JPH0725769A - Alloplinol solution for medicine and production thereof - Google Patents

Abstract

PURPOSE:To obtain a homogeneous and stable liquid formulation having a large solubility of alloplinol and suitable viscosity and provide production thereof. CONSTITUTION:The alloplinol solution for medicine containing alloplinol as an effective component and comprised of an aqueous solution containing at least one mixed component selected from glycerin, polyethylene glycol(PEG) and D-sorbitol and production thereof.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicinal liquid preparation comprising a uniform and stable solution of allopurinol and a method for producing the same. The medicinal solution according to the present invention is particularly useful for prevention and / or treatment of stomatitis. Further, the medicinal solution according to the present invention can be used for the prevention and / or treatment of stomatitis associated with cancer treatment such as chemotherapy and X-ray treatment.

[0002]

2. Description of the Related Art It is known that disorders of the oral mucosa such as stomatitis occur due to the administration of anticancer agents or the radiation treatment. The disorder is characterized by ulceration and the associated intense pain. As a result, the patient suffers from inability to eat food, difficulty in speech, dysgeusia, salivation disorder, etc., and the quality of life (QOL) of the patient is extremely deteriorated, making it difficult to continue treatment. Its mechanism of occurrence is considered to be the direct action of the above anticancer agents on the oral mucosa.

As a method for treating the above oral disorders, especially stomatitis, a method of applying azulene ointment, steroid ointment or the like to a patient, or a gargle method using cold water or a mouthwash containing a bactericide has been reported.

In recent years, as a measure for preventing or treating the above stomatitis, a method of gargle using allopurinol, which is conventionally known as a therapeutic drug for gout, has been proposed (Cancer, Vol. 65, 1879-1882). page,
1990, Cancer and Chemotherapy, Volume 16, 3449-345.
Allopurinol, carboxymethylcellulose (CMC) or a water-soluble salt thereof and water, allopurinol liquid preparation (JP-A-3-106817).
It has been attempted to mix it with water in the presence of sodium polyacrylate (PANA) and use it as a gargle.

However, in the above liquid preparation, allopurinol itself is poorly soluble in water, and the liquid preparation cannot be stably stored for a long period of time. Moreover, the preparation method is very complicated, for example, allopurinol and P
The gargle liquid consisting of ANA and water is prepared by first powdering allopurinol in a mortar, adding PANA powder to it, and then mixing and then adding water little by little to grind to remove gel-like water. The operation was very complicated, as it floated on the surface and was left for a whole day and night. Under these circumstances, it has been desired to develop an allopurinol liquid formulation that can be used immediately and easily when needed and can be stably stored for a long time.

[0006]

OBJECT OF THE INVENTION It is an object of the present invention to provide an allopurinol solution which can be stably stored for a long period of time and a method for producing the same. Further, the present invention has a feature such that allopurinol can be brought into sufficient contact with the affected part during gargle, or that allopurinol can be retained continuously in the oral mucosal tissue after gargle, for the prevention of stomatitis having a uniform and appropriate viscosity. It aims at providing an agent and / or a therapeutic agent.

[0007]

DISCLOSURE OF THE INVENTION The present invention contains allopurinol as an active ingredient, and contains glycerin, polyethylene glycol (P
EG) and an aqueous solution containing at least one compounding ingredient selected from D-sorbitol.

The present invention also provides a method for producing the above-mentioned medicinal liquid preparation of allopurinol. The present invention will be described in detail below. The liquid medicine for allopurinol according to the present invention contains allopurinol as an active ingredient,
It contains at least one compounding ingredient selected from glycerin, polyethylene glycol and D-sorbitol. As the polyethylene glycol, PEG 200 to 20000, preferably PEG 200 to 6000, and more preferably PEG 200 to 4000 are used.

Examples of the solubilizing agent optionally used include propylene glycol, sodium polyacrylate, carboxymethyl cellulose or polysorbate, and organic amines such as meglumine capable of forming a salt with allopurinol. it can.

These solubilizing agents may be used in combination of two or more kinds. The pH of the pharmaceutical liquid preparation of allopurinol according to the present invention is preferably on the acidic side, and the value of this pH varies depending on the concentration of allopurinol in the liquid preparation and the type or concentration of the solubilizing agent used in combination, but the pH range is 2 To pH 6, more preferably pH 3 to p
It is H5.

