Medical product and foodstuff or beverage for pancreas improvement

FIELD: medicine.

SUBSTANCE: invention refers to medicine, pharmaceutics and food industry and concerns a medical product, foodstuff or a beverage for pancreas improvement, containing compounds 9,19-cyclolanostan-3-ol and-or 24-methylene-9,19-cyclolanostan-3-ol as an active compound, and pancreas improvement method.

EFFECT: invention ensures improved clinical effectiveness.

19 cl, 3 tbl, 2 ex

 

The technical field to which the invention relates

The present invention relates to drug and food or drink for improving functions of the pancreas containing compound that can be safely ingested and has the effect to protect the cells of pancreatic internal secretion or improve the function of cells of pancreatic internal secretion.

Description of the prior art

The pancreas is an organ consisting of tissues of the glands of internal secretion called pancreatic islets (islets of Langerhans), and tissues, glands of external secretion, secreting gidrolizuemye enzymes.

In the islets of Langerhans present in β-cells, α-cells, δ-cells, cells of pancreatic polypeptide, etc, and they significantly affect the control of blood glucose and metabolism. Among them β-cells play a particularly important role as the cells producing insulin.

Diabetes mellitus is a frequently observed metabolic disorder found in about 10% of the adult population in Japan. In accordance with the epidemiology, dysfunction of β-cells of the pancreas, which is considered one of the causes of diabetes, while dysfunction of β-cells necessarily observed in indie is ibodov with hyperglycemia edge type, individuals demonstrating normal glucose tolerance also include individuals demonstrating expressed reduced function of β-cells at a rate of 30%. Moreover, it is specified that in adults, leading srednespetsialnyh way of life in modern Japan often develops insulin resistance to a greater or lesser extent, and it is assumed that the ratio of people suffering from insulin resistance, those who do not suffer from dysfunction of β-cells, glucose level in the blood is not increased, and those who suffer from dysfunction of β-cells, glucose level in blood increases to a level consistent with normal glucose tolerance, to a level consistent with hyperglycemia edge type (non-Patent document 1).

Currently, despite the fact that with the disorder of pancreatic cancer using therapy to activate spontaneous recovery of function of the pancreas, is based on eliminating the cause of pathological conditions or factors of any therapeutic method or agent for a reliable recovery of the functions of the pancreas after the reduction has not been used, and in the clinical field requires agents to protect cells of the pancreas or agents to improve the damaged cells of the pancreas.

Violation of options and pancreas refers to a pathological condition, which endocrine or exocrine function of the pancreas is reduced or abnormally raised.

As prior art against agents for treating disorders of the pancreas are agents containing as the active ingredient neurotrophic factors such as BDNF, (Patent document 1), agents containing as active ingredient a derivative of glycerol (Patent document 2), agents that improve the function of the pancreas, containing betacellulin proteins or their mutants (Patent document 3), and so on Up to the present time it was believed that BDNF is released from the Central part of the small DRG neuron with other transmitters during inflammation or nerve damage and participates in the maintenance of signal transduction pain through tyrosine phosphorylation of the NMDA receptor on cells of the dorsal horn (non-Patent document 2), and thus it was considered that it is limited to real world applications.

In addition, derivatives of glycerol disclosed in Patent document 2, are compounds described in Patent document 4, and represent the agents containing the activity antithrombotic-activating factor (PAF) for therapeutic and preventive treatment of DIC, shock, allergies, acute pancreatitis, cerebral convulsions when Subaru modelnom bleeding, etc, and also it was found that they have the effect to prevent treat and improve the progress of ORGANOTIN developed in the processes of organ preservation coronary heart condition, obstruction of blood flow caused by reperfusion of blood after transplant or surgery, etc. But it is difficult to argue that these agents are suitable for chronic diseases of the pancreas without these symptoms.

In addition, agents that improve the function of the pancreas, containing betacellulin proteins or mutants disclosed in Patent document 3 also have effect on undifferentiated pancreatic stem cells and thus activate their differentiation into pancreatic β-cells producing insulin, and the effect of promoting differentiation of undifferentiated stem cells into other cells of the pancreas, such as F-cells that produce pancreatic polypeptide, and the effect cannot be expected in terms of depletion of immature cells. In addition, although the mRNA of these proteins detected in various organs except the brain, for example, in the liver, kidney, pancreas, and so on, the details of their functions are almost completely clear, and, therefore, cannot be argued that they can be directly used for clinical cases.

In addition, in the patent to umenta 5 has been revealed, what compounds having lanolinovy skeleton or 3,4-scalenotomy skeleton, have activity enhance the action of insulin. The effect of these compounds is to strengthen the action of insulin to stabilize differentiation of adipocyte, and its effect on diseases of the pancreas is unknown.

In addition, as prior art in respect of compounds with Cyclopentanone skeleton, was discovered a method of obtaining cyclobutanol or cyclopentolate ester of ferulic acid (Patent document 6), and tranquilizers (Patent document 7), lipid-lowering drugs (Patent document 8), interferon inductors (Patent document 9), agents that induce ovulation (Patent document 10), and drugs for the prevention of carcinogenesis (Patent document 11), containing as an active ingredient 24-methylenecycloartanol. In addition, to date there have been reported that compounds having Cyclopentanone skeleton, have a protective effect on the function of the pancreas, or have protection act of pancreatic tissue.

The genusAloein the familyLiliaceaeis a group of plants, including Aloe vera (Aloebarbadensis Miller), Aloe arborescens (Aloearborescens Miller var. natalensis Bergerand so on, and empirically it is known that they have the different efficiency. Known levels of art concerning the use of plants of the genusAloeinclude immunomodulating polysaccharides (Patent document 12), agents that improve the immunosuppression containing botanology fraction of aloe extract or aloin (Patent document 13), agents that inhibit protein synthesis of HSP60 family containing derivatives alone (Patent documents 14-16), proteins having the activity of a lectin obtained from the peel of the leaf aloe Vera (Patent document 17), application for improving the level of glucose in the blood (non-Patent document 3-5, Patent document 18-21), etc.

