JPH0899883A - Therapeutic agent for pancreatitis - Google Patents

Abstract

PURPOSE: To obtain a therapeutic agent for pancreatitis, containing a phosphoric diester of ascorbic acid with tocopherol, having inhibiting actions on pancreatic phosholipase A2 and low toxicity and excellent in safety. CONSTITUTION: This therapeutic agent for pancreatitis contains a phosphoric diester of the formula (R1 and R2 are each H or methyl), e.g. L-ascorbic acid or DL-α-tocopherol phosphoric diester potassium. The agent can orally or parenterally be administered and the daily dose thereof is preferably, e.g. about 1-100mg for an adult at a time in the case of a parenteral injection and about 10-1000mg for an adult at a time several times in the case of a medicine for internal use. The therapeutic agent has better therapeutic effects than those of camostat mesilate which is a commercially available therapeutic agent for pancreatitis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a useful therapeutic agent for pancreatitis. More specifically, the present invention relates to a useful therapeutic agent for pancreatitis containing a phosphodiester compound of ascorbic acid and tocopherol or a pharmaceutically acceptable salt thereof.

[0002]

BACKGROUND OF THE INVENTION In humans, pancreatic phospholipase A ₂ (PL
A ₂₎ (in addition to type I), membrane bound as type II phospholipase A _2, is secreted phospholipase A ₂ is present. The biochemical properties of these phospholipases A ₂ are very different.

Of these, pancreatic phospholipase A ₂ is one of the digestive enzymes synthesized in the pancreas and secreted in pancreatic juice. Pancreatic phospholipase A ₂ is activated by trypsin which is a protease in the duodenum, has a function of mixing with bile and decomposing solubilized phospholipid. Since pancreatic phospholipase A ₂ easily decomposes cell membranes composed of phospholipids and the lyso compound produced at that time exhibits strong cytotoxicity, pancreatic phospholipase A ₂ has been conventionally associated with the onset and exacerbation of acute pancreatitis. Has been attracting attention. In humans, the substance that inhibits the pancreatic phospholipase A ₂ activity (inhibitor) is not present, pancreatic phospholipase A ₂ is by migrating into the blood, are considered as causing a strong cytotoxicity during severe pancreatitis . As a drug having such a pharmacological action, citicoline and the like have been conventionally known.

On the other hand, type II phospholipase A ₂ (non-pancreatic type), which is detected at a high concentration in inflammatory local exudates, is considered to be deeply involved in inflammation. The mechanism of inflammatory action is, for example, that arachidonic acid is produced from phospholipids of cell membranes by type II phospholipase A ₂ , and further, prostaglandin (P
A route to G) and a route to leukotriene (LT) by lipoxygenase are known. Since steroid drugs inhibit type II phospholipase A ₂ ,
It is known as an anti-inflammatory agent that blocks both pathways.

Thus, although the type I and type II enzymes phospholipase A ₂ have very different biochemical properties, they are involved in pancreatic phospholipase A ₂ (type I) and inflammation-related II. A drug that sufficiently inhibits the activities of both type phospholipase A ₂ (non-pancreatic type) is not yet known in the pharmaceutical field.

[0006]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
Focusing on the pancreatic phospholipase A ₂ activity inhibitory action, the present inventors have conducted intensive research. As a result, a phosphodiester compound of ascorbic acid and tocopherol, which is already known as an anti-inflammatory agent having a phospholipase A ₂ inhibitory action (Japanese Patent Publication No. 1-27044), is a pancreatitis treatment having a pancreatic phospholipase A ₂ inhibitory action. It was also found to be useful as an agent. The present invention has been completed based on this new finding.

The present invention provides an excellent therapeutic agent for pancreatitis containing a phosphodiester compound or a pharmacologically acceptable salt thereof.

[0008]

That is, the present invention provides the following formula:

[0009]

[Chemical 2]

[In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ] The phosphodiester compound represented by these, or its pharmacologically acceptable salt (henceforth "this compound") is related with the therapeutic agent for pancreatitis.

The present compound used for the therapeutic agent for pancreatitis of the present invention is, for example, Japanese Patent Publication No. 2-44478 or JP-A-62-2.
It can be appropriately synthesized according to the method described in JP-A-05091 or in accordance with these.

The compound used in the therapeutic agent for pancreatitis of the present invention is, in addition to the above-mentioned use as an anti-inflammatory agent, an anti-cataract agent, a prophylactic / therapeutic agent for menopausal disorders, and a cosmetic having a skin-beautifying effect (Japanese Patent Publication No. 2-44478). No.), an anti-ulcer agent (JP-A-63)
No. 270626), and various uses such as a preventive / therapeutic agent for ischemic organ injury (Japanese Patent Laid-Open No. 2-111722) are already known.

However, it is disclosed that the present compound is useful as an anti-inflammatory agent, and the above-mentioned JP-B-1-2 is disclosed.
No. 7044 discloses that this compound has an inhibitory action on phospholipase A ₂ derived from rat gastric mucosa, and does not disclose any inhibitory action on pancreatic phospholipase A ₂ which is a pharmacological action useful for the treatment of pancreatitis. It has not been. Therefore, it cannot be easily conceived that the present compound is useful as a therapeutic agent for pancreatitis.

The compound used in the therapeutic agent for pancreatitis of the present invention, whether it is a free compound or a pharmacologically acceptable salt thereof, can be appropriately used for the purpose of the present invention. . Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and other salts. Any salt can be used as appropriate as long as it is a pharmacologically acceptable salt.

