JPH0892093A - Water-based pharmaceutical preparation of 9-methyl-3-(1 h-tetrazol-5-yl)-4h-pyrido (1,2-a)pyrimidin-4-one - Google Patents

Abstract

PURPOSE: To obtain a water-based pharmaceutical preparation causing no crystal deposition even after preserved for a long period, highly excellent in preservability because of causing no TBX decomposition and being stable in pH level, thus esp. useful when used as a nasal drop, eye drop or liniment. CONSTITUTION: This water-based pharmaceutical preparation contains, as active ingredient, 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a] pyrimidin-4-one or a physiologically permissible salt thereof except those containing 0.05-0.5% (W/ V) of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt, 0.1-0.5% (W/V) of potassium hydrogenphosphate and 0.005-0.2% (W/V) of potassium dihydrogenphosphate}.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aqueous preparation of an antiallergic drug, more specifically the following formula

[0002]

[Chemical 1]

9-Methyl-3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one potassium salt represented by
It is tentatively called X. 2) aqueous preparations, especially nasal drops, eye drops and coatings.

[0004]

2. Description of the Related Art TBX is a compound described in Japanese Examined Patent Publication (Kokoku) No. 60-50197, which is used for allergic bronchial asthma.
It is known to suppress or prevent the symptoms of allergic reaction such as allergic rhinitis.
(9), P. 727, 728, 1984: Inhibitory effect of TBX in type I allergic reaction model and histamine, SRS-A (slow-reacting substance of anaphylaxis)
The release inhibiting effect of such chemical mediators is described. In addition, gastroenterology (Ga
Strenterology), 88 (5), p. 1
In 354 and 1985, it is described that TBX is effective in treating gastritis and gastric ulcer, which are due to the protective action of gastric cells.

[0005]

As for chemical mediator release-suppressing type antiallergic agents which are currently on the market, oral agents for the purpose of systemic action are mainly used. However, patients with allergic rhinitis, ophthalmitis, dermatitis,
Especially for infants, it is difficult to say that the dosage form is optimal because of the frequency of side effects. Therefore, topical therapeutic agents such as nasal drops for allergic rhinitis, eye drops for allergic ophthalmitis, and application agents for allergic dermatitis are effective from the viewpoint of reducing side effects and efficiently expressing drug efficacy. It can be said to be a dosage form.

The present invention is an antiallergic drug, TBX.
It is an object of the present invention to provide aqueous preparations such as nasal drops, eye drops and ointments.

The conditions that the aqueous preparation must have are aseptic, that there is no foreign matter mixed in, that the tonicity and pH of the body fluid at the administration site are not so different from those of the drug,
Further, it is physically and chemically stable even after long-term storage. TBX is a water-soluble substance, but TB
When X is used as an aqueous solution, crystals are likely to precipitate and there is a problem in storage stability. For example, TBX concentration is 0.02-2.0
% (W / V) 10 days later, 0.002% (W / V
In the case of V), crystals precipitated after 12 days. So TBX
For the purpose of preventing the precipitation of crystals, a solubilizing agent such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol, glycerin, etc. was added to the aqueous solution of 1. Also known as ophthalmic buffers are Hind-Goyan buffers, Gifford buffers and Pallice (P
alitzsch) buffer [New Pharmacy Review (Nankodo), 1980 edition, p. 39-41], no satisfactory effect was obtained. The present inventors confirmed these findings by their own experiments.

[0008]

[Means for Solving the Problems] The inventors of the present invention have studied the aqueous preparation of TBX in view of the above-mentioned problems, and found that it can be stored for a long time by adding potassium monohydrogenphosphate and potassium dihydrogenphosphate. Even if the crystals do not precipitate,
The inventors have completed the present invention knowing that TBX is not decomposed.

The aqueous preparation of the present invention has TBX, potassium monohydrogenphosphate and potassium dihydrogenphosphate concentrations of 0.0 and 0.05, respectively.
5 to 0.5% (W / V), 0.1 to 0.5% (W / V
V), 0.005 to 0.2% (W / V) is preferable, and a preservative and an isotonicity agent can be added if necessary. As the aqueous preparation of the present invention, nasal drops, eye drops and coatings are preferable, and they can also be used as liquid preparations such as injections, inhalants and ear drops.