[Patent Document 1] International Publication Number WO 00/62796

[Patent document 2] Japan Patent Laid Room 07-285866

[Patent document 3] Japan Patent Laid Room 09-188630

[Patent document 4] Laid the Japan Patent Number 10-045604

[Patent document 5] Laid the Japan Patent Number 10-330266

[Patent document 6] Paved the Japan Patent Number 50-160262

[Patent document 7] Laid the Japan Patent Number 55-153719

[Patent document 8] Laid the Japan Patent Number 59-027824

[Patent document 9] Laid the Japan Patent Number 59-036623

[Patent Document 10] Laid the Japan Patent Number 59-073600

[Patent document 11] Laid the Japan Patent Number 2003-277269

[Patent document 12] Unexamined Publication International is a native of the patent Application in Japanese Language Room 2001-520019

[Patent document 13] Laid the Japan Patent Number 08-208495

[Patent document 14] Laid the Japan Patent Number 10-120576

[Patent document 15] Laid the Japan Patent Number 10-045604

[Patent document 16] Laid the Japan Patent Number 10-036271

[Patent document 17] Laid the Japan Patent Number 09-059298

[Patent document 18] Laid the Japan Patent Number 60-214741

[Patent document 19] Laid the Japan Patent Number 2003-286185

[Patent document 20] U.S. Patent Number 4598069

[Patent document 21] Application for U.S. Patent Publication Number 2003/0207818

[Non-patent document 1] Nippon Rinsho, Room 748, T. 1,

pages 615-617, 1999

[Non-patent document 2] Nippon Rinsho, Room 808, T. 2,

pages 405-409, 2002

[Non-patent document 3] Phytomedicine, I. 3, pp. 245-248, 1996

[Non-patent document 4] Phytotherapy Research, So 15, pp. 157-161, 2001

[Non-patent document 5] the Study of Herbal medicine, So 7, pages 37-42, 1993

Disclosure of Invention

The aim of the present invention to provide a drug and food or drink, suitable for improving the functions of the pancreas that contain no adverse ingredients for medicines and food product or beverage, from raw materials that can be safely taken from the point of view, based on experience, for the food product and easy recip is but.

The authors of the present invention conducted a thorough investigation to achieve the above purposes. As a result, they found that compounds having Cyclopentanone skeleton, can be safely ingested, and they had activities for the improvement of the functions of the pancreas, especially activity to protect cells pancreatic internal secretion or improve the function of cells of pancreatic internal secretion. The present invention was achieved on the basis of the above discoveries.

Thus, the present invention relates to drug and food or drink for improving functions of the pancreas that contain as active ingredient a compound that Cyclopentanone skeleton.

More specifically the present invention relates to drug and food or drink for improving functions of the pancreas that contain as active ingredient a compound represented by the following General formula (1).

In this formula, R1 represents an unbranched or branched alkyl group containing from 6-8 carbon atoms, which may contain no double bond or contain 1 or 2 double bonds and may not contain the Hydra is xinnuo group and carbonyl group, or contain 1 or 2 hydroxyl groups and carbonyl groups, R2 and R3 each independently represents a hydrogen atom or methyl group, and R4 forms C=O with the carbon atom that is part of a cycle, or is a group represented by any of the following formulas.

According to a preferred variant implementation of a drug and food or drink in accordance with the present invention improve the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the function of cells of pancreatic internal secretion.

According to a preferred variant implementation of the above medicines and food product or beverage R2 and R3 of the above compounds represent a methyl group, and R4 represents a hydroxyl group. In addition, according to a preferred variant implementation of the above medicines and food product or beverage R1 of the above compounds represented by any of the following formulas.

-CH2-CH2-CH2-CH(CH3)2

-CH2-CH2-CHRa-C(CH3)2Rb

(where Ra represents any Deputy from hydrogen atom, hydroxyl or methyl group, and Rb represents a hydrogen atom or hydroxyl group)

-CH2 -CH2-CH(CH2CH3)-CH(CH3)2

-CH2-CH2-CHRc-C(CH3)=CH2

(where Rc represents any Deputy from hydrogen atom, hydroxyl or methyl group)

-CH2-CH2-C(=O)-C(CH3)=CH2

-CH2-CH2-C(=CH2)-CH(CH3)2

-CH2-CH2-CH=C(CH3)2

-CH2-CH=C(CH3)-CH(CH3)2

-CH2-CH2-C(=CHCH3)-CH(CH3)2

In addition, according to a particularly preferred variant the execution of the above drug and food or drink above connection is a 9,19-cyclopentan-3-ol and 24-methylene-9,19-cyclopentan-3-ol.

In addition, according to a preferred variant of execution of the above medicinal product contains from 0.001 to 10% of the above compound by dry weight.

In addition, according to a preferred variant of execution of the above food product or beverage contains from 0.0001 to 1% of the above compound by dry weight.

The present invention additionally relates to a medicinal product to improve the functions of the pancreas containing extract with an organic solvent or hot water extract of a plant, or part thereof as the active ingredient, and contains from 0.01 to 10% by dry weight compounds, represented by the above General formula (1), and food or drink for improving functions of the pancreas, which contains the extract with an organic solvent or hot water extract of a plant, or part thereof as the active ingredient and contains from 0.0001 to 1% by dry weight of the compounds represented by the above General formula (1), and preferably, to improve the functions of the pancreas was in the protection of cells of pancreatic internal secretion or improve the function of cells of pancreatic internal secretion. In addition, according to a preferred variant implementation of a drug and food or drink in accordance with the present invention the above plant is preferably a plant of the familyGramineaeorLiliaceaeand according to a particularly preferred variant the execution of the above named plant of the familyLiliaceaeis the plant referred to the genusThe Aloe.

The present invention additionally relates to the above food product or drink with attached indicating that they are used to improve the functions of the pancreas.

