WO1998043643A1

WO1998043643A1 - Aqueous acyclovir solution preparations

Info

Publication number: WO1998043643A1
Application number: PCT/JP1998/001340
Authority: WO
Inventors: Mitsutoshi Kusumoto; Toshio Kasama; Mitsuru Noto; Susumu Oguro; Yuuki Nogami; Isao Hanazome; Tomoyuki Okamoto
Original assignee: Toa Medicine Co., Ltd.
Priority date: 1997-04-01
Filing date: 1998-03-26
Publication date: 1998-10-08

Abstract

Aqueous solution preparations of acyclovir, which is an antiviral agent hardly soluble in aqueous solutions having a pH value around neutrality and thus being applicable as drugs, wherein the solubility of acyclovir is sustained in the state of a stable aqueous solution. These preparations are obtained by solubilizing acyclovir by using boric acid and at least one solubilizing agent selected from among polyvinyl alcohol, hydroxyethylcellulose, methylcellulose and hydroxypropylmethylcellulose and regulating the pH value of the resultant aqueous solution within a range of 3 to 9. These preparations are usable as eye drops and nasal drops.

Description

Description acyclovir aqueous solution technical field

The present invention relates to an aqueous solution of acyclovir, which is an antiviral drug, and more particularly, to acyclovir, which is sparingly soluble in water, particularly a neutral pH which is hardly soluble in a neutral pH, and thus can be applied as a pharmaceutical. The present invention relates to an aqueous solution preparation which secures the solubility of acyclovir which is difficult to dissolve in an aqueous solution of the compound. Background art

Acyclovir (generic names: JAN, INN) [Chemical name: 9 — [(2-hydroxyhydroxy) methyl] guanine] is an antiviral agent with a purine skeleton, and is simply a herpes virus and varicella.広く Widely used as a treatment for infectious diseases caused by shingles virus, that is, herpes simplex, varicella, shingles, encephalitis, meningitis, etc. that occur in patients with reduced immune function (malignant tumor, autoimmune disease, etc.) It is a compound used clinically.

However, acyclovir has extremely low solubility in water, and is sparingly soluble, especially at pH near neutrality.Even if it is dissolved, crystals precipitate out in a short time, and it can be stored for a long time. The development of certain aqueous formulations has been described as difficult. For this purpose, acyclovir preparations that are currently used clinically are supplied as tablets, granules, ophthalmic ointments or lyophilized injections (injectable solutions that are dissolved at the time of use). At present, no formulation has appeared.

By the way, for treatment of keratitis caused by simple herpes virus, Clovir ophthalmic ointment is used, but ophthalmic ointment has the problems that it is relatively difficult to administer by itself and that the feeling of use is not very good. Therefore, development of an aqueous solution formulation that can be easily administered by patients themselves and that can be used as an ophthalmic solution of acyclovir with a good feeling of use is expected. Recently, there has been proposed an administration method for nasal absorption of a drug having low solubility in water. This is a formulation technique for absorbing a drug through the venous plexus of the nasal mucosa lamina propria of the nasal cavity. From this point of view, the development of an aqueous formulation containing acyclovir that can be a good nasal drop is expected. For this reason, several studies have been made on aqueous solutions of acyclovir. For example, Japanese Patent Application Laid-Open No. 7-247216 discloses a basic aqueous solution of acyclovir (having a pH of 10 to 1). 3) aqueous solution containing an aromatic carboxylic acid, an aliphatic carboxylic acid, an oxycarboxylic acid, a chelating agent and an alkali metal salt thereof as a stabilizer, or an antioxidant to a basic aqueous solution of acyclovir. Injectables containing sulfites have been proposed.

However, application of these infusions of acyclovir to aqueous solutions such as eye drops and nasal drops is inappropriate because the pH is too high. In addition, for application as eye drops or nasal drops, the pH of the aqueous solution must be 9 or less, but if the pH is 9 or less, acyclovir crystals precipitate in large quantities from the aqueous solution. However, it has a drawback that it cannot be applied to eye drops or nasal drops as a realistic aqueous solution preparation of acyclovir.