The aqueous preparation of the present invention has a TBX of 0.05 to 0.
5% (W / V) potassium monohydrogen phosphate is 0.1-0.5
% (W / V), potassium dihydrogen phosphate is 0.005-
As long as it is contained in a concentration range of 0.2% (W / V),
Preservatives, tonicity agents and the like may be added as necessary.
The aqueous preparation of the present invention does not precipitate crystals even when left in a cold place for a long period of time in order to satisfy use in cold regions at room temperature and in winter.
It is an aqueous preparation which does not decompose X and has extremely excellent storage stability. Further, since the pH is stable in the range of 7.7 to 8.3, it is suitable for nasal drops, eye drops and coating agents. Since the nasal drops, eye drops, and coating agents are used by opening the container and repeating them, those having excellent storage stability even in the open state are preferable. Since the aqueous preparation of the present invention is stable even when left open, it is suitable as a nasal drop, an eye drop and a coating agent.

In the aqueous preparation of the present invention, an ordinary preservative may be used, but from the viewpoint of storage stability, potassium sorbate and sodium dehydroacetate are preferable, and benzalkonium chloride, benzethonium chloride and 2-phenylethanol are crystalline. Was easily deposited.

Next, experimental results will be shown when TBX was dissolved in purified water alone, when a solubilizing agent was added, and when Hind-Goryan buffer, Gifford buffer and Pariche buffer were used.

The determination of crystal precipitation is based on the visual inspection method of the Japanese Pharmacopoeia. Various specimens are put in a glass container, sealed and left to stand, and observed at a position of a brightness of 3000 to 5000 lux using a white light source. The case of precipitation was indicated by +, and the case of no crystal precipitation was indicated by-.

The sterilized purified water described below means purified water that has been sterilized by dark heat in an autoclave at 121 ° C. for 20 minutes.

[When Dissolved in Purified Water Alone] TBX was dissolved in sterilized purified water so as to have various concentrations, and the TBX was dissolved at room temperature for 3 days.
Observations were made after standing for 10 days and 12 days. The results are shown in the table below.

[0016]

[Table 1]

[When a solubilizing agent is added] TBX0.
Dissolve 5 g and a solubilizer in sterile purified water, adjust the pH to about 8.0 by adding 0.4 g of sodium citrate, and adjust the total amount to 100 ml to prepare a 0.5% (W / V) solution of TBX. did. The following table shows the results when the solution was left at room temperature.

[0018]

[Table 2]

[When a known buffer solution is used] Hind-Goyan buffer solution 0.40 g of sodium dihydrogen phosphate, 0.47 g of sodium monohydrogen phosphate and 0.43 g of sodium chloride are dissolved in sterile purified water, Next, add 0.5 g of TBX to make the total amount 1
A 0.5% solution of TBX was prepared as 00 ml. The solution was left at room temperature and 5 ° C.

(Result) TB at room temperature and 5 ° C.
Crystals precipitated instantly after the dissolution of X.

Gifford's buffer 1.24 g boric acid, 0.74 g potassium chloride and 2.12 g sodium carbonate are dissolved in sterile purified water and then TB
When 0.20 g of X was added to adjust the total amount to 100 ml to prepare a 0.2% solution of TBX, the pH of the solution was 7.9. The solution was left at room temperature and 5 ° C.

(Results) Crystal precipitation was clearly observed after 3 months at room temperature and after 1 month at 5 ° C.

Pariche buffer solution 1.91 g of borax and 1.24 g of boric acid were dissolved in sterilized purified water, and then 0.2 g of TBX was added to a total volume of 100 ml.
As a 0.2% solution of TBX was prepared as
H was 8.2. The solution was left at room temperature and 5 ° C.

(Results) Crystal precipitation was clearly observed after 3 months at room temperature and after 1 month at 5 ° C.

As described above, when TBX is dissolved in purified water, when a solubilizing agent is added, when a known buffer solution is used, the TBX can be rapidly or instantly in a stoppered state and within 3 months even if it is slow. Crystals precipitated.

The storage stability of the aqueous preparation of the present invention in the sealed state and the open state is shown.