Further, the above mentioned drug and food or drink is also essentially nazyvautsa the drug and food or drink in accordance with the present invention".

The present invention additionally relates to the use of compounds represented by the above chemical formula (1)or its containing composition to obtain drugs to improve the functions of the pancreas. According to a preferred version of the application according to the present invention improve the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion. According to a preferred version of the application according to the present invention is the above compound or containing composition contains from 0.001 to 10% of the above compound by dry weight.

The present invention additionally relates to a method for protection of cells of pancreatic internal secretion or enhance cell function, which contains the introduction of the compounds represented by the above chemical formula (1)or its containing composition to the individual cells of pancreatic internal secretion which must be protected or function of the cells which should be improved. According to a preferred variant implementation of the method in accordance with the present invention improve the functions of the pancreas is before the storage cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion. According to a preferred variant of the process according to the present invention, the above composition contains from 0.001 to 10% of the above compound by dry weight.

Below, preferred embodiments of the present invention will be explained in detail. However, the present invention is not limited to the following preferred options perform and can be a free way changed within the framework of the present invention.

According to one variant of execution drug and food or drink in accordance with the present invention contains as active ingredient a compound that Cyclopentanone skeleton and having the activity of improving the function of the pancreas, especially the activity of protection of cells of pancreatic internal secretion, or activity improve the function of cells of pancreatic internal secretion (hereinafter also referred to as "compound in accordance with the present invention"). Cyclopentanone skeleton indicates the connection represented by the following General formula (2).

Specific examples of the compounds containing Cyclopentanone skeleton include compounds represented by the above General formula (1). The number of double bonds, prisutstvie is participating in the connection, containing Cyclopentanone skeleton is not specifically limited. In addition, the number of double bonds present in the cycle, also not specifically limited. When there are two or more double bonds, they can be paired. The drug and food or drink according to the present invention may contain two or more types of compounds in accordance with the present invention.

In the compound of the above General formula (1) in accordance with the present invention R1 is an unbranched or branched alkyl group containing from 6-8 carbon atoms, which may contain no double bond or contain 1 or 2 double bonds and may not contain a hydroxyl group and carbonyl group, or contain 1 or 2 hydroxyl group and carbonyl group, R2 and R3 each independently represents a hydrogen atom or methyl group, and R4 forms C=O with the carbon atom that is part of a cycle, or is a group represented by any of the following formulas.

In the above General formula (1) R1 preferably represents any of groups represented by the following formulas.

(i)- (CH2-CH2-CH2-CH(CH3)2

(ii) -CH2-CH2-CHRa-C(CH3)2Rb

(where Ra performance is made by any Deputy of a hydrogen atom, hydroxyl or methyl group, and Rb represents a hydrogen atom or hydroxyl group)

(iii) -CH2-CH2-CH(CH2CH3)-CH(CH3)2

(iv) -CH2-CH2-CHRc-C(CH3)=CH2

(where Rc represents any Deputy from hydrogen atom, hydroxyl or methyl group),

(v) -CH2-CH2-C(=O)-C(CH3)=CH2

(vi) -CH2-CH2-C(=CH2)-CH(CH3)2

(vii) -CH2-CH2-CH=C(CH3)2

(viii) -CH2-CH=C(CH3)-CH(CH3)2

(ix) -CH2-CH2-C(=CHCH3)-CH(CH3)2

In addition, in the above General formula (1) R2 and R3 preferably represent a methyl group, and R4 represents a hydroxyl group.

Most preferred as the above compounds are compounds represented by the following formulas, 9,19-cyclopentan-3-ol (formula (3)and 24-methylene-9,19-cyclopentan-3-ol (formula (4)).

Thus, 9,19-cyclopentan-3-ol is a compound represented by the above General formula (1), where R2 and R3 represent a methyl group, R4 represents a hydroxyl group, and R1 represents a group represented by the above formula (i). In addition, 24-m is tilen-9,19-cyclopentan-3-ol is a compound, represented by the above General formula (1), where R2 and R3 represent a methyl group, R4 represents a hydroxyl group, and R1 represents a group represented by the above formula (vi).

Connection in accordance with the present invention may be cycloartenol (formula (5)or 24-methylcyclopentanol (formula (7)). Both of these compounds are compounds represented by the above General formula (1), where R2 and R3 represent a methyl group, R4 represents a hydroxyl group, and R1 represents a group represented by the above formula (vii), in cycloartenol or a group represented by the above formula (ii) (Ra = CH3, Rb = H), 24-methyl-cycloartenol.

Connection in accordance with the present invention can be chemically obtained in a known manner of production. For example, methods of obtaining cycloartenol (formula (5)and 24-methylenecycloartanol (trivial name of 24-methylene-9,19-cyclopentan-3-ol, formula (4))were disclosed in Laid the Japan Patent Number 57-018617, and the method of receiving cycloartenol (formula (6)) of γ-oryzanol and the method of synthesis of compounds with the use of the product of its hydrolysis as a source material disclosed in Laid the Japan Patent Number 2003-277269. In addition, when estately R1 of General formula (1) contains a double bond, can be obtained from various derivative compounds using methods of converting part of a double bond to the aldehyde by the reaction of ozone decomposition and binding of phosphonate, methods of addition of hydrogen to a part of a double bond or a method of oxidizing part of a double bond with ozone to convert it into an aldehyde or acid. In addition, methods of production is not limited by methods of chemical synthesis, and compounds can be biologically produced by using a microorganism, etc., alternatively, they can be produced using enzymes derived from microorganisms.

The drug and food or drink in accordance with the present invention may contain one type or two or more arbitrary types of the above-mentioned compounds.

It is known that compounds having Cyclopentanone skeleton found in plants of the familiesLiliaceae, Leguminosae, Gramineae, Solanaceae, Musaceaeand so on (see Phytochemistry, U.S.A., 1977, Vol. 16, pp.140-141; Handbook of phytochemical constituents of GRAS herbs and other economic plants, 1992, U.S.A., CRC Press; Hager''s Handbuch der Pharmazeutischen Praxis, Vols. 2-6, 1969-1979, Germany, Springer-Verlag, Berlin). Accordingly, the compounds can be extracted from these plants using this method, as extrac the Oia organic solvent or extraction with hot water.

