JP2002338461A - Therapeutic agent for nasal disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a prophylactic/therapeutic agent for nasal diseases enabling the side effects to be significantly inhibited because of the inclusion of tranexamic acid or a salt thereof in view of the finding that a vasoconstrictor is a cause of the side effects, i.e., nasal discharge and sneeze, after application of a medicament for nasal diseases. SOLUTION: This prophylactic/therapeutic agent for nasal diseases comprises tranexamic acid or a salt thereof and a vasoconstrictor. A side effect inhibitor for the vasoconstrictor comprising tranexamic acid or a salt thereof as the active ingredient is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive and / or therapeutic drug for nasal diseases in which side effects due to administration of a vasoconstrictor are suppressed.

[0002]

2. Description of the Related Art In the improvement of congestion and congestion of nasal mucosa (upper respiratory tract) in rhinitis such as acute rhinitis, chronic rhinitis, hypertrophic rhinitis, vasomotor rhinitis, allergic rhinitis, drug-induced rhinitis, and for diagnosis and treatment. For the purpose of facilitating intubation of an endoscope or the like from the nasal cavity, a vasoconstrictor such as epinephrine and a local anesthetic such as lidocaine are administered into the nasal cavity.

[0003]

It is known that when these drugs are administered intranasally, side effects such as rhinorrhea and sneezing frequently occur. However, preparations for intranasal administration contain not only vasoconstrictors and local anesthetics but also preparation additives such as preservatives, and the cause of these side effects is unknown. It was believed to be due to secondary hyperemia of the local mucosa with use.

Accordingly, an object of the present invention is to clarify the causes of side effects caused by the use of these intranasal preparations, and to provide a drug for nasal diseases free of such side effects.

[0005]

The present inventors have examined the causes of side effects of intranasal preparations, and found that a vasoconstrictor is the causative component, and the side effects are more remarkable by administration of tranexamic acid or a salt thereof. Simultaneously or with a vasoconstrictor and tranexamic acid or a salt thereof,
It has been found that continuous administration can be used as a prophylactic or therapeutic drug for nasal diseases with few side effects, and the present invention has been completed.

That is, the present invention provides a prophylactic and / or therapeutic drug for nasal diseases containing tranexamic acid or a salt thereof. The present invention also provides a prophylactic and / or therapeutic drug for nasal diseases, comprising tranexamic acid or a salt thereof and a vasoconstrictor. The present invention further provides a vasoconstrictor side effect suppressant comprising tranexamic acid or a salt thereof as an active ingredient.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS It has not been known that side effects of intranasal preparations for improving congestion and congestion in the upper respiratory tract are due to vasoconstrictors. As shown in the Examples below, the present inventor epinephrine, a typical example of a vasoconstrictor, and chlorobutanol, a preservative (chemical name:
(1,1,1-Trichloro-2-methyl-2-propanol) and sodium sulfite were compared with the occurrence of side effects caused by a commercially available product and the occurrence of side effects caused by an intranasal preparation containing only each of these components. As a result, side effects of rhinorrhea and sneezing were observed only in the vasoconstrictor administration group. Therefore, it has now become clear for the first time that these side effects are due to vasoconstrictor administration. Further, it has been found that these side effects caused by the administration of a vasoconstrictor are significantly suppressed by the administration of tranexamic acid or a salt thereof.

The tranexamic acid used in the present invention has a chemical name of trans-4-aminomethylcyclohexanecarboxylic acid and is a component conventionally used as an antiplasmin agent. It is not known that it can be used as a drug for nasal diseases and that side effects caused by vasoconstrictors can be suppressed.

The salts of tranexamic acid include mineral salts such as hydrochloride, nitrate and sulfate, organic acid salts such as methanesulfonate, alkali metals such as sodium salt, potassium salt, calcium salt and magnesium salt; Earth metal salts and the like can be mentioned. As tranexamic acid or a salt thereof, tranexamic acid is preferable.

[0010] The content of tranexamic acid or a salt thereof in the drug for nasal diseases of the present invention may be 0.001 to 30% by weight, particularly 0.01 to 20% by weight, as long as the side effect of the vasoconstrictor can be reduced. % Is preferred.

Examples of the vasoconstrictor include epinephrine, naphazoline, tetrahydrozoline, oxymetazoline, tramazoline, phenylephrine, midodrine, methoxamine, dihydroergotamine and salts thereof. Here, examples of the salt include mineral salts such as hydrochloride, nitrate and sulfate, and organic acid salts such as methanesulfonate. Of these, epinephrine, naphazoline, tetrahydrozoline, oxymetazoline, and tramazoline are preferred, and epinephrine, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, oxymetazoline hydrochloride, and tramazoline hydrochloride are more preferred.

