JPH0761937A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:To obtain an anti-inflammatory agent capable of suppressing the inflammation reaction in the living body advantageously by a topical or a systemic administration. CONSTITUTION:An anti-inflammatory agent containing a calcium antagonistic substance, specifically nifedipine, nicardipine, nimodipine, verapamil, diltiazem, cinnarizine or flunarizine as an effective component.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-inflammatory agent, and more particularly to a drug which comprises a compound having a calcium antagonistic activity as an active ingredient and suppresses an inflammatory reaction in a living body.

[0002]

2. Description of the Related Art Substances and drugs in the body act from the outside of the cell to the site of action of the cell membrane, and then induce changes in mediators in the cell. , Intracellular calcium (Ca) plays an important role, and phosphorylation of proteins including enzymes is an important step. This phosphorylation is cyclic
AMP, cyclic GMP, calmodulin and protein kinase C play important roles. The presence of Ca is often required for their activation, and vice versa.
It is also useful for moving and using. Ca is high in extracellular fluid and extremely low in free intracellular Ca, but Ca is stored in organelles inside the cell, and when cells are stimulated, a channel mediated by membrane excitation ( Depolarization-dependent Ca channel)
Ca influx from the outside of the cell and release from the intracellular storage site due to the influx of Ca from the cell and the influx of Ca via the receptor reaction, etc., and the intracellular Ca concentration is increased.

It is a so-called Ca antagonist (Ca channel inhibitor) that suppresses the depolarization-dependent Ca channel and suppresses the intracellular influx of Ca. It has been widely used in various cardiovascular diseases because it suppresses the uptake of Ca ²⁺ , dilates cerebral blood vessels and coronary blood vessels, and lowers peripheral blood vessel resistance to show hypotensive effects. However, it is not known until now that calcium channel blockers suppress the inflammatory response.

In addition, inflammatory diseases include physical, mechanical,
It is a disease that presents a pathological phenomenon in which redness, fever, swelling, pain and dysfunction are caused by inflammation caused as a defense repair response of the body to stimulation of chemical, biological and immune factors. The reaction is nothing but a physiological reaction. Therefore, it is important to suppress and remove mainly the over-defensive portion and lead to healing without losing the beneficial reaction as defense repair.

[0005] Inflammation is a flow of biological reactions, which is a complex reaction in which many media are organically functioning in association with each other, not involving a single media, and there are various reaction patterns. , To alleviate the symptoms,
Various anti-inflammatory agents are used including symptomatic drugs.

Although the mechanism of the inflammatory reaction is still unknown, it has been clarified considerably, and histamine, serotonin, bradykinin, prostaglandin (PG) E ₂ .PGI ₂ , leukotriene ( In addition to vasoactive factors mainly acting on vascular endothelial cells such as LT) C ₄ · D ₄ and platelet activating factor (PAF), leukocyte migration factor (LTB ₄ , PA
F, lymphokines, etc.) and cell growth factors (interleukin-1, lymphokines, etc.) are known. Inflammation, as represented by allergic inflammation, is often deeply involved in the immune reaction.

On the other hand, living cells regulate various cell functions in response to foreign stimuli, and efficiently transmit information from outside to inside of cells. It is thought that exogenous information is converted into intracellular second messengers such as cyclic nucleotides and Ca ²⁺ , and finally the desired function is expressed through protein phosphorylation. The transduction system that operates depends on the type of cell and the type of stimulus, but the major signal transduction systems adenyl cyclase / cyclic AMP system and phospholipase C / Ca ²⁺ system interact, and
It is known that the second messenger inositol triphosphite acts as a Ca mobilization factor. Thus, even in the inflammatory reaction, Ca ²⁺ at the cellular level
Is believed to play an important role, but there are still many parts that are still not fully understood as to how and in what tissue the actual inflammatory reaction works in the living body.

[0008]

Based on such information, the present inventor has conducted a study on the action of Ca in the inflammatory reaction, and found that calcium antagonists showed endophthalmitis, rhinitis, bronchitis, and skin. The present invention has been completed by finding that it has an excellent effect on inflammatory diseases such as flames.

That is, the present invention provides an anti-inflammatory agent containing a calcium antagonistic substance as an active ingredient.

In the present invention, as the calcium antagonistic substance, dihydropyridine derivatives such as nifedipine, nicardipine and nimodipine, phenylalkylamine (papaverin) derivatives such as verapamil, benzodiazepine derivatives such as diltiazem, piperazine derivatives such as cinnarizine and flunarizine, and These include pharmaceutically acceptable salts.

The anti-inflammatory agent of the present invention can be prepared as a topical preparation such as an eye drop, a nasal drop and a skin agent, or a systemic preparation such as an injection, an oral preparation and a suppository. Such formulations are prepared by conventional formulation means conventional in the art using pharmaceutical carriers, excipients and other additives, the use of which is generally permitted.

Although the dose of the anti-inflammatory agent of the present invention varies depending on the type and degree of inflammation, age, etc., it is generally 0.1-100 mg / day for local administration, orally systemically administered to an adult. In the case of, the dose is preferably 50-500 mg / day, and in the case of parenteral systemic administration, it is preferably 10-100 mg / day.

[0013]

EXAMPLES The present invention will now be described with reference to examples, but the present invention is not limited thereto.