In the present invention although the connection in accordance with the present invention can be purified by the methods described above, etc. may also be used such composition, as an extract of a plant or part thereof, provided that it contains an effective amount of the compounds.

Specifically, examples of the plant belonging to the familyLiliaceae,include plants belonging tothe genus AloeorAllium.Examples of plants of the genusAloeinclude Aloe vera(Aloe barbadensis Miller), Aloe ferox Miller, Aloe africana Miller, Aloe arborescen Miller var. natalensis Berger, Aloe spicata Bakeretc.

Despite the fact that when the connection is in accordance with the present invention or its containing compositions can be used above the whole plant, it is preferable to use his mesophyll (clear gel portion). Such plant or part thereof is ground using a homogenizer, etc. and, thus, szhizhajut, and connection in accordance with the present invention or its containing composition is extracted from the crushed product using an organic solvent or hot water. Examples of the organic solvent include alcohols such as methanol, ethanol and butanol; esters such as methyl acetate, ethyl acetate, propyl and butyl acetate; ketones such as acetone and metriso telethon; ethers, such as diethyl ether and petroleum ether; hydrocarbons such as hexane, cyclohexane, toluene and benzene; halogenated hydrocarbons, such as tetrachloride, dichloromethane and chloroform; heterocyclic compounds such as pyridine; glycols such as ethylene glycol; polyhydric alcohols such as polyethylene glycol; nitrile solvents such as acetonitrile, mixtures of these solvents, etc. in Addition, these solvents may be anhydrous or aqueous. Among these solvents, particularly preferred are a mixture of ethyl acetate/butanol (3:1) and a mixture of chloroform/methanol (2:1).

As extraction method : you can use the method used for conventional extraction component plants. Usually use, for example, a method of heating under reflux 1-300 parts by weight of an organic solvent with 1 part by weight of fresh plant or dried plants with heating at the temperature of boiling point of the solvent or lower and stirring or shaking, or the way to perform the extraction by ultrasonic treatment at room temperature. The raw extract can be obtained by extraction of the insoluble substances from the extraction liquid using a suitable method such as filtration or centrifugation.

Neo is operated extract can be purified by various types of chromatography, such as normanniana or ortofena column chromatography on silica gel. When normalizes column chromatography on silica gel as a solvent for elution using a gradient mixture of chloroform/methanol, a compound in accordance with the present invention elute with the dilution factor chloroform:methanol = approximately 25:1. In addition, when obetovannoi column chromatography on silica gel as a solvent for elution using a mixture of hexane/ethyl acetate (4:1), a compound in accordance with the present invention elute in fractions, eluruumi at an early stage.

The resulting fraction can be further purified by HPLC, etc.

In addition, the connection used for the present invention can also be obtained by means of chemical synthesis or biological or enzymatic method using microorganisms, enzymes, etc.

Connection structure in accordance with the present invention can be confirmed, for example, mass spectrometry (MS)spectroscopy nuclear magnetic resonance (NMR), etc.

Connection in accordance with the present invention has the effect of improving the function of the pancreas, in particular the action of the protection of cells of pancreatic internal secretion or de is a result improve the function of cells of pancreatic internal secretion. In this respect, it can be used as an active ingredient of a drug and food or drink for improving functions of the pancreas, in particular the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion. In the present invention the protection of cells of pancreatic internal secretion involves the protection of cells of pancreatic internal secretion from denaturation due to various causes or prevention of a decrease in the ability of production of insulin by the cells of pancreatic internal secretion. In addition, the improvement of the functions of the cells of pancreatic internal secretion involves increased production of insulin by the cells of pancreatic internal secretion, the ability of producing insulin which decreases. Denaturation of cells of pancreatic internal secretion, or protection of cells of pancreatic internal secretion, or improvement of the functions of cells of pancreatic internal secretion can be assessed by observation under the microscope part of the pancreatic tissue of the animal or by measuring the levels of insulin in serum.

Through the above steps is connected to the e in accordance with the present invention can prevent a reduction in the ability of production of insulin by the cells of pancreatic internal secretion and increase the capacity of production of insulin by the cells pancreatic internal secretion, the ability of producing insulin which decreases.

In respect of mice db/db used in the examples below, it is known that damage to the pancreas is observed with age in the course of a week (Science, 153, 1127-1128, 1966). Despite this, it was reported that if these mice to enter N-acetyl-L-cysteine, vitamin C and vitamin E as compounds having the effect of antioxidants, in combination, a decrease in the number of β-cells in the pancreas can be partially prevented (Diabetes, 48, 2398-2406, 1999), although the dose of N-acetyl-L-cysteine is 100 g/60 kg, and is expected to require the introduction in extremely high doses. In contrast, in accordance with the present invention can be expected that the protection of cells of pancreatic internal secretion or action improve the function of cells of pancreatic internal secretion can be achieved with a small dose.

Medicinal product in accordance with the present invention can be used as an active ingredient means for the prevention or treatment of diseases caused by hypofunction of cells of pancreatic internal secretion, such as, for example, a disorder of the function of the pancreas in acute pancreatitis, chronic pancreat what those diabetes type I and diabetes type II, hypofunction of the pancreas, associated with senile decline in insulin secretion, etc. in Addition, because the connection is in accordance with the present invention shows low toxicity, it can also be used in conjunction with antitumor agent in the treatment of pancreatic cancer. Preferably, the agent used for the treatment of hyperglycemia among diseases associated with reduced ability to produce insulin, are not included in the scope of the medicinal product in accordance with the present invention.