The content of the vasoconstrictor in the drug for nasal diseases of the present invention varies depending on the drug, but is preferably 0.001 to 5% by weight, particularly preferably 0.01 to 1.5% by weight.

The dosage form of the drug for nasal diseases of the present invention is preferably a preparation for intranasal administration (nasal drops) which can be locally administered into the nasal cavity. Specific examples include liquid preparations, spray preparations, coating preparations, nasal drops, ointments and the like.

The drug for nasal diseases of the present invention exerts the effect of a vasoconstrictor, that is, hyperemia and / or various diseases in the upper respiratory tract.
Alternatively, it is only necessary to remove congestion, and various diseases in the upper respiratory tract include rhinitis such as acute rhinitis, chronic rhinitis, hypertrophic rhinitis, vasomotor rhinitis, allergic rhinitis, drug-induced rhinitis and the like.

In the drug for nasal diseases of the present invention, a vasoconstrictor acts to remove the above-mentioned hyperemia and congestion, while tranexamic acid or a salt thereof acts to suppress the side effects of the vasoconstrictor. May be blended in one formulation, but formulations containing each of these may be supplied separately and used simultaneously or successively. Here, when the two preparations are separately supplied, either one may be used first.

The preparation of the drug for nasal diseases of the present invention can be prepared by known preparation techniques, and a suitable preparation additive is added to the preparation within a range not to impair the effects of the present invention. Can be. Pharmaceutical additives include excipients, binders, disintegrants, flow agents, emulsifiers, stabilizers, preservatives, and the like. The dosage of the prophylactic and / or therapeutic agent for nasal diseases of the present invention and the side effect inhibitor of the vasoconstrictor to a patient is appropriately examined according to the patient's sex, age, symptoms, frequency of administration, and the like. Just decide.

[0017]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example (1) Patients Outpatients complaining of massive nasal discharge and the side effects of sneezing after spraying a topical preparation containing epinephrine, which is a vasoconstrictor, onto the nasal mucosa. (2) Questions (a) Time from spraying epinephrine to the nasal mucosa until the onset of symptoms of watery rhinorrhea and sneezing (b) Duration of symptoms (c) Type of symptoms (d) Site (e) Number of times the nose was blown (3) Drugs used (a) Epinephrine solution commercially available [epinephrine (1 mg /
mL), containing chlorobutanol (3 mg / mL) and sodium sulfite (0.5 mg / mL) (Daiichi Pharmaceutical)] This formulation was diluted 5-fold with physiological saline to give 0.2 mg / mL as epinephrine, Each nostril was used by spraying 0.3 mL. (B) Each physiological saline solution containing 0.6 mg / mL of chlorobutanol or 0.1 mg / mL of sodium sulfite. Each nostril was sprayed with 0.3 mL and used. (C) Lidocaine hydrochloride (5 mg / mL) in saline solution
3 mL was sprayed into each nostril and used. (D) Tranexamic acid aqueous solution (1 g / 10 mL) 0.3 mL
Was used by spraying into each nostril. (4) Means of study A patient who had previously complained of massive rhinorrhea and the occurrence of sneezing after spraying epinephrine and lidocaine and asked the above question again was returned to the hospital. The pre-patients were divided into a lidocaine administration group (42), a chlorobutanol and sodium sulfite administration group (20), and an epinephrine administration group to evaluate side effects. The tranexamic acid 10% aqueous solution was sprayed on nasal mucosa immediately after administration of epinephrine to 24 patients who received epinephrine. After spraying epinephrine and lidocaine on the nasal mucosa, the nasal secretions of 10 patients complaining of side effects were stained with Hansel and observed under a microscope, and eosinophils and mast cells were observed cytologically. Changes in color tone, such as redness or paleness of the nasal mucosa, and the degree of swelling were observed by rhinoscopy. (5) Results (a) As shown in Table 1, the time from the intranasal administration of the drug to the onset of symptoms of watery rhinorrhea and sneezing was about 30 to 60 minutes in most patients. .

[0019]

[Table 1]

As shown in Table 2, the symptoms of side effects lasted for almost two days, but in some cases they lasted for 2-3 hours or 3 days.

[0021]

[Table 2]

(B) As shown in Table 3, most patients suffered from numerous outflows of watery nasal discharge and side effects from sneezing. Several patients did not sneeze, but complained of watery rhinorrhea. Some also complained of soreness when breathing through the nose. No patient complained of nasal congestion.