Also, Japanese Patent Application Laid-Open No. 8-268892 proposes an aqueous solution preparation in which a dissolution aid is mixed with acyclovir. In this aqueous solution formulation Polyvinylpyrrolidone is used as a dissolution aid for cyclovir, and a certain degree of solubility is ensured. However, a 0.1% aqueous solution of acyclovir using 5% polybulpyrrolidone has been used as an aqueous solution formulation that can be stored for a long period of time because crystals of acyclovir are precipitated in 10 days under refrigerator storage conditions. It still has its drawbacks. Therefore, an object of the present invention is to provide an aqueous solution of acyclovir which has solved the above problems. That is, the pH of a solution suitable for eye drops and nasal drops was set in the range of 3 to 9, and in the aqueous solution in which acyclovir was dissolved, no crystal precipitation of acyclovir was observed. It is intended to provide an aqueous solution preparation that can be stored for a long time.

Furthermore, the present invention relates to an ophthalmic solution particularly applied to the treatment of keratitis caused by simple herpes virus, which has been difficult to administer by the patient itself and has not been used well. An object of the present invention is to provide an aqueous solution preparation as an eye drop instead of an eye ointment.

Another object of the present invention is to provide an aqueous solution preparation as a nasal agent capable of nasal administration. Disclosure of the invention

To this end, a first aspect of the present invention provides acyclovir as at least one member selected from the group consisting of boric acid and polybutyl alcohol, hydroxyshethyl cellulose, methylcellulose or hydroxypropylmethylcellulose. Disclosed is a mouth building aqueous solution which is solubilized by a solubilizing agent. In this case, the present invention particularly has a concentration of acyclovir in the aqueous solution of about 0.01 to 0.5%, preferably about 0.05 to 0.3%, and more preferably about 0.05 to 0.2%. An aqueous solution formulation is provided.

The present invention also provides an aqueous solution of acyclovir which has a boric acid concentration of 0.1 to 3%, preferably 0.3 to 2%, and more preferably 0.5 to 1.8%.

Furthermore, the present invention provides an aqueous solution of acyclovir wherein the pH of the aqueous solution is in the range of 3 to 9, preferably 5 to 8.

Accordingly, the present invention provides, in the above-described specific embodiment, boric acid having a concentration of 0.1 to 3%, preferably 0.3 to 2%, more preferably 0.5 to 1.8%, and Solubilized with at least one solubilizing agent selected from polyvinyl alcohol, hydroxyethyl cellulose, methylcellulose or hydroxypropylmethylcellulose, and has a pH of 3 to 9, preferably 5 to 8. The present invention provides an aqueous solution of 0.01 to 0.5%, preferably 0.05 to 0.3%, more preferably 0.05 to 0.2% of acyclovir therein.

In another aspect, the present invention provides an aqueous solution of acyclovir comprising the above composition used as an eye drop, and further provides an aqueous solution of acyclovir comprising the above composition used as a nasal drop. . BEST MODE FOR CARRYING OUT THE INVENTION

The aqueous solution of acyclovir provided by the present invention is characterized in that it is a stable aqueous solution in which crystals of acyclovir do not precipitate even under long-term storage conditions. This point is characterized by the fact that boric acid and polybutyl alcohol are used for acyclovir. At least one solubilizing agent selected from the group consisting of hydroxyethyl cellulose, methylcellulose and hydroxypropylmethylcellulose Is achieved by using

Incidentally, polyvinyl alcohol, hydroxymethyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose used in the present invention are generally used as solubilizers. Thus, a satisfactory aqueous solution formulation cannot be obtained even if the solubility of acyclovir is improved. However, surprisingly, when used in aqueous solution of acyclovir in combination with boric acid, the long-term storage stability of the resulting aqueous solution of acyclovir was very good. Such a point has not yet been studied at all, and is a completely unexpected new technology obtained as a result of intensive studies by the present inventors. The concentration of acyclovir in the aqueous solution preparation provided by the present invention may be 0.00 from the viewpoint of the applied therapeutic purposes such as the fact that the aqueous solution formulation is used as an eye drop or a nasal drop and the effective concentration for expressing the effect of acyclovir. It is about 1-0.5%, preferably about 0.05-0.3%, particularly preferably about 0.05-0.2%.

The concentration of boric acid used for dissolving acyclovir is about 0.1 to 3%, preferably about 0.3 to 2%, particularly preferably about 0.5 to 1.8%. I just need.

On the other hand, the amount of polybutyl alcohol, hydroxyethyl cellulose, methylcellulose, or hydroxypropylmethylcellulose cannot be determined unconditionally depending on the concentrations of acyclovir and boric acid in the aqueous solution. It is sufficient if used in a sufficient amount to secure Polyvinyl alcohol includes completely saponified products and partially saponified products, but it is preferable to use partially saponified products. No.