In addition, because the skin of the leaf Aloe vera contains barbaloin and aloe-emodin, has a laxative effect, it is conventionally considered adverse as a drug and food or drink for which is not expected laxative effect. Thus, it is preferable that the composition containing the compound in accordance with the present invention, did not contain these ingredients. In addition, also as the active ingredient of the medicinal product for protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion, you can use Aloe vera mesophyll and the product of its grinding.

Connection in accordance with the present the invention can be used as an active ingredient of a medicine and a food or beverage in accordance with the present invention in pure form. In addition, the extract with an organic solvent or hot water extract of a plant or part thereof containing the compound in accordance with the present invention (hereinafter referred to as "extract, etc."), can also be used as an active ingredient of a drug and food or drink. In this case, the above extract, etc. that must be contained in a medicinal product, preferably contains from 0.001 to 10% by dry weight, more preferably from 0.01 to 1% by dry weight, particularly preferably from 0.05 to 1% by dry weight of the compounds in accordance with the present invention. In addition, the above extract, etc. that must be contained in the food product or beverage, preferably contains from 0.0001 to 1% by dry weight, more preferably from 0.001 to 1% by dry weight, particularly preferably 0.005 to 1% by dry weight of the compounds in accordance with the present invention. The above extract, etc. may contain two or more types of compounds in accordance with the present invention. In addition, the above extract, etc. may be a solution or can also be lyophilized or spray dried in the usual way, and it can be stored or used as a powder.

As a medicinal product in accordance the present invention the connection in accordance with the present invention or its containing composition, such as extract, etc. in pure form or in combination with pharmaceutically acceptable carrier, can be orally or parenterally administered to the mammal, including humans. In the medicinal product in accordance with the present invention the connection in accordance with the present invention may be a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include metal salts (inorganic salts)and organic salts, including, for example, listed in the "Remington''s Pharmaceutical Sciences," 17th edition, p.1418, 1985. Specific examples include, without limitation, salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, Hydrobromic and sulfate, and salts of organic acids such as malate, maleate, fumarate, tartarate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluensulfonate, pamoate, salicylate and stearate. In addition, the salt may be a salt with a metal such as sodium, potassium, calcium, magnesium and aluminum, or a salt with amino acid such as lysine. In addition, a solvate, such as the hydrates of the above compounds or pharmaceutically acceptable salts, are also within the present invention.

Dosage form of the drug in accordance with the present invention are not specifically limited and can be appropriately in the bran depending on therapeutic purpose. Its specific examples include tablet, pill, powder, solution, suspension, emulsion, granule, capsule, syrup, suppository, injection, ointment, band-AIDS, eye drops, nasal drops, etc. For cooking can be used additives used in conventional therapeutic or prophylactic agents for diseases of internal organs such as the pancreas, as pharmaceutical carriers, such as excipients, binders, agents for cleavage, lubricants, stabilizers, flavoring agents, diluents, surfactants and solvents for injection. In addition, provided that the effect in accordance with the present invention is not lost, the connection in accordance with the present invention or its containing extract, etc. may be used in combination with other drugs, with the effect of improvements in the flow, or prevention of disease of the pancreas.

Despite the fact that the number of connections in accordance with the present invention or its containing extract, etc. contained in the medicinal product in accordance with the present invention is not specifically limited and can be appropriately selected, the number may be, for example, from 0.001 to 10% by weight, preferably from 0.01 d is 1% by weight, particularly preferably from 0.05 to 1% by mass in units of the number of connections in accordance with the present invention.

Using medicines in accordance with the present invention can be prevented various diseases, complications, etc., which developed due to hypofunction of cells of pancreatic internal secretion, and the risk of these diseases, complications and so on can be reduced.

Examples of such various diseases and complications developed due to hypofunction of cells of pancreatic internal secretion include nervous disorders, nephropathy, retinopathy, cataract, macrovascular disease, diabetes, etc.

The introduction of the medicinal product in accordance with the present invention are not specifically limited and can be appropriately selected according to the method of treatment of the target disease. In addition, the route of administration is preferably determined depending on the dosage form, age, gender, and other characteristics of patients, severity of patient symptoms, etc.

The dose of the active ingredient in a medicinal product in accordance with the present invention is appropriately selected depending on the dosage, age, sex, severity of disease, other characteristics of patients, etc. the Number is about connections in accordance with the present invention as the active ingredient are usually chosen from the range of preferably from 0.001 to 50 mg/kg/day, more preferably from 0.01 to 1 mg/kg/day, as estimated dose. In addition, when using the extract etc. containing the compound in accordance with the present invention, the dry weight of the extract, etc. to choose from a range preferably from 0.1 to 1000 mg/kg/day, more preferably from 1 to 100 mg/kg/day, as estimated quantity. In any case, the dose can be taken once or several times as divided portions a day.

Connection in accordance with the present invention or its containing extract, etc. may be added to food or drink. The shape and property of the food or drink is not specifically limited provided that the effect of the active ingredient is not reduced, and food or drink can be taken orally, and they can be produced in the usual manner with the use of raw materials normally used for food or drink except that add to the above active ingredient.

The number of compounds in accordance with the present invention or its containing extract, etc. contained in the food product or beverage in accordance with the present invention is not specifically limited and can be appropriately selected. For example, a connection in accordance with the present image is Itanium or containing extract, etc. contained in the food product or beverage in an amount of from 0.0001 to 1% by weight, preferably from 0.001 to 1% by weight, particularly preferably 0.005 to 1% by weight, in units of number of connections in accordance with the present invention.

Food product or a beverage in accordance with the present invention can be used for various applications, which use the effect of protection of the cells of pancreatic internal secretion or effect improve the function of cells of pancreatic internal secretion. For example, they can be used as a food product or a beverage suitable for individuals with low production of insulin, individuals with a weakened function of insulin", "individuals with concerns regarding the functions of the pancreas", food product or beverage, useful to reduce or eliminate risk factors of diseases associated with lifestyle, such as diabetes, caused by hypofunction of the pancreas and pancreatitis caused by excessive alcohol consumption and stress.