The amount of glycerin, polyethylene glycol or D-sorbitol used as a compounding ingredient in the liquid preparation of the present invention is determined by setting the concentration of the allopurinol liquid preparation,
Although it depends on the type and combination of the solubilizing agents used in combination, it is usually 0 to 350 parts for glycerin, 0 to 250 parts for polyethylene glycol, and 0 to 500 parts for D-sorbitol per 1 part by weight of allopurinol. .

The acid used for adjusting the pH is
Preferable examples include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, oxalic acid, benzoic acid, methanesulfonic acid and tosylic acid. Two or more kinds of these acids can be used in combination.

The method for producing the liquid agent according to the present invention will be described below. The allopurinol liquid preparation of the present invention is prepared by suspending or dissolving (1) allopurinol and the above-mentioned compounding components in water together with other solubilizers if desired, and then adjusting the pH of the resulting liquid preparation to an acidic side. Do you manufacture
Or (2) suspending or dissolving the above-mentioned compounding ingredients and the above-mentioned dissolution aid in water, adjusting the pH of the obtained liquid agent to an acidic side, and then suspending or dissolving allopurinol in this liquid agent Can be manufactured by.

When suspending or dissolving allopurinol and the above-mentioned compounding ingredients or a suitable solubilizing agent in water, they may be heated with stirring if necessary. The temperature range to be heated varies depending on the form of allopurinol, the amount used or the type, form, amount used, combination of the solubilizing agents used in combination, but it is usually an appropriate temperature range from room temperature to the boiling point, and preferably room temperature. ~ 90 ° C.

In the above-mentioned production method (1) or (2), the method of adjusting the pH of the liquid preparation of the present invention to the acidic side is carried out by optionally using a pharmacologically acceptable acid or base. For example, if the pH of the suspension or solution consisting of allopurinol and the above-mentioned components is basic, then by adding the required amount of acid, for example a suspension consisting of allopurinol and other components Or if the pH of the solution is acidic, add the required amount of base to obtain the desired p
It can be adjusted to H.

Examples of the above-mentioned bases are hydroxides, bicarbonates and carbonates of alkali metals such as lithium, potassium and sodium, such as potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, sodium hydroxide and carbonic acid. Examples thereof include sodium hydrogen and sodium carbonate.

In the above-mentioned method for producing a liquid agent, the insoluble matter may be removed by suction filtration or pressure filtration at any time, if desired.

The liquid according to the present invention can be used as it is, but may be sterilized if desired.
Sterilization can be carried out by a conventional method, for example, by heating at about 100 ° C. The heating time is preferably within about 30 minutes.

The allopurinol liquid preparation according to the present invention is stable for a long period of time and, at the same time, has excellent properties as a medicine. That is, a liquid preparation having a high concentration of allopurinol can be obtained and is uniform and stable, and at the same time, by adjusting the viscosity to an appropriate level depending on the dissolution aid used, allopurinol can be attached to the oral mucosa for a long time.

The allopurinol liquid preparation of the present invention may be used as it is, or may be diluted appropriately before use. Further, the liquid agent according to the present invention is a salt usually used for a drug, such as potassium chloride,
You may add sodium chloride etc. The invention is described in more detail in the examples below.

[0021]

【Example】

(Example 1) Polyethylene glycol (PEG400
0) 9.0 g was dissolved in 21 g of water boiled and cooled in a nitrogen stream, 30 mg of allopurinol was added, and the mixture was stirred at 50 ° C. for 40 minutes in a nitrogen stream. After cooling to 25 ℃,
After suction filtration, the filtrate was heat sterilized at 95 ° C. for 10 minutes to obtain a clear solution containing allopurinol.

(Example 2) Polyethylene glycol (P
18.0 g of EG4000) was dissolved in 12 g of water boiled and cooled under a nitrogen stream, 30 mg of allopurinol and 300 mg of sodium carboxymethyl cellulose were added, and the mixture was stirred at 50 ° C. for 40 minutes under a nitrogen stream. 25
After cooling to 0 ° C, the total liquid volume was adjusted to 30 ml with distilled water and the pore size was adjusted to 0.
2.5 kg / cm ² with a 45 μm membrane filter
Pressure filtration under pressure gave an allopurinol-containing clear solution.

