WO2002026234A1 - Eye drops comprising acyclovir suspension - Google Patents

Abstract

It is intended to provide eye drops comprising an acyclovir suspension whereby the precipitation/sedimentation and crystal transition of acyclovir can be prevented. Eye drops containing an acyclovir suspension which comprise acyclovir and at least one compound selected from the group consisting of polyacrylic acid, carboxyvinyl polymer, carboxymethylcellulose, alginic acid and pharmaceutically acceptable salts thereof and by which the precipitation/sedimentation of acyclovir can be prevented.

Description

 Specification

 Acyclovir suspension eye drops

Technical field

 TECHNICAL FIELD The present invention relates to an ophthalmic oral ophthalmic suspension capable of suppressing the sedimentation and deposition of acyclovir suspended particles.

Background art

 A simple virus is a type of virus that infects the skin, mucous membranes, nerves, etc., and is divided into type 1 and type 2. Type 1 lives around the lips and eyes, type 2 lives in the genitals and anus. Type 1 virus is a virus that causes lip health, and most people are infected with this virus by adulthood, but it is clear when infected for the first time. Only about 10% of patients have severe symptoms, usually no normal symptoms, and only slight swelling and pain in the mouth and throat. After the initial infection, the virus lurks in the nerve cells that control the eyes and skin. However, it suddenly develops when the resistance of the body or the skin decreases.

 The most common type of skin disease caused by simple herpes type 1 is lip herbs, which are formed by small blisters gathering on the lips. It is mildly feverish and painful, but subjective symptoms are generally mild and self-healing.

—On the other hand, the most common eye disease caused by simple herpes type 1 is corneal infection. This is a recurring process, and in very rare cases, blindness. A corneal infection caused by simple virus will begin on the surface, causing the eyes to turn red, mildly painful, and light sensitive, but usually not worse. . However, a corneal infection may recur in one in four people within two years. Infections can spread deeper into the cornea, causing the cornea to become cloudy and irritated in the eyes.Chronic ulcers in the cornea caused by simple hernia are very difficult to heal. It will be. If the cornea is severely clouded and vision is significantly reduced, corneal transplantation may be necessary. In addition, in people with very low resistance, simple hernia may be present in parts of the eye other than the cornea (such as the retina) and other parts of the body. It can also infect parts (such as the brain). Therefore, when simple herpes virus infects the eye, it is necessary to promptly give appropriate treatment.

 Acyclovinole (9 — {[2-hydroxyethoxy] methyl} guanine) is an antiviral agent that has high selectivity for herpes group virus-infected cells and low damage to normal cells. It is used in the form of tablets, ointments and the like.

 Acyclovir has a low solubility in water of 0.1% wV and is sparingly soluble. It is soluble in acidic or alkaline aqueous solutions, but is unstable in aqueous solutions. Therefore, when used as an ophthalmic preparation for keratitis caused by simple herpes virus, it is used in the form of an ointment.

 Applying an ointment to the patient's own eyes is quite painful and painful, and it is a highly resistant act.In addition, it is necessary to administer it about 5 times a day. It is troublesome and not easy. Another problem is that white vaseline, which is used as a base in the preparation of ophthalmic ointments, blocks the field of vision every time it blinks after being applied to the eyes. For this reason, there has been a strong demand for ophthalmic acyclovir preparations in the form of eye drops.

 When injection mouth is used as an injection, sodium hydroxide is added as a pH regulator, solubilized to a pH of 10 or more, converted into an aqueous solution, freeze-dried, and dissolved when used. . However, the aqueous solution could not be used as an eye drop because the pH was 10 or more.

 The present inventors have been investigating the use of a dissolving agent to make pacific mouth building into an aqueous formulation (WO 99/6 3968, WO 99/1 6447), but in any case, the prescription of a water solution near neutral was used. On the other hand, it was not sufficient to dissolve a stable amount of asci mouth building in a stable and uniform manner over a long period of time to obtain the same antiviral activity as ophthalmic ointment ointment. Attempts have also been made to use acyclovir as a suspension ophthalmic solution (JP-A-10-287552, JP-A-11-228386). There are serious problems such as:

In order to obtain sufficient antiviral activity, it is necessary to make the content of ascid mouth building 1 to 3 w / v%, and the drug content is higher than that of ordinary suspension eye drops. For this reason, Although the number of suspended particles in Shikuguchi Building increases, these suspended particles easily settle and accumulate during storage of the drug product. Once settled, the suspended particles form a hard cake, and it is very difficult to re-disperse the suspended particles once formed. Therefore, it becomes difficult to administer a certain amount of oral mouth building over time with such an oral mouth suspension, and the effective concentration of acyclovir decreases, and sufficient antiviral activity is obtained. I can't get it.

 In addition, it was clarified that when the acyclovir suspension was stored, a crystal transition occurred from the plate-like crystals to the needle-like crystals, and that the needle-like crystals or the original plate-like crystals grew. There were problems such as the change in pharmacokinetics of oak mouth building in ocular tissues due to crystal transition, and the increase in irritation during eye drops depending on the crystal form.

 In order to obtain drug approval, the quality must be stable, usually three years, at least one year or more. From this viewpoint, stable acyclovir suspension eye drops have been demanded. Summary of the Invention

 The present invention has been made in view of the above circumstances, and has as its object to provide an acyclovir suspension ophthalmic solution capable of suppressing sedimentation and deposition of acyclovir suspension particles.

 The present invention is an acyclovir suspension ophthalmic solution capable of suppressing the sedimentation and / or crystal transition of aciguchi building.