In respect of the food or beverage in accordance with the present invention, the expression "protection of cells of pancreatic internal secretion or improve the functions of the cells of the pancreas internal before the AI" means, what treatment or prevention of various health disorders caused by hypofunction of cells of pancreatic internal secretion, and protection functions of the islets of Langerhans", "improvement of the functions of the islets of Langerhans", "protection functions β cells, improving functions of β cells, increase the production of insulin, preventing decrease the production of insulin, increasing the activity of insulin, preventing reduction of the activity of insulin, and so illustrates the present invention as terms having a similar meaning of the above term "protection cells of pancreatic internal secretion or improve the functions of the cells of the pancreas internal secretion".

In addition, a food product or a beverage in accordance with the present invention useful for the prevention of disease caused by hypofunction of cells of pancreatic internal secretion, such as for example, a disorder of the function of the pancreas in acute pancreatitis, chronic pancreatitis, diabetes type I and diabetes type II, hypofunction of the pancreas, associated with senile decline in insulin secretion, etc. in Addition, a food product or a beverage in accordance with the present invention can be used for the pros who ACTICE various diseases, complications, etc. caused by hypofunction of cells of pancreatic internal secretion, and can reduce the risk of these diseases, complications, etc. in Addition, since the connection in accordance with the present invention shows low toxicity, food product or beverage in accordance with the present invention used with antitumor agent in the treatment of cancer of the pancreas, is also useful for the patient.

Examples of such various diseases and complications caused by hypofunction of cells of pancreatic internal secretion include nervous disorders, nephropathy, retinopathy, cataract, macrovascular disease, diabetes, etc.

Food product or a beverage in accordance with the present invention is preferably sold as food or drink with the accompanying indication that the food or drink is used for protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion, for example, "food or drink containing a compound which has the effect of protection of the cells of pancreatic internal secretion and the effect of improving the function of cells of pancreatic internal secretion, marked as 'To protect cells in the gastric glands of internal secretion or improve the functions of the cells of pancreatic internal secretion'", "food or drink containing an extract of the plants identified as 'For protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion'", "food or drink containing an extract of Aloe vera, marked as 'To protect cells pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion'" etc.

The language used for such instructions, as noted above, it is not necessarily limited to the expression "To protect cells pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion", and any other wording that expresses the effect of the protection cells of pancreatic internal secretion or effect of improving the functions of cells of pancreatic internal secretion, certainly falls within the scope of the present invention. It is also possible in itself formulation, for example, specifying, based on different applications, allowing consumers to recognize the effect of protection of the cells of pancreatic internal secretion or effect improve the function of cells of pancreatic internal secretion. Examples include indications Suitable for individuals with low levels of producer the of insulin", "Suitable for individuals who have impaired the function of insulin", "Useful for reducing or eliminating risk factors of diseases associated with lifestyle, such as diabetes mellitus, is caused by decreased activity or level of production of insulin, pancreatitis, caused by excessive alcohol consumption and stress, and so on

Above, the term "instruction" includes all actions for the message consumer to the above application and any instructions, mentioning or explaining the above application that fall under the "instructions" in accordance with the present invention, regardless of the purpose, content, target material, media, etc. instructions. However, the indication is preferably performed with the phrase, allowing consumers to directly recognize the above application. Specific examples include the actions as instructed by the above-noted application on the goods or packaging of goods related to food product or beverage in accordance with the present invention, the steps for the appointment, supply, demonstrations for the appointment or the supply or import of such goods or packaging of goods, noted above application, demonstration, or dissemination of advertisements, price lists or bottom of the bills relating to goods, indicating marked what about the above application, or providing information, including content specifying noted above, the use of electromagnetic means (the Internet, etc) and so on

This indication is preferably an indication approved by the administration and so on (for example, an indication in the form, based on the approval, qualified on the basis of any of the various legal systems, submitted by the administration), and it is particularly preferably represents an indication of the advertising materials in the areas of marketing such as packaging, containers, catalogs, brochures and advertising at the point of sale, other documents etc.

Examples of instructions further include instructions as a healthy food product, a functional food product, a food product to power the intestinal system, food for special dietary uses, a food product with the declared nutrient function, imaginary medicine, etc, as well as indications approved by the Ministry of health, Ministry of labour and social protection, for example, instructions, approved on the basis of food for specific medical applications and similar systems. Examples of the latter include instructions as food for specific medical applications, specify as food for specific medical applications skilled at what was stated on the usefulness of the health guidance on the impact on the structure and functions of the body, specifying the alleged decrease the risk of disease, etc, and, more specifically, typical examples include instructions as food for specific medical applications (in particular, the guidelines apply to health)presented in enforcing the provisions of the law on health protection (the Japanese Ministry of health, Ministry of labour and social protection, Ministerial decision No. 86, April 30, 2003), and similar instructions.

Examples

The present invention will be more specifically explained with reference to the following examples. However, the scope of the present invention is not limited to the following examples.

Examples of preparing compounds having Cyclopentanone skeleton will be given below.

[Example 1 retrieve]

9,19-cyclopentan-3-ol (formula (3)), 24-methylene-9,19-cyclopentan-3-ol (formula (4)), cycloartenol (formula (5)and 24-methylcyclopentanol (formula (7)) were obtained by the method described below.

To 8.0 g of γ-oryzanol (Oryza Oil & Chemical Co., Ltd.) added 250 ml of distilled water, 50 g of sodium hydroxide, 150 ml of isopropanol and 150 ml of ethanol and 150 ml of methanol and the mixture was heated under reflux for chasov using mantle. After the reaction, the reaction mixture was poured into 1300 ml of water, and the produced white precipitate was isolated by filtration with suction. For washing off the remaining alkali residue obtained by filtration, besieged in 1000 ml of water and then collected by filtration with suction. This procedure was repeated twice, and eventually the remainder liofilizirovanny under reduced pressure to obtain 5,91 g of the hydrolyzate of oryzanol. This hydrolysate was purified by HPLC to obtain 2435 mg of cycloartenol and 1543 mg 24-methylene-9,19-cyclopentan-3-ol.