(Example 3) Polyethylene glycol (P
12 g of EG1500) was dissolved in 18 g of distilled water, 30 mg of allopurinol and 300 mg of sodium carboxymethyl cellulose were added, and the mixture was stirred at 95 ° C. for 10 minutes. After cooling to 25 ° C, methyl p-aminobenzoate 30
mg was added, and the total amount was adjusted to 30 ml with distilled water, and suction filtration was performed using filter paper (JIS 5 type C) to obtain a clear solution containing allopurinol.

(Example 4) Polyethylene glycol (P
EG400) 6g, allopurinol 30mg, sodium polyacrylate 45mg and distilled water 24g,
The mixture was stirred at 70 ° C for 30 minutes. After cooling to 25 ° C, the total liquid volume was adjusted to 30 ml with distilled water, suction filtration was performed using a filter paper (JIS 5 type C), and the filtrate was heat sterilized at 95 ° C for 10 minutes to obtain a clear solution containing allopurinol.

Example 5 15 g of glycerin, 30 mg of allopurinol, 240 mg of sodium carboxymethyl cellulose and 15 g of distilled water were added and dissolved under nitrogen stream at 40 ° C. for 50 minutes while stirring. After cooling to 25 ° C, the total liquid volume was adjusted to 30 ml with distilled water and the pore size was 0.45.
Pressure filtration was performed at a pressure of 2.5 kg / cm ² with a μm membrane filter to obtain a clear solution containing allopurinol.

Example 6 24 g of 70% D-sorbitol solution, 30 mg of allopurinol, 30 mg of sodium polyacrylate and 6 g of distilled water were added, and the mixture was added at 15 ° C. at 15 ° C.
Stir for minutes. After cooling to 25 ° C, 30 mg of methyl p-aminobenzoate was added, and the total liquid volume was adjusted to 30 ml with distilled water, and then 2.5 with a membrane filter having a pore size of 0.45 µm.
Pressure filtration was performed at a pressure of kg / cm ² to obtain a clear solution containing allopurinol.

Example 7 Polyethylene glycol (P
EG4000) 7.5 g is dissolved in distilled water 12.5 g,
Then, add 15 mg of allopurinol and 450 mg of sodium carboxymethyl cellulose,
Stir for minutes. After cooling to 25 ℃, add distilled water to bring the total volume to 30
The solution was made up to a volume of 0.4 ml and filtered through a membrane filter having a pore size of 0.45 μm at a pressure of 2.5 kg / cm ² to obtain a clear solution containing allopurinol.

(Example 8) Polyethylene glycol (P
EG400) 9g, allopurinol 60mg, sodium polyacrylate 15mg and distilled water 21g,
The mixture was stirred under a nitrogen stream at 45 ° C for 45 minutes. After cooling to 25 ° C, make up the total liquid volume to 30 ml with distilled water and make the pore size 0.45μ.
The mixture was subjected to pressure filtration with an m membrane filter at a pressure of 2.5 kg / cm ² to obtain a clear solution containing allopurinol.

(Example 9) 16.5 g of glycerin, 24 mg of allopurinol and 13.5 g of distilled water were added, and 6
The mixture was stirred at 5 ° C for 35 minutes. After cooling to 25 ° C., 30 mg of methyl p-aminobenzoate was added, the total liquid volume was adjusted to 30 ml with distilled water, and suction filtration was performed using a filter paper (JIS5 type C) to obtain a clear solution containing allopurinol.

(Example 10) Glycerin 7.
5 g, PEG 1.5 g, and Hibiswako 60 mg were added, and after adjusting the pH to 4.5 with NaOH, allopurinol 30
mg was added and the mixture was stirred at 90 ° C. for 3 minutes. Next, water was added to adjust the total amount to 30 ml to obtain a liquid agent.

(Example 11) Glycerin 7.
5 g, PEG 1.5 g, and Carbopol 60 mg were added, pH was adjusted to 4.5 with NaOH, and allopurinol 0.1.
6 g was added and the mixture was stirred at 40 ° C. for 3 minutes. Next, water was added to adjust the total amount to 30 ml to obtain a liquid agent.