Example 1 Using a mature male colored rabbit having a body weight of 2.0 to 2.5 kg, a corneal cylinder method, which is a method in which a drug solution is placed in a glass cylinder on the cornea and contacted for a certain period of time [opened: Japanese Society of Ophthalmology 92 (2): 1553-1564 (1988). ] Was applied correspondingly, and PGE ₂ was administered exogenously. Single-dose administration of arachidonic acid metabolites such as PGE ₁ , PGE ₂ , PGF ₂ α and LTD ₄ to induce inflammation in the eye is shorter than endotoxin in a short time (about several hours). Shows reaction. In this experiment,
A solution of 25 μg / ml or 50 μg / ml of PGE ₂ dissolved in physiological saline (containing 5% or less of ethanol) was applied to the cornea for 4 minutes to create an almost constant endophthalmitis. It was used as a control group.

As the calcium antagonistic substance, nicardipine, diltiazem and verapamil were used and prepared into an injection solution having the following formulation. 50 to 50 injections
It was intravenously administered at a rate of 1,000 μg / kg, and was divided into a single-administration group immediately before or immediately after PGE ₂ stimulation and a triple-administration group 30 minutes before or 60 minutes after. As an important index of an anterior ocular segment inflammatory reaction, a flare value (ph that can be converted into a protein concentration by using a laser flare cell meter [FC-1000, Kowa Co., Ltd.] that can directly measure the protein concentration (ph
(Oton number) was measured over time. The results are shown in Tables 1 to 3.

Formulation Example 1 (injection solution 1: 1 ml) Nicardipine hydrochloride 0.5 mg D-sorbitol 20 mg Hydrochloric acid Appropriate amount Distilled water for injection Appropriate amount

Formulation Example 2 (injection solution 2: 1 ml) Nicardipine hydrochloride 1 mg D-sorbitol 40 mg Hydrochloric acid Appropriate amount Distilled water for injection Appropriate amount

Formulation Example 3 (injection solution 3: 1 ml) Diltiazem hydrochloride 2.5 mg Glucose 20 mg Hydrochloric acid proper amount Distilled water for injection proper amount

Formulation Example 4 (injection solution 4: 1 ml) Diltiazem hydrochloride 5 mg Glucose 40 mg Hydrochloric acid proper amount Distilled water for injection proper amount

Formulation Example 5 (injection solution 5: 1 ml) Verapamil hydrochloride 2.5 mg Sodium chloride 7 mg Hydrochloric acid Appropriate amount Distilled water for injection Appropriate amount

Formulation Example 6 (injection solution 6: 1 ml) Verapamil hydrochloride 5 mg Sodium chloride 6 mg Hydrochloric acid Appropriate amount Distilled water for injection Appropriate amount

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

Example 2 An endophthalmitis was prepared in the same manner as in Example 1. An eye drop having the following formulation was prepared, and was instilled every 15 minutes for 2 hours from 30 minutes before PGE ₂ stimulation. The results are shown in Table 4.

Formulation Example 7 (in eye drop 1: 1 ml) Nicardipine hydrochloride 0.5 mg Sodium chloride 5 mg Benzalkonium chloride 0.02 mg Sterile purified water Appropriate amount

Formulation Example 8 (in ophthalmic solution 2: 1 ml) Verapamil hydrochloride 5 mg Sodium chloride 7 mg Benzalkonium chloride 0.02 mg Sterile purified water Appropriate amount

Formulation Example 9 (in eye drops 3: 1 ml) Diltiazem hydrochloride 5 mg Sodium chloride 5 mg Benzalkonium chloride 0.02 mg Sterile purified water Appropriate amount

Formulation Example 10 (in eye drops 4: 1 ml) Diltiazem hydrochloride 10 mg Sodium chloride 7 mg Ethyl paraoxybenzoate 0.2 mg Sterile purified water Appropriate amount

[0030]

[Table 4]

Example 3 According to Example 1, a PGE ₂ (250 μg / ml) solution was instilled once to prepare experimental conjunctivitis. On the other hand, an eye drop was prepared in the same manner as in Example 2, and was instilled from 30 minutes before PGE ₂ stimulation to every 30 minutes until after 3 hours. As an index of conjunctivitis, a method of evaluating the degree of impaired conjunctival tissue using reduced glutathione (GSH) and serum protein leaked into tears via the conjunctiva [Kai et al., Journal of Japan Ophthalmology 92 (2): 1553 -1
564 (1988). ] Was applied correspondingly and it measured over time.
The results are shown in Table 5.

[0032]

[Table 5]

[0033]

INDUSTRIAL APPLICABILITY The anti-inflammatory agent of the present invention can advantageously suppress the inflammatory reaction of the living body by local or systemic administration.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61K 31/495 9454-4C 31/55 9454-4C // C07C 255/43 9357-4H C07D 211 / 90 281/10 E 295/02 A 295/06 A (72) Inventor Shigeyoshi Kai 1570 Terada, Tateyama-cho, Nakashinkawa-gun, Toyama Prefecture (72) Inventor Takuhiro Kaji 1-4-4 Nishimachi, Takaoka-shi, Toyama Prefecture (72) Inventor Hideki Hirata 45 Kurose, Toyama City, Toyama Prefecture Shinkai Domus 2081 (72) Inventor Sadao Takayanagi 447-1 Kamikomachi, Omiya City, Saitama Prefecture

Claims (2)

[Claims] 1. An anti-inflammatory agent containing a calcium antagonistic substance as an active ingredient. 2. The anti-inflammatory agent according to claim 1, wherein the calcium antagonistic substance is nifedipine, nicardipine, nimodipine, verapamil, diltiazem, cinnarizine or flunarizine.