The resulting cycloartenol used for the synthesis of 9,19-cyclopentan-3-ol. In a sealed autoclave filled cycloartenol in the amount of 302 mg, 150 ml of isopropanol and 1.0 g of powdered 5% of the catalyst is palladium/carbon, the internal atmosphere was replaced by nitrogen gas and then injected hydrogen gas with a pressure of 3 kg/cm2. The mixture was heated with stirring and when the temperature reached 50°C, the hydrogen pressure was brought to 5 kg/cm2. The reaction was allowed to proceed for 6 hours with compensation of absorbed hydrogen additional hydrogen to maintain the pressure. The reaction mixture was filtered to remove the catalyst, concentrated and then purified using column chromatography on silica gel (manifesting solvent: 100% chloroform) for p the receipt of 275 mg 9,19-cyclopentan-3-ol. 24-Methylcyclopentanol synthesized using as source material 24-methylene-9,19-cyclopentan-3-ol. In a sealed autoclave was filled 24-methylene-9,19-cyclopentan-3-ol in the amount of 78 mg, 150 ml of isopropanol and 1.0 g of powdered 5% of the catalyst is palladium/carbon, the internal atmosphere was replaced by nitrogen gas and then injected hydrogen gas with a pressure of 3 kg/cm2. Then the mixture was heated with stirring and when the temperature reached 50°C, the hydrogen pressure was brought to 5 kg/cm2. The reaction was allowed to proceed for 6 hours with compensation of absorbed hydrogen additional hydrogen to maintain the pressure of 5 kg/cm2. The reaction mixture was filtered to remove the catalyst, concentrated and then purified using column chromatography on silica gel (manifesting solvent: 100% chloroform) to obtain 69 mg of 24-methylcyclopentanol.

Examples obtain the extracted compositions containing a compound that Cyclopentanone skeleton, with the use of Aloe vera (Aloe barbadensis Milleras the source material will be described below.

[Example 2 retrieve]

Aloe vera (Aloe barbadensis Millerwithout the peel in the amount of 100 kg was razziali using a homogenizer, added 100 l of mixture exploitive ether/butanol (3:1) and stirred. The mixture was left n the night for the separation of mixtures exploitive ether/butanol and aqueous layer was recovered mixture exploitive ether/butanol. Extracted composition containing a compound that Cyclopentanone skeleton, which was obtained by concentration of the mixture exploitive ether/butanol under reduced pressure, weighed 13,5, Measurement of LC-MS this composition revealed that the content of 9,19-cyclopentan-3-ol was 10 mg and the content of 24-methylene-9,19-cyclopentan-3-ol was 70 mg

[Example 3 retrieve]

To the powder of Aloe vera in the amount of 1 kg was added to 10 l of a mixture of chloroform/methanol (2:1) and kept it in the mixture overnight at room temperature and then restored a mixture of chloroform/methanol. Organic solvents were completely removed from this mixture at 28°C to obtain 83 g of a composition containing a compound that Cyclopentanone skeleton. Measurement of LC-MS composition was revealed that the content of 9,19-cyclopentan-3-ol constituted 25.8 mg and 24-methylene-9,19-cyclopentan-3-ol was 24 mg.

[Test example 1]

This test was performed to assess the validity of the protection functions of cells of pancreatic internal secretion (capacity for producing insulin) compounds having Cyclopentanone skeleton, using mice, db/db, known as an animal model for hypofunction or dysfunction of the pancreas tissue of the pancreas.

(1) Preparation is brazza

As test samples 1 and 2 respectively, used 9,19-cyclopentan-3-ol and 24-methylene-9,19-cyclopentan-3-ol obtained above in the Example of obtaining 1.

(2) Method of test

In this test, were used 6-week-old male mice db/db (purchased from Clea Japan, Inc). These mice were divided into groups, each of which consisted of 7 animals. Each test sample was dissolved in DMSO and brought a concentration of 0.1 or 1 μg/ml with physiological saline. The final concentration of DMSO was brought up to 0.2%. Model mice disorders of the pancreas oral was administered 1 ml of the test sample once a day every day for 42 days with the help of the probe. Insulin levels in serum were measured at the 43rd day continuous injection using an insulin Lbis ELISA kit for mice (Shibayagi Co., Ltd.

(3) the results of the test

Insulin levels in serum at the 43rd day of continuous introduction of the samples shown in Table 1. When the test sample 1 or 2 was introduced with a concentration of 1 μg/animal insulin levels in serum were 160 and 170% compared to the level observed in the negative test, respectively, and thus explicitly observed effect of the protection functions of the pancreas (the ability to producing insulin) due to protection from dysfunction of the pancreas. With the another hand, when introduced with a concentration of 0.1 μg/animal, there was no significant effect of the protection functions of the pancreas. During the period of introduction was not observed absolutely no side effect, taking into account the weight of the body and the detection of pathologies.

Table 1
Insulin levels in serum at the 43rd day of continuous introduction
SampleInsulin levels in serum at the 43rd day of introduction
(ng/ml)
<p with respect to the negative pattern>
Negative sample1,99±0,66
Test sample 1 (1 µg)3,19±0,78<0,017*>
Test sample 1 (0.1 ág)1,74±0,26<0,16>
Test sample 2 (1 µg)3,39±1,35<0,041*>
Test sample 2 (0.1 ág)1,94±0,56<0,14>
*indicates statistically significant difference

[Test example 2]

In this test the effect of compounds containing Cyclopentanone skeleton, in the protection of pancreatic tissue was investigated using mice, db/db, known as an animal model for pancreatic hypofunction or dysfunction of pancreatic tissue.

(1) sample Preparation

As test samples 1 and 2 respectively, used 9,19-cyclopentan-3-ol and 24-methylene-9,19-cyclopentan-3-ol obtained above in the Example of obtaining 1.