(Example 12) Glycerin 7.
5 g, PEG 1.5 g and citric acid 60 mg were added and the pH was adjusted to 4.2 with NaOH. 30 mg of allopurinol was added and stirred at 90 ° C. for 3 minutes. Next, water was added to adjust the total amount to 30 ml to obtain a liquid agent.

Example 13 18 g of water was mixed with 3.
75 g, 2N hydrochloric acid 1.15 g and PANA 250 mg were added, and the pH was adjusted to 4.0 with NaOH. 25 mg of allopurinol was added and stirred at 90 ° C. for 3 minutes. Then, water was added to adjust the total amount to 25 ml to obtain a liquid agent.

EXAMPLE 14 19 g of water was mixed with 3.
75 g, PEG 1.25 g, 2N hydrochloric acid 1.1 g, PA
200 mg of NA was added to adjust the pH to 4.0, 25 mg of allopurinol was added, and the mixture was stirred at 90 ° C. for 3 minutes. Next, water was added to adjust the total amount to 30 ml to obtain a liquid agent.

(Example 15) Glycerin 7.
5g, PEG 1.5g, CMC 180mg,
The pH was adjusted to 4.0 with hydrochloric acid at 60 ° C, 30 mg of allopurinol was added, and the mixture was stirred at 90 ° C for 3 minutes. Next, water was added to make the total volume 30 ml, whereby a liquid preparation was obtained.

(Examples 16 to 33) The amount of allopurinol was set to 30 mg (0.1% (W / V)), and the liquid formulations shown in Table 1 were prepared according to the following Examples.

The abbreviation Glyc in the table represents glycerin, and the numerical value representing the amount of the solubilizing agent added in parentheses is the liquid agent 30.
The weight of each solubilizing agent with respect to ml is expressed in% (W / V).

[0038]

[Table 1]

Reference Example 1 Cancer and Chemotherapy, 17:93
An allopurinol formulation was prepared according to the method described on page 1-933, (1990). (Production method) sodium carboxymethyl cellulose 5 g
And 500 mg of allopurinol in a sterilized mortar,
Sterile purified water was added, and the mixture was stirred and passed through a 50-mesh sieve. Sterile purified water was added to the obtained filtrate to bring the total volume to 500 ml.

Reference Example 2 Allopurinol 3 in 29 g of water
0 mg and PANA 240 mg were added, and it stirred at 90 degreeC for 30 minutes. After cooling to 25 ° C, add water to bring the total volume to 3
By adjusting the volume to 0 ml, the liquid preparation (the pH of this liquid preparation is 8.
4) was obtained.

(Stability Test) The stability of the liquid preparation of the present invention will be described below. Test method: 0.1 obtained in the above examples according to the present invention
The stability of the% allopurinol solution was tested by determining the remaining amount of allopurinol after heating at 90 ° C. for 24 hours by HPLC.

The results are shown in Table 2. In the table, the remaining amount of allopurinol is represented by a relative ratio with the content before the test being 1.

[0043]

[Table 2]

The liquid agent according to the present invention was very stable in the pH range, especially in the pH range of 3 to 5, and no change was observed in the appearance and the like.

In addition, the long-term stability of the above-mentioned liquid preparation is determined by filling the ampoule with the liquid preparation by a conventional method and storing it at 40 ° C for 6 months.
It was tested by determining the allopurinol content in the sample by HPLC. The content of allopurinol after the test was expressed as a relative ratio, with the content before the test being 1. In addition, the state of crystal precipitation and the appearance were also observed. The results are shown in Table 3.

[0046]

[Table 3]

As is clear from the above results, the liquid preparation of the present invention was very stable on the acidic side. In particular, the liquid formulation using PANA as a solubilizing agent was not only clear in appearance even after the test, but no crystals of allopurinol were deposited even when left at room temperature.

Next, the preventive and / or therapeutic effect test method for the stomatitis of the liquid agent of the present invention and the result thereof will be shown. (Test method) In the experiment, male Golden Syrian hamsters having a body weight of about 60 g were used in groups of 5 and the following groups A and B were used.
As a group and a group C, the effect of the liquid preparation of the present invention on stomatitis was tested.

