humans and livestock such as cows, horses, pigs, sheep, goats, rabbits, dogs, cats, lions, elephants,
Giraffes, bears, gorillas, monkeys, chimpanzees and other zoos and other mammals, mice, rats, guinea pigs and other experimental animals, chickens and other poultry,
Examples include pet birds, reptiles, amphibians, and fish. The dose is usually 0.1 mg / kg body weight of these animals.
At a dose of μg to 500 mg / day, these may be administered in divided doses, for example, once to six times a day, and the dose may be appropriately increased or decreased depending on the age, symptoms, etc. of the administration subject. Although the administration route is not particularly limited, it can be injected intravenously, intramuscularly, intradermally, subcutaneously, or rectally. In addition, by preparing an ointment, it can be applied to the eye, oral cavity, nasal cavity, skin, etc., suppositories and jellies, eye drops, nasal drops, nasal and oral cavity absorbents, aerosols, sprays, It can also be administered as an oral preparation or the like. In order to prevent the rapid degradation or inactivation of the active substance in vivo, the active substance is converted into a suitable formulation component, for example, alcoholic,
It is also possible to prepare a preparation using an oily or fatty physiologically harmless solid or liquid material such as lecithin, or a suspension or a liposome thereof, and a long-lasting preparation.

The drug according to the present invention may be used for other drugs such as various antidiabetic drugs, therapeutic drugs for pancreatitis, antiobesity drugs, lipid-lowering drugs, antiatherosclerotic drugs, therapeutic drugs for peripheral neuropathy, hepatic drugs, renal drugs, etc. It can be administered together with a biological response modifier such as an activator, and these can be added to the preparation to enhance the clinical effect as a mixture.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited to these Examples.

Example 1 Injection vial formulation _{FTS · CH 3 COOH · 2H 2} O and (Mitsui Seiyaku Kogyo Co., Ltd.) 1 mg was dissolved in distilled water and filtered Jokinro, filled into vials and lyophilized.

EXAMPLE 2 Injectable ampoules preparation _{FTS · CH 2 COOH · 2H 2} O ( manufactured by Mitsui Chemical Industry Co., Ltd.) 5 mg was dissolved in physiological saline, filtered Jokinro, filled into ampoules.

Example 3 Injection for Subcutaneous Injection FTS · CH ₃ COOH · 2H ₂ O (manufactured by Mitsui Pharmaceutical Co., Ltd.) was suspended at 2 mg per unit dose in a 2% carboxymethylcellulose PBS (phosphate buffered saline) solution. Lipomal consisting of soy phosphatide (Huhtamaki OY / Leiras Pharmaceuti
cals) or Intral, an oil-in-water emulsion for intravenous use
It was mixed with ipid (Cutter Laboratories). Lipomal
When using FTS, the FTS-dissolved PBS solution and Lipomal were mixed in equal amounts.

When using Intralipid, 2.5 ml of FTS-dissolved PBS solution, T
0.1 ml of ween 80 (manufactured by Sigma Chemicals) and Intralipid
4.6 ml were mixed.

Example 4 Liposomal Formulations There are three types of liposome formulations having different charges, and these are further classified into four types in terms of structure.

There are three types of charge: neutral, positive, and negative. Structurally, multilamellar liposomes (MLV, multilamellar vesicle) and small unilamellar liposomes (SUV, small unilamellar vesicl)
e) and large unilamellar liposomes (LUV, large unil
amellar vesicle) and several films with a structure similar to LUV (REV, reverse-phase evaporation vesi)
cle) are known.

FTS-encapsulated neutral-charge liposomes Phosphatidylcholines, phospholipids such as sphingomyelin, and a cholesterol chloroform solution are mixed in a molar ratio of 2: 1, 4: 1, or 1: 1. Distilled under reduced pressure, 1 / 100-1 / 100
A solution of 0 equivalent of FTS in PBS (phosphate buffered saline) was added, and thoroughly mixed with a Vortex mixer to obtain MLV.

Further, SUV was obtained by sonication at a phase transition temperature (Tc) of the phospholipid or higher.

An aqueous calcium chloride solution was added to the obtained SUV, and the mixture was incubated at 37 ° C. for 1 hour to fuse. Then, EDTA was added, and the mixture was incubated at 37 ° C. for 30 minutes to remove Ca ^++.
V was obtained.

The method for preparing REV is as follows. That is, after the solvent was distilled off from the chloroform solution of lipid under reduced pressure, diethyl ether was added and dissolved in a sufficient amount to give PBS of FTS.
The solution was added and sonicated to form a uniform single phase solution. After the obtained solution was concentrated under reduced pressure at room temperature, a PBS solution was added and thoroughly mixed with a Vortex mixer to obtain REV.