[0023]

[Table 3]

In many patients, symptoms occurred on both sides of the nasal cavity, but in a few cases, it occurred only on one side of the nasal cavity (Table 4).

[0025]

[Table 4]

[0026] Due to the occurrence of massive rhinorrhea, most patients have blown their nose innumerably.

[0027]

[Table 5]

Even after blowing the nose, a feeling of fullness of rhinorrhea remained in the nose. The rhinorrhea spilled out like water, and the patient had to carry a handkerchief or tissue paper to remove the rhinorrhea. Rhinorrhea was low in viscosity and watery. Most patients had massive rhinorrhea symptoms after the first dose of epinephrine, but some had symptoms after several doses.

(B) Some patients had nasal allergy due to house dust or pollen. No changes were seen in the allergic symptoms before and after the side effects occurred. Neither eosinophils nor mast cells were found in the nasal secretions.

(C) Local observation of nasal mucosa showed congestion and redness, but no pale color, thickening causing nasal congestion, and nasal congestion were not observed.

(D) Patients who complained of massive nasal discharge and sneezing due to topical administration of epinephrine and lidocaine were re-administered with epinephrine alone and the symptoms recurred. However, no side effects occurred in patients receiving lidocaine alone.

(E) When chlorobutanol and sodium sulfite were administered to a patient who complained of watery rhinorrhea and sneezing by administration of epinephrine and lidocaine, no side effect occurred.

(F) When a 10% aqueous solution of tranexamic acid was administered immediately after administration of epinephrine to 24 patients who had side effects caused by administration of epinephrine, 22 of 24 patients did not have abnormal rhinorrhea or sneezing side effects. (Effective rate 92%).

From the results of the above (a) to (e), side effects such as rhinorrhea and sneezing caused by administration of drugs for nasal diseases are not caused by lidocaine or preservatives, but are also caused by long-term continuous use. Nor is it apparently caused by the vasoconstrictor epinephrine.

It can be seen that the extremely frequent side effects such as rhinorrhea and sneezing caused by the vasoconstrictor can be suppressed by administration of tranexamic acid at a high effective rate of 92%.

[0036]

According to the present invention, it is clear that the cause of rhinorrhea and sneezing after application of a drug for nasal diseases is a vasoconstrictor, and the side effects can be significantly prevented by tranexamic acid or a salt thereof. .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4174 A61K 31/4174 31/48 31/48 45/00 45/00 A61P 11/02 A61P 11 / 02 F term (reference) 4C084 AA19 MA59 NA06 ZA412 ZA591 ZA592 ZC752 4C086 AA01 AA02 BC38 CB22 MA01 MA02 MA04 MA10 MA59 NA06 ZA59 ZC75 4C206 AA01 AA02 FA10 FA44 KA01 MA01 MA02 MA04 MA14 NA06 ZA59 Z75

Claims (9)

[Claims] 1. A preventive and / or therapeutic agent for nasal diseases, comprising tranexamic acid or a salt thereof. 2. A preventive and / or therapeutic agent for nasal diseases, comprising tranexamic acid or a salt thereof and a vasoconstrictor. 3. The method according to claim 1, wherein the vasoconstrictor is epinephrine, naphazoline, tetrahydrozoline, oxymetazoline, tramazoline, phenylephrine, midodrine, methoxamine.
The prevention of nasal diseases according to claim 1 or 2, which is selected from dihydroergotamine and salts thereof.
Or therapeutic drugs. 4. The preventive and / or therapeutic drug for nasal diseases according to claim 1, wherein the tranexamic acid or a salt thereof is tranexamic acid. 5. An agent for suppressing side effects of a vasoconstrictor comprising tranexamic acid or a salt thereof as an active ingredient. 6. The method according to claim 6, wherein the vasoconstrictor is epinephrine, naphazoline, tetrahydrozoline, oxymetazoline, tramazoline, phenylephrine, midodrine, methoxamine.
The side-effect inhibitor according to claim 5, which is selected from dihydroergotamine and salts thereof. 7. The method according to claim 5, wherein the tranexamic acid or a salt thereof is tranexamic acid. 8. The method according to claim 5, wherein the side effect of the vasoconstrictor is a side effect of intranasal administration of the vasoconstrictor.
The side-effect inhibitor according to the above item. 9. The side-effect inhibitor according to claim 5, wherein the side effect of the vasoconstrictor is rhinorrhea and / or sneezing.