In the aqueous solution preparation of the present invention, in particular, the pH of the aqueous solution is adjusted to a range of 3 to 9 which is optimal for eye drops, for example, by using boric acid. Even when polyvinyl alcohol, hydroxyethyl cellulose, methylcellulose or hydroxypropylmethylcellulose is used in combination, no crystal precipitation of acyclovir is observed. In the aqueous solution preparation of the present invention, if necessary, various isotonic agents, preservatives, thickening agents, PH regulators and other excipients, which are widely used in the technical field of aqueous solution preparations. May be added.

Examples of such isotonic agents include sodium chloride, potassium chloride, sodium citrate, glycerin, d-sorbitol, d-mannitol, xylitol, propylene glycol and the like. Preferably, glycerin is added. The tonicity agent is preferably blended so that the osmotic pressure ratio of the aqueous solution preparation of the present invention is in the range of 0.5 to 3.0, particularly preferably 0.8 to 1.5. Is good.

Examples of preservatives include parabens such as methylparaben, ethylparaben, and propylparaben; quaternary ammonium salts such as benzalkonium chloride and benzenetonium chloride; phenyl alcohol; chlorobutanol; and preferably parabens. Good to add.

Further, as the thickening agent, polybutylpyrrolidone, alginic acid, co- ^ sodium droitin sulfate, polyethylene glycol and the like can be used. In the aqueous solution preparation of the present invention, polyvinyl pyrrolidone as such a thickening agent is used in combination with boric acid, polyvinyl alcohol, and hydroxyxide. It has proved particularly preferred to use with one or more solubilizers selected from tylcellulose, methylcellulose or hydroxypropylmethylcellulose.

As the PH adjuster in the present invention, borax, phosphoric acid, carbonic acid and alkali metal salts thereof, such as hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and the like can be used, and preferably borax is added. Is good. In the aqueous solution preparation of the present invention, the pH is preferably in the range of 3 to 9, and more preferably the pH is in the range of 5 to 8.

Other excipients include sulfite compounds, sodium edetate, sodium glutamate, sodium thiosulfate, epsilonaminocaproic acid, creatine, glucose, monoethanolamine, benzyl alcohol, various nonionics Alternatively, an amphoteric surfactant or the like can be used.

These isotonic agents, preservatives, thickeners, PH regulators and other excipients are used in the aqueous solution provided by the present invention under the condition that dissolved aciclovir is stored for a long period of time. It is appropriately selected and used within a range that does not cause crystal precipitation and according to the intended use of the aqueous solution preparation.

Therefore, in a more specific preferred embodiment of the aqueous solution preparation of the present invention, acyclovir is used at a concentration of 0.1 to 3%, preferably 0.3 to 2%, more preferably 0.5 to 1.8%. And solubilized with at least one solubilizing agent selected from the group consisting of boric acid, and polyvinyl alcohol, hydroxyethyl cellulose, methylcellulose, or hydroxypropylmethylcellulose, and its pH is 3 to 9 Preferably, the concentration of acyclovir is between 0.01 and 0.5%, preferably between 0.05 and 0.3%, more preferably between 0.05 and 0.2%. It is an aqueous solution, and polyvinylpyrrolidone is added to it. It is also an aqueous solution of acyclovir added. In the aqueous preparation of acyclovir of the present invention prepared in this manner, acyclovir is dissolved in a stable state, and crystals of the suspended substance acyclovir precipitate in the aqueous solution even under long-term storage conditions. The pH of the aqueous solution is not in the range of 3 to 9, but it can be formulated into good eye drops or nasal drops.

Therefore, as a preferable specific example in another embodiment of the present invention, use of the specific aqueous solution of acyclovir described above as an eye drop and use as a nasal preparation capable of nasal administration are also mentioned. Example

Hereinafter, the present invention will be described in detail with reference to Examples and a storage stability test, but the present invention is not limited to these Examples.

Example 1:

1,400 mg of boric acid, 800 mg of borax and 350 mg of polyvinyl alcohol were added to sterile purified water, and dissolved by heating and stirring. Then, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and the total volume was adjusted to 10 Om1 with sterile purified water. The solution was sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.8.

Example 2:

L Boric acid, OO Omg, borax 280 mg, and polyvinyl alcohol 70 Omg were added to sterile purified water, and dissolved by heating and stirring. Next Then, add 1 Omg of methyl paraoxybenzoate, 20 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 1.0 mg of glycerol to this solution, and bring up the total volume to 100 ml with sterile purified water. The solution was sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.3.