FTS-encapsulated positively charged liposomes The preparation method is the same as that for the neutrally charged liposomes described above, except for the components of the lipid.

Phosphatidylcholines, phospholipids such as sphingomyelin, cholesterol, and positively charged higher aliphatic amines such as stearylamine in a molar ratio of 7: 2: 1 or 4: 1: 1.
And the mixture was used as a lipid component, and FTS was encapsulated in the same manner.

FTS-encapsulated negatively charged liposomes, phosphatidylcholines, phospholipids such as sphingomyelin, cholesterol and dicetyl phosphate,
Negatively charged higher aliphatic esters such as sulfatide were mixed at a molar ratio of 7: 2: 1 or 4: 1: 1 to obtain lipid components, and FTS was encapsulated in the same manner.

EXAMPLE 5 Ointment _{FTS · CH 3 COOH · 2H 2} O ( manufactured by Mitsui Chemical Industry Co., Ltd.) 2 mg was dissolved in purified water. Next, 25 g of white petrolatum, 20 g of stearyl alcohol, 4 g of HCO-60 and 1 g of glyceryl monostearate were mixed, mixed and prepared in advance, 12 g of propylene glycol, 0.1 g of methyl parahydroxybenzoate, 0.1 g of an aqueous solution of 0.1 g of propyl paraoxybenzoate (FTS Was added and thoroughly mixed to obtain an emulsion, and the mixture was cooled and solidified to continue the mixing operation.

Example 6 suppository _{FTS · CH 2 COOH · 2H 2} O ( manufactured by Mitsui Chemical Industry Co., Ltd.) 10 mg was dispersed in prewarmed Hadofuatsuto were a total volume of 2g.

Example 7 Nasal Capsule 0.05 mg of FTS was dissolved in 29.95 mg of Miglyol 812 neutral oil (Dynamite Nobel) under aseptic conditions. This solution was filled into a conventional unit-dose dispenser, which was mounted on a drive capsule before use.

Example 8 Nasal drops The following amounts of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride and EDTA-disodium salt were dissolved in distilled water at room temperature. Dissolve FTS in this solution,
Spent by membrane filter.

FTS 0.10mg sodium monohydrogen phosphate ・ 2H ₂ O 0.30mg sodium dihydrogen phosphate ・ 12H ₂ O 10.10mg benzalkonium chloride 0.10mg ethylenediaminetetraacetic acid-disodium salt (EDTA) 0.50mg sodium chloride 4.50mg distilled water 987.60 mg pH value 5.0 ± 0.3 Example 9 Nasal Spray Formulation 2 mg of FTS · CH ₃ COOH · 2H ₂ O (manufactured by Mitsui Pharmaceutical Co., Ltd.) is suspended in hydroxypropylcellulose or hydroxypropylmethylcellulose and sprayed with a spray formulation machine Agent.

Hereinafter, examples of pharmacological experiments and toxicity experiments on the drug of the present invention will be described.

Experimental Example 1 Effect of Single Administration of FTS on Diabetic Rats Male Wistar rats (body weight: 180 to 220 g) were fasted for 24 hours, and then anesthetized by intraperitoneal injection of sodium pentobarbital. Next, alloxan dissolved in 0.1 M phosphate buffer (pH 7.4) was dissolved in an amount of 75 mg / kg, or 15 mg / rat, or dissolved in 0.1 M sodium citrate buffer (pH 4.5).
TZ was injected intravenously via the tail vein at a dose of 75 mg / kg or 15 mg / rat. At the same time, the FTS-administered group was intravenously injected with 60 μg / kg of FTS into a rat, and the control group was intravenously injected with PBS. Blood was collected from the jugular vein over time to measure the blood glucose level and plasma AG level in the acute phase of diabetes.
Blood glucose is measured using the Fuji Dri Chem 2000 analyzer system (Fuji P
hoto Film Co.), AG value is gasli-quid chromatog of Shimadzu
It was measured by raphy. The results are shown in Tables 1, 2 and 3 below.

Experimental Example 2 Effect of Frequent Administration of FTS on Diabetic Rats Male Wistar rats (body weight 250 g) were treated as in Experimental Example 1, and alloxan 20 mg was injected intravenously via the tail vein. At the same time, FTS 15 μg in the FTS administration group /0.3 ml PBS / III was injected intravenously, and in the case of the control group, PBS was injected intravenously. After 20 hours and 4
Four hours later, 20 μg / 0.1 ml PBS / III was subcutaneously injected into the FTS administration group, and PBS was subcutaneously injected into the control group. The mice were sacrificed 71 hours later, and blood glucose levels and plasma AG levels in the subacute stage of diabetes were measured. Table 4 shows the results.