[Preservation in a sealed container] TBX, potassium monohydrogen phosphate, potassium dihydrogen phosphate and, if necessary, potassium sorbate as a preservative were dissolved in sterile purified water so as to have a predetermined concentration. The obtained aqueous preparation was placed in a glass container, tightly closed, and stored at room temperature and 5 ° C. The results are shown in Table 3. The judgment at each passage was made based on the above-mentioned visual inspection method. Thin layer chromatography (TLC) uses a silica gel thin layer plate, and the developing solvent is methanol: benzene: acetone: ammonia water (5: 4: 1: 1). Further, the observation ends at the time when crystals are precipitated, and the TLC is at that time.

[0028]

[Table 3]

[Open storage] The samples, which were used for Test Nos. 1 and 2 in Table 3 and stored in a tightly closed container for 15 months, were continuously stored at room temperature with the glass container opened. No crystals precipitated even after 10 days. TLC was also one spot.

[0030]

The aqueous preparation of the present invention has a TBX concentration of 0. 05
~ 0.5% (W / V), potassium monohydrogen phosphate 0.1-0.5% (W / V), potassium dihydrogen phosphate,
By adjusting the concentration to 0.005 to 0.2% (W / V), crystals do not precipitate for a long period of time at both room temperature and a cold place (5 ° C.), and TBX does not decompose, which is extremely excellent. It is a formulation. Further, since it is stable even in an open state, it is particularly useful as a nasal drop, an eye drop and a coating agent which are used by repeatedly opening the container.

[0031]

EXAMPLES Next, examples of production of the aqueous preparation of the present invention will be shown with examples, but these do not limit the present invention.

Example 1 TBX 1.0 g, potassium monohydrogen phosphate 3.0 g, potassium dihydrogen phosphate 0.15 g
And 1.0 g of potassium sorbate were dissolved in sterile purified water to make the total amount 1000 ml. The pH of the solution was 8.1. This solution was filtered using a 0.45 μm membrane filter to obtain a TBX 0.1% (W / V) solution. This solution was filled in a spray type nasal drop container to prepare a nasal drop.

[Example 2] 1.0 g of TBX, 1.0 g of potassium monohydrogen phosphate, 0.05 potassium dihydrogen phosphate
g, potassium chloride 3.0 g and potassium sorbate 1.
0 g was dissolved in sterile purified water to make the total amount 1000 ml. The pH of the solution was 8.0. 0.45 of this solution
TBX after filtration using a membrane filter of μm
A 0.1% (W / V) solution was obtained. This solution was filled in a container for eye drops to prepare an eye drop.

[Example 3] TBX (2.0 g), potassium monohydrogen phosphate (3.0 g), potassium dihydrogen phosphate (0.2 g) and sodium dehydroacetate (0.1 g) were dissolved in sterilized purified water to make a total volume of 1000 ml. The pH of the solution was 8.1. This solution was filtered using a 0.45 μm membrane filter to obtain a TBX 0.2% (W / V) solution. This solution was filled in a plastic coating container with a sponge to obtain a coating agent.

Claims (11)

[Claims] 1. Containing 9-methyl-3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one or a physiologically acceptable salt thereof as an active ingredient. Aqueous formulation (9-methyl-3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a]
Pyrimidin-4-one potassium salt 0.05-0.5%
(W / V), potassium monohydrogen phosphate 0.1-0.5%
(W / V) and potassium dihydrogen phosphate 0.005 to 0.
(Excluding those containing 2% (W / V)). 2. The aqueous preparation according to claim 1, which contains at least one buffer solution selected from potassium phosphate-based buffer solutions. 3. The aqueous preparation according to claim 2, wherein the buffer solution is a combination of potassium monohydrogen phosphate and potassium dihydrogen phosphate. 4. The aqueous preparation according to claim 1, containing at least one buffer selected from sodium phosphate-based or borate-based buffers. 5. The aqueous preparation according to claim 4, wherein the buffer solution is a combination of sodium monohydrogen phosphate and sodium dihydrogen phosphate. 6. The aqueous preparation according to claim 4, wherein the buffer solution is a combination of boric acid and sodium carbonate. 7. The aqueous preparation according to claim 4, wherein the buffer solution is a combination of boric acid and borax. 8. The active ingredient is 9-methyl-3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a].
The aqueous preparation according to claims 1 to 7, which is a pyrimidin-4-one potassium salt. 9. The aqueous preparation according to claim 1, wherein the dosage form is a nasal drop. 10. The aqueous preparation according to claim 1, wherein the dosage form is an eye drop. 11. The aqueous preparation according to claim 1, wherein the dosage form is a coating agent.