(2) Method of test

In this test, were used 6-week-old male mice db/db (purchased from Clea Japan, Inc). These mice were divided into groups, each of which consisted of 7 animals. Each test sample was dissolved in DMSO and drove concentration of 1 μg/ml with physiological saline. The final concentration of DMSO was brought up to 0.2%. Model mice orally was administered 1 ml of the test sample once a day every day for 42 days with the help of the probe. On the 43rd day of continuous introduction of the removed pancreas was divided into three parts above, center and lower side of the duodenum and were fixed with formalin and then the usual way to prepare paraffin blocks. From paraffin blocks were prepared slices, and is subjected to staining with hematoxylin-eosin. Using ocular micrometer on the microscope ("ECLIPSE E600", NIKON CORP.) on each slice was measured quantity of islets of Langerhans present in sections 3 points of the pancreas, and the area of the islet of Langerhans, with the largest area.

(3) the results of the test

The number of islets of Langerhans in the sections of the pancreas at the 43rd day of continuous introduction of the samples are shown in Table 2, and the maximum area of the islets of Langerhans in the same day are shown in Table 3. The number of islets of Langerhans of mice that were administered the test sample 1 or 2 was 149 and 148% in the number of islets of Langerhans in mice which were injected negative sample, respectively, and it was found that this number was obviously great. Similarly, the maximum value of the square of the islets of Langerhans in mice that were administered the test sample 1 or 2, remained at 1.8 and 3.1 times more compared to the values observed in the negative test, and thus it was found that the reduction of the islets of Langerhans in the investigation of disorders of the pancreas have been prevented. From these results it was found that 9,19-cyclopentan-3-ol and 24-methylene-9,19-cyclopentan-3-ol have the effect of protecting the tissues of the pancreas, especially endocrine cells.

Table 2
The number of islets of Langerhans in the pathological sections of the pancreas treated mice
SampleThe number of islets of Langerhans in the sections on the 43rd day of introduction (pieces)<p with respect to the negative pattern>
Negative sample40,3±9,7
Test sample 1 (1 µg)60,0±14,8<0,006*>
Test sample 2 (1 µg)59,6±11,6<0,005*>
*indicates statistically significant difference

Table 3
The maximum value of the square of the islets of Langerhans in the pathological sections of the pancreas treated mice
SampleThe maximum value of the square of the islets of Langerhans in the introduction x 103(μm2) <p with respect to the negative pattern>
Negative sample44,5±17,7
Test sample 1 (1 µg)78,6±3,3<0,04*>
Test sample 2 (1 µg)140,0±102,8<0,05*>
*indicates statistically significant difference

Industrial applicability

The drug and food or drink in accordance with the present invention can be safely administered or taken inside and have protection activity of cells of pancreatic internal secretion and improve the functions of the cells of pancreatic internal secretion. In addition, the active ingredient of the medicinal product and food product or beverage in accordance with the present invention can be produced from plants that can be safely taken inside with experience-based perspective in relation to the food product and easily accessible, such as a plant of the familyLiliaceaesuch as Aloe vera (Aloe barbadensis Milleror familyGramineae.

1. Drug for improving functions of pojulu the internal gland, which contains as an active ingredient 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol.

2. The drug according to claim 1, where the improvement of the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion.

3. The drug according to claim 1, which contains from 0.001 to 10% above compounds in relation to the dry weight of the drug.

4. Drug to improve the functions of the pancreas, which contains a composition comprising as active ingredient an extract with an organic solvent or hot water extract of a plant selected from the families Liliaceae, Gramineae and Solanaceae, or its parts, and extract with an organic solvent or hot water extract of a plant or part thereof contains from 0.001 to 10% 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol in relation to the dry weight of the drug.

5. The drug according to claim 4, where the improvement of the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion.

6. The drug according to claim 4, in which the above plant of the family Liliaceae a Aloe vera (Aloe barbadensis Miller).

7. Food or drink for improving functions of the pancreas, which contains 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol.

8. Food or drink according to claim 7, where the improvement of the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion.

9. Food or drink according to claim 7, which contains from 0.0001 to 1% above compounds in relation to the dry weight of the food product or beverage.

10. Food or drink for improving functions of the pancreas, which contains a composition comprising as active ingredient an extract with an organic solvent or hot water extract of a plant selected from the families Liliaceae, Gramineae and Solanaceae, or its parts, and extract with an organic solvent or hot water extract of a plant or part thereof contains from 0.0001 to 1% 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol in relation to the dry weight of the food product or beverage.

11. Food product or beverage of claim 10, where the improvement of the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion.

12. Pisew the th product or beverage according to claim 11, in which the above plant of the family Liliaceae is a Aloe vera (Aloe barbadensis Miller).

13. Food or drink according to any one of claims 7 to 12 with the attached indicating that food or drink is used for the improvement of the functions of the pancreas.

14. The use of 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol, or containing it(them) of the composition, to obtain medicines to improve the functions of the pancreas.

15. The application 14, in which the improvement of the functions of the pancreas lies in the protection of cells of pancreatic internal secretion or improve the functions of the cells of pancreatic internal secretion.

16. Use 14 or 15, in which the above composition is an extract of a plant selected from the families Liliaceae, Gramineae and Solanaceae, or portion thereof, containing from 0.001 to 10% above compounds in relation to the dry weight of the drug.

17. The way to improve the functions of the pancreas, which includes 9,19-cyclopentan-3-ol and/or 24-methylene-9,19-cyclopentan-3-ol, or containing it(them) of the composition to the individual, the function of the pancreas which need to be improved.

18. The method according to 17, in which the improvement of the functions of the pancreas lies in the protection of cells pagelogo the first endocrine gland or improve the functions of the cells of pancreatic internal secretion.

19. The method according to 17 or 18, in which the above composition is an extract of a plant selected from the families Liliaceae, Gramineae and Solanaceae, or portion thereof, containing from 0.001 to 10% above compounds in relation to the dry weight of the composition.



 

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