Experimental example 3 Long-term administration effect of FTS to BB rats BB rats were bred in a clean room, and divided into groups of 2 males and 5 females as a control group and 2 males and 5 females as a FTS administration group. , 100 μg / 0.3 ml PB for FTS administration group
S / animal and control group were injected with intraperitoneal injection of PBS once a week,
The body weight was measured once a week. The urinary glucose of each rat was examined over time, and the weight-decreased and weakened rats were sacrificed to Med.At that time, the BS, leukocyte count, lymphocyte subset, etc. were measured, and the histopathology of the pancreas was measured. An inspection was also performed. The results are shown in Table 5 and FIG.

Experimental Example 4 Toxicity test The active ingredient FTS was added to a group of 5 ddY 5-week-old male mice at 5 mice per group.
Subcutaneous administration of 50 mg / kg and 100 mg / kg each for 14 days each day showed no toxicity.

Experimental Example 5 Toxicity test 5 groups of 10-week-old wister rats were treated with the active substance
FTS 30 mg / kg was administered subcutaneously for 21 consecutive days, but no toxicity was observed.

As described above, the drug according to the present invention has an excellent preventive / therapeutic effect for the above-mentioned diseases, which cannot be obtained by conventional drugs and the like, in that it can be enhanced by immunization or activation of a biological defense system. It is a breakthrough. In particular, in the case of diabetes, FTS has been shown to have an effect of suppressing subacute or acute hyperglycemia even in single administration as well as in frequent administration to drug-induced diabetic rats. In some cases, FTS has the effect of suppressing the progression of the early stage of the onset of diabetes and preventing pancreatic islets of Langerhans from being damaged or damaged (preventing the establishment of IDDM). Thus, the present invention avoids such effort and pain from patients who have to undergo lifelong insulin injections due to destruction of the islets, and avoids frequent testing, dieting, etc. In terms of point, it will provide an innovative treatment.

In addition, once the onset of diabetes, the administration of the agent of the present invention caused the symptoms to be maintained with slight destruction of the island of La,
It can prevent progression to severe diabetes. The administration of the medicament according to the present invention is different from conventional oral diabetic drugs and symptomatic drugs such as insulin. There is hope for the development of a therapeutic method that aims at the root treatment of diabetes. In addition, by preventing the deterioration of diabetes by administering the drug according to the present invention, it can be expected to prevent the onset of neurological disorder, blindness, myocardial infarction, stroke, renal disorder, and the like, which are associated with and associated with diabetes. Furthermore, the agent according to the present invention is also useful for the treatment of pancreatic exocrine system diseases such as acute pancreatitis and chronic pancreatitis.In addition, with pancreatitis, insulin secretion is reduced due to destruction of the islet of La and is accompanied by diabetes. Even in cases, various symptoms can be ameliorated. The nonapeptide (FTS) used in the drug of the present invention is a peptide derived from an animal and is a natural substance, and therefore has a similar amino acid sequence.
Unlike FTS analogs (analogs), it is non-toxic in living organisms and does not have problems such as antigenicity and anafurax-shock. Therefore, the drug according to the present invention can be used as a safe and useful medicine for humans and animals.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of one example (Experimental Example 3) of a pharmacological experiment showing the effect of the drug of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display A61K 38/22 ADN A61K 37/24 ACS ADP ACV AEH AEH (72) Inventor Akira Kobayashi Mobara-shi, Chiba Togo 2141 Miyanodai Apartment No. 46 (72) Inventor Yusaku Ishizuka 21 Homonmaki Osato-cho, Naka-ku, Yokohama-shi, Kanagawa Prefecture No. 16425 (JP, A) JP-A-58-52225 (JP, A) U.S. Pat. No. 4,098,777 (US, A) Cellular Immunology, Vol. 91, No. 2 (1985) p. 325-335 Diabetes Research, Vol. 6, No. 1 (Jan. 1987) 21-27

Claims (3)

(57) [Claims] 1. A nonapeptide having the following amino acid sequence: Alternatively, prevention of pancreatic disease and other diseases characterized by containing an ester, amide or a pharmaceutically acceptable salt thereof (excluding Zn complex salt) at the carboxyl group of asparagine at the C-terminus as an active ingredient. -Therapeutic agents. 2. The disease preventive / therapeutic agent according to claim 1, wherein the pancreatic disease is diabetes. 3. The agent for preventing or treating a disease according to claim 1, wherein the pancreatic disease is pancreatitis.