Example 3:

1,400 mg of boric acid, 800 mg of borax and 350 mg of polyvinyl alcohol were added to sterile purified water, and dissolved by heating and stirring. Next, 13 mg of methyl parahydroxybenzoate, 17 mg of propyl para-hydroxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and 100 mg of hydroxyxetyl cellulose was further added. . The total volume was adjusted to 100 ml with sterile purified water, and then sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.8.

Example 4:

1,400 mg of boric acid, 800 mg of borax and 350 mg of polyvinyl alcohol were added to sterile purified water, and dissolved by heating and stirring. Next, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and 10 Omg of hydroxypropyl methylcellulose was further added. The total amount was adjusted to 10 Om1 with sterile purified water, and then sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution and its pH was 7.8. Example 5:

1,400 mg of boric acid, 800 mg of borax and 350 mg of polyvinyl alcohol were added to sterilized purified water, and dissolved by heating and stirring. Next Then, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and 2,000 mg of polyvinylpyrrolidone was further added. The total volume was made up to 100 ml with sterile purified water, and the solution was sterilized by filtration to obtain an aqueous solution of an oral building. This solution was a clear aqueous solution and its pH was 7.8.

Example 6:

1,600 mg of boric acid, 60 Omg of borax and 35 Omg of polyvinyl alcohol were added to sterilized purified water, and dissolved by heating and stirring. Next, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and the total amount was adjusted to 10 Om1 with sterile purified water. The solution was sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.5.

Example Ί:

1,500 mg of boric acid, 750 mg of borax and 35 mg of polybutyl alcohol were added to sterilized purified water, and dissolved by heating and stirring. Next, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 100 mg of acyclovir and 200 mg of glycerin were added to this solution, and the total amount was adjusted to 10 Om1 with sterile purified water. The solution was sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.7.

Example 8: 1,500 mg of boric acid, 750 mg of borax, 350 mg of polybutyl alcohol, and 250 mg of hydroxyxethyl cellulose were added to sterilized purified water, and dissolved by heating and stirring. Then the solution was added to this solution. Add 13 mg of methyl perfate, 17 mg of propyl paraoxybenzoate, 150 mg of acyclovir, 1,000 mg of glycerin, 500 mg of d-mannitol, and 2,000 mg of polyvinylpyrrovidone, and sterile purified water. The total volume was adjusted to 100 ml and sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution and had a pH of 7.1.

Example 9:

1,500 mg of boric acid, 750 mg of borax, 350 mg of polybutyl alcohol and 250 mg of methylcellulose were added to sterilized purified water, and dissolved by heating and stirring. Then, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 15 Omg of acyclovir, 1,000 mg of glycerin, 500 mg of d-mannitol and 2,000 mg of polybutylpyrrolidone were added to this solution. Was added, the total amount was adjusted to 100 ml with sterile purified water, and the mixture was sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.1. Example 10:

1,500 mg of boric acid, 750 mg of borax, 30 Omg of hydroxyxethyl cellulose and 300 mg of hydroxypropylmethylcellulose were added to sterilized purified water, and dissolved by heating and stirring. Next, 13 mg of methyl paraoxybenzoate, 17 mg of propyl paraoxybenzoate, 50 mg of acyclovir, 1,000 mg of glycerin, 500 mg of d-mannitol, and 2,000 mg of polyvinylpyrrolidone were added to this solution. Then, the total amount was adjusted to 10 Om1 with sterilized purified water, and then sterilized by filtration to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution, and its pH was 7.5.

Example 11: Dagger

1,500 mg of boric acid, 75 mg of borax and 300 mg of hydroxyxethyl cellulose were added to sterilized purified water, and dissolved by heating and stirring. Next, 13 mg of methyl paraoxybenzoate, 17 mg of peptic pill of paraoxybenzoate, 200 mg of acyclovir, 500 mg of glycerin, 500 mg of benzyl alcohol and 2,0 mg of polyvinylpyrrolidone were added to this solution. 100 mg was added, and the total amount was adjusted to 100 ml with sterile purified water, followed by filtration and sterilization to obtain an aqueous solution of acyclovir. This solution was a clear aqueous solution and had a pH of 7.6.

As a comparative example, an aqueous solution formulation of the following formulation without using boric acid and polybutyl alcohol of the present invention was obtained.