The therapeutic agent for pancreatitis of the present invention may contain one kind or two or more kinds of the present compounds in an appropriate combination depending on the purpose and need.

The compound used as an active ingredient in the therapeutic agent for pancreatitis of the present invention has extremely low toxicity and excellent safety, and therefore can be advantageously used for the purpose of the present invention [for example, L-ascorbic acid. , DL-α-tocopherol phosphate diester potassium (hereinafter abbreviated as EPC-K) LD ₅₀ : oral administration 5 g / kg (rat), intravenous injection 100 mg / kg (rat) or more].

The therapeutic agent for pancreatitis of the present invention is appropriately used orally or parenterally. As the form of the preparation, for example, any of solid preparations such as tablets, granules, powders, capsules and liquid preparations such as injections can be appropriately prepared by a known method. For these preparations, commonly used excipients, binders, disintegrants, dispersants, reabsorption promoters, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers and Various additives such as pH adjusters may be used as appropriate.

When the present compound is used as a therapeutic agent for pancreatitis, the dose is the type of compound used, the age and weight of the patient,
Depending on the indication and its dosage form, for example, in the case of an injection, about 1 to 100 mg once a day for an adult, and for an oral drug, several times a day for an adult, a dose of about 10 to 1000
It is recommended to administer about mg.

The therapeutic agent for pancreatitis of the present invention may contain other therapeutic agent for pancreatitis and / or a component exhibiting a different kind of medicinal effect unless the object of the present invention is violated.

[0020]

The present invention will be described in more detail below with reference to Examples and Formulation Examples.

[Example 1] For severe ethionine pancreatitis
Effect of the present compound The effect of the present compound on the ethionine severe pancreatitis model, which is a model of severe human pancreatitis, was tested. The effect determination was performed based on the inhibitory effect on the deviation of amylase into the blood, which is an index of pancreatitis.

Test substance : Test substance: L-ascorbic acid, DL-α-tocopherol phosphate diester potassium (abbreviation: EPC-K) 141 mg / 10 ml / kg, p. o. Control substance: distilled water 10 ml / kg, p. o. Camostat mesilate (manufactured by Ono Pharmaceutical Co., Ltd.) 100 mg / 10 ml / kg, p. o.

Animals used : In this test, 30 BALB / c female mice, weighing about 18 g, purchased from Japan SLC (SLC) were used. Mouse temperature is 24 ± 4
Bred in a breeding room in a constant environment of ℃, humidity 55 ± 15%,
The diet was choline deficient 0.5 in the ethionine pancreatitis-induced group.
% Ethionine-added food (prepared by SLC) is freely given,
Lab MR stock (trade name) (manufactured by Nippon Nosan Kogyo) was freely given to the untreated group. Water was freely given to both the ethionine pancreatitis-induced group and the untreated group. The mice were fasted 12 hours before the start of feeding.

Test method : The test substance was administered 12 hours after the start of ingestion of the diet containing ethionine. Blood was collected 24 hours and 48 hours after the start of ingestion of the diet containing ethionine, and the amount of amylase in serum was measured.

Test results : The results are shown in Table 1.

[0026]

[Table 1] Effect group of this compound on elevation of serum amylase level in ethionine pancreatitis Number of cases 0 hours 24 hours 48 hours Distilled water 8 14023 ± 1383 12368 ± 1853 41342 ± 16494 EPC-K 8 14573 ± 3132 12926 ± 2217 16257 ± 9763 * 1 Camostat mesylate 7 13978 ± 1012 12628 ± 1542 36288 ± 13921 No treatment 7 13386 ± 1394 16376 ± 1558 13029 ± 1950 * 1 Each value represents the average ± standard error. The unit of measurement is the international unit (mU / ml).

Significant difference from distilled water administration group * 1; p <
0.01.

As is clear from Table 1, in the distilled water administration group, no increase in serum amylase was observed at 24 hours after the start of ingestion of the diet containing ethionine, but the serum amylase level after 48 hours was 41342. ± 16494 (mU / ml)
And the amount of untreated amylase was significantly increased. On the other hand, in the compound-administered group, the serum amylase level 48 hours after the start of ingestion of the diet containing ethionine was 16257.
It was ± 9763 (mU / ml), which significantly suppressed the increase in serum amylase level in the distilled water administration group, and was within the normal range. On the other hand, 48 hours after administration of the camostat mesylate group, the value was 36288 ± 13921 (mU / ml), and no amylase elevation inhibitory effect was observed.

From the above results, it was found that this compound has a superior pancreatitis therapeutic effect than that of the commercially available pancreatitis therapeutic agent camostat mesilate.

[Formulation Example 1] Oral tablet EPC-K 100 mg Lactose 75 mg Starch 20 mg Polyethylene glycol 6000 5 mg The above components are admixed in a conventional method to give a tablet for 1 tablet.
A sugar coating may be added if necessary.

[Formulation Example 2] Injection EPC-K 200 mg Mannitol 5.0 g 1N-sodium hydroxide Appropriate amount distilled water Total amount 100 ml pH 6.5 The above components are mixed by a conventional method and sterile filtered. The filtrate is aseptically filled into glass ampoules in an amount of 5 ml each, and the mixture is sealed to obtain an injection.

[0032]

INDUSTRIAL APPLICABILITY The preparation of the present invention can be advantageously used for prevention and treatment of pancreatitis.

Claims (1)

[Claims] 1. The following formula: [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ] A therapeutic agent for pancreatitis, which comprises a phosphodiester compound represented by the formula or a pharmacologically acceptable salt thereof.