(Group A: Liquid formulation of the present invention) Example 3 of the present invention
The solution obtained in No. 0 was applied to the left and right cheek pouches of a hamster with a cotton swab and then rubbed with a wire brush to give 5-FU (150 mg
/ Kg) was intraperitoneally administered, and then the solution was again applied with a cotton swab (day 0). Then, with a cotton swab on day 3, apply the liquid agent to the left and right cheek sac of the hamster, rub it, and remove with 5-FU.
After (100 mg / kg) was intraperitoneally administered, the liquid agent was applied again with a cotton swab. For day 4 to day 6, after applying the solution with a cotton swab, 5-FU (100 mg / kg) was administered and the solution was applied again with the cotton swab.

(Group B: Conventional preparation) Other than using the allopurinol preparation obtained in Reference Example 1 as a conventional preparation,
The treatment was performed in the same manner as the group A.

(C group: control group) The left and right cheek pouches of the hamster were rubbed with a wire brush to give 5-FU (150 mg / k).
g) was intraperitoneally administered (day 0). Then, day3
Then, scrape the cheek pouches on the left and right of the hamster into the 5-FU (1
(00 mg / kg) was intraperitoneally administered. day4 to da
5-FU (100 mg / kg) was administered to y6.

The animals in each group were sacrificed on day 7, and the cheek pouches on the left and right were excised, and the presence or absence of stomatitis was confirmed by the gross and histological findings of the cheek pouch.

(Test Results) (Group A) Of the 10 cases of the left and right buccal pouches, 3 cases were macroscopically black and ulcerated. In addition, histological ulcer was exhibited in 3 out of 10 cases. (Group B) Out of 10 cases of the left and right cheek pouches, 8 cases were macroscopically black and ulcerated. In addition, 8 out of 10 cases showed histological ulcer images. (Group C) Out of 10 cases of the left and right buccal pouch, 9 cases were macroscopically black and ulcerated. In addition, histological ulcer images were present in 9 out of 10 cases.

(Test Example 2) The preventive and / or therapeutic effect on stomatitis was compared in the same manner as in the above Test Example using the solution obtained in each of the above Examples and a sample in which the solution was stored at 40 ° C. for 6 months. However, similar results were obtained.

[0055]

Industrial Applicability According to the present invention, it is possible to provide a uniform and stable liquid agent having a high solubility of allopurinol and an appropriate viscosity, and a method for producing the same. This solution can be stored for a long period of time and is very useful as a mouthwash for the prevention and / or treatment of stomatitis. Also,
By providing the liquid agent according to the present invention, it was difficult to store the conventional liquid agent for a long period of time, and therefore, it was extremely useful in medical treatment because the troublesomeness of having to prepare the allopurinol liquid agent by spending a long time each time was treated. is there.

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Claims (5)

[Claims] 1. An allopurinol as an active ingredient, glycerin, polyethylene glycol (PEG),
And a liquid medicine for allopurinol, which comprises an aqueous solution containing at least one compounding ingredient selected from D-sorbitol. 2. The allopurinol pharmaceutical liquid preparation according to claim 1, wherein the liquid preparation has a pH on the acidic side. 3. At least one of the formulation components selected from glycerin, polyethylene glycol (PEG), and D-sorbitol is suspended or dissolved in water together with allopurinol, optionally with a solubilizer, and then obtained. A method for producing a pharmaceutical liquid preparation of allopurinol, which comprises adjusting the pH of the obtained aqueous solution or suspension to an acidic side. 4. A solution or solution obtained by suspending or dissolving in water at least one of the compounding ingredients selected from glycerin, polyethylene glycol (PEG), and D-sorbitol, optionally together with other solubilizing agents. A method for producing a pharmaceutical liquid preparation of allopurinol, which comprises adjusting the pH of a suspension to an acidic side, and then suspending or dissolving allopurinol in this dissolution or suspension. 5. The allopurinol medicinal solution is a preventive and / or therapeutic agent for stomatitis.
Or the pharmaceutical liquid preparation of allopurinol described in 2.