Acyclovir 0.1% Polyvinylpyrrolidone 6.0 0 0 0% Boric acid 0.90 0% Borax 0.20 0% Methyl parahydroxybenzoate 0.01 3% Propyl paraoxybenzoate 0.01 3% glycerin 0.1 100% purified water ―

100 ml in total amount Storage stability test 1: Change in cold storage:

The storage stability under refrigerator storage conditions was examined using both the aqueous solution formulation of acyclovir obtained in Example 1 and the aqueous solution formulation obtained in Comparative Example, which are the aqueous solution formulations of the present invention. Each test solution was placed in a polyethylene container and stored in a refrigerator, and changes in the solution over time were observed.

As a result, the medicinal solution of the comparative example became cloudy in seven days under refrigerator storage conditions and precipitation of acyclovir crystal was observed.However, the medicinal solution of Example 1 of the present invention showed that The solution remained transparent even on the moon, no change in the appearance of the drug solution was observed, and no crystal precipitation of acyclovir occurred. Storage stability test 2: Changes under severe and accelerated conditions:

With respect to the aqueous solution preparation of the present invention, changes in the content of acyclovir in the drug solution under severe conditions were examined.

Method :

The drug solution of the aqueous solution of acyclovir obtained in Example 1, which is the aqueous solution preparation of the present invention, was placed in a polyethylene container and allowed to stand at a temperature of 60 ° C. The change in the content of acyclovir in water was determined by liquid chromatography (HPLC).

In addition, the chemical solution was left under a light exposure condition of 120,000 lux, and similarly, the change in the content of acyclovir in the chemical solution was determined by HPLC.

The solution was left under accelerated conditions at a temperature of 40 ° C and a humidity of 75%, and after 1 month, 3 months and 6 months, changes in the content of acyclovir in the drug solution were determined by HPLC. I asked.

Result:

The content of acyclovir at the start of the test of the test drug solution was assumed to be 100%, and the change in the content of acyclovir in the drug solution under each test condition was expressed as a residual rate, and is shown in the following table. Table: Severity and acceleration test results

As is clear from the results in the table, the aqueous solution of acyclovir of the present invention does not show a decrease in the content of acyclovir under any severe or accelerated test conditions, and has excellent storage stability. It is understood that. Under these severe and accelerated test conditions, no crystal precipitation of acyclovir was observed in the test solution. In the same test, no decrease in the content of acyclovir was found in the chemical solution of the aqueous solution of acyclovir based on the formulation in the other examples. Industrial applicability

As described above, in the present invention, acyclovir was solubilized with boric acid and at least one or more solubilizing agents selected from polybutyl alcohol, hydroxyethyl cellulose, methylcellulose and hydroxypropylmethylcellulose. The use of the aqueous solution preparation has an advantage that an ophthalmic and nasal aqueous solution preparation having good storage stability and free from crystal precipitation of acyclovir from the aqueous solution can be provided.

In particular, acyclovir ophthalmic solution using this aqueous solution can be administered by the patient itself and has a good feeling of use compared to ophthalmic ointment, and corneal caused by simple herpes virus can be used. It has a great contribution to the treatment of inflammation.

Claims

The scope of the claims

1. Acyclovir is solubilized with boric acid and at least one solubilizing agent selected from polyvinyl alcohol, hydroxyethyl cellulose, methylcellulose, or hydroxypropylmethylcellulose. Acyclovir aqueous solution preparation.

2. The aqueous solution of acyclovir according to claim 1, wherein acyclovir is solubilized with boric acid and polybutyl alcohol.

3. The aqueous solution of acyclovir according to claim 2, further comprising at least one of hydroxyxethyl cellulose, methyl cellulose and hydroxypropyl methyl cellulose.

4. The aqueous solution of acyclovir according to claim 1, wherein acyclovir is solubilized with boric acid, hydroxyshethyl cellulose and / or hydroxypropylmethylcellulose.

5. The aqueous solution of acyclovir according to any one of claims 1 to 4, wherein the concentration of acyclovir in the aqueous solution is 0.01 to 0.5%.

6. The aqueous solution of acyclovir according to any one of claims 1 to 4, wherein the concentration of boric acid is 0.1 to 3%.

7. The aqueous solution of acyclovir according to any one of claims 1 to 6, further comprising polybutylpyrrolidone.

8. The aqueous solution of acyclovir according to any one of claims 1 to 7, wherein the pH of the aqueous solution is in the range of 3 to 9.

9. The aqueous solution of acyclovir according to any one of claims 1 to 8 as an eye drop.

10. The aqueous solution of acyclovir according to any one of claims 1 to 8 as a nasal drop.