 The first acyclovir suspension ophthalmic solution of the present invention is acyclovir, and at least one selected from the group consisting of polyacrylic acid, carboxybutyl polymer, carboxymethylcellulose, alginic acid, and pharmaceutically acceptable salts thereof. Which suppresses sedimentation of acyclovir.

The ophthalmic suspension of acyclovir of the second invention comprises acyclovir, and at least one compound selected from the group consisting of methylcellulose, carboxymethylcellulose, and pharmaceutically acceptable salts thereof. Crystal transfer is suppressed. The third ophthalmic suspension of acyclovir according to the present invention contains acyclovir, carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and is capable of suppressing the sedimentation and crystal transition of the aciclovir building.

 As the carboxymethylcellulose salt, carboxymethylcellulose sodium is preferred.

 When the ophthalmic oral building suspension ophthalmic solution of the present invention contains carboxymethylcellulose sodium and chlorobutanol is used as a preservative, the tonicity agent may be sodium chloride, glycerin, D-mannitol, or And propylene glycol are preferably used.

 When the ophthalmic oral building suspension ophthalmic solution of the present invention contains carboxymethylcellulose sodium and parabens are used as preservatives, propylene glycol is preferably used as the tonicity agent.

 When the ophthalmic oral building suspension ophthalmic solution of the present invention contains carboxymethylcellulose sodium and thimerosal is used as a preservative, the tonicity agent may be sodium chloride, glycerin, D-mannite, or propylene. Glycol is preferably used. Detailed Disclosure of the Invention

 Hereinafter, the present invention will be described in detail.

In this specification, the sedimentation of the Ashiguchi Building means that the suspended particles of the Ashiguchi Building settle and deposit during storage of the drug product, and as a result, the sedimented suspended particles form a hard cake. Means that acyclovir undergoes a crystal transition, which means that acyclovir undergoes a crystal transition from a plate-like crystal to a needle-like crystal, and further the needle-like crystal or the original plate-like crystal grows. Also, that these are suppressed means that these phenomena are suppressed as compared with a case where acyclovir is simply suspended in water. The ophthalmic suspension of ophthalmic solution of the present invention contains aciclovir which is an anti-herbal agent as an active ingredient. The acyclovir used in the present invention also includes this pharmaceutically acceptable salt. The pharmaceutically acceptable salts include, for example, hydrochloride, sulfate, nitrate, acetate, citrate, sodium salt, potassium salt, calcium salt And the like.

 The present inventors studied the effects of various additives on the sedimentation and Z or crystal transition of the ash mouth building, and as a result, found that the additive having an inhibitory effect on the sedimentation and the Z or crystal transformation of acyclovir. The agent was found, and the present invention was completed. A first aspect of the present invention is characterized in that it contains polyacrylic acid, carboxyvinyl polymer, carboxymethylcellulose, alginic acid, or a pharmaceutically acceptable salt thereof. It is. These additives may be used alone or in combination of two or more.

 In a pharmaceutical sense, a physically stable suspension means that the particles are uniformly dispersed throughout the dispersion. However, in practice, it is almost impossible to maintain such a state for a long period of time so that the particles do not settle. Therefore, two approaches are usually considered when designing a suspension formulation. One is the uniform dispersion of non-agglomerated particles by using a structured base, and the other is the application of the principle of flocculation, which sediments quickly but is easily resuspended by gentle shaking. Making turbid flocks. When the former non-agglomerated system is used, there is a problem that a hard cake is formed when the particles finally settle.

 The present inventors added various additives to the suspension of the mouth-mouthed building, and screened the additives causing the suspended particles of the mouth-opening to cause flocculation.

 As a result, it was found that polyacrylic acid, carboxyvinyl polymer, carboxymethyl cellulose, alginic acid, and salts thereof caused flocculation of suspended particles of acyclovir.

 The second suspension of ophthalmic suspension of the present invention is characterized by containing methylcellulose, carboxymethylcellulose, or a pharmaceutically acceptable salt thereof. These additives may be used alone or in combination of two or more.

As described above, it is clear that when the acyclovir suspension is stored, a crystal transition occurs from the plate-like crystals to the needle-like crystals, and further, it is clear that the needle-like crystals or the original plate-like crystals grow. became. When acyclovir undergoes such a crystal transition, eye tissue It is not preferable because the pharmacokinetics of the oral mouth building changes in, and the crystal form may cause an increase in irritation upon instillation.

 The present inventors added various additives to the suspension of acyclovir, and screened the additive for suppressing the crystal transition of acyclovir during storage (5 ° C. or 25 ° C.). As a result, it was revealed that methinoresenololose, canoleboxy methinoresenololose, and salts thereof suppress the crystal transition of acyclovir.

 As the additive for suppressing the crystal transition of the lacquer building, carboxymethyl resenorelose is particularly preferred.

 Drugs are usually stored at room temperature. For this reason, the temperature of the stored drug fluctuates depending on the outside air temperature. Assuming this, the suspension of ash mouth building to which methylcellulose, carboxymethylcellulose or a salt thereof was added was stored at a temperature cycle of 5 ° C to 40 ° C (one week each). The temperature cycle of 5 ° C to 40 ° C is a severe condition in which foreign substances are likely to occur in pharmaceuticals. Methylcellulose failed to suppress the crystalline transition of acyclovir in this temperature cycle test. On the other hand, carboxymethylcellulose and its salts were able to suppress the crystal transition of ash mouth building in the temperature cycle test.

 The combination of the additive for suppressing the sedimentation and accumulation of the ash mouth building used in the first invention and the additive for suppressing the crystal transition of the ash mouth building used in the second invention is used. An acyclovir suspension ophthalmic solution capable of simultaneously suppressing both sedimentation and crystal transition can be obtained.

 Such acyclovir suspension ophthalmic solution is also one of the present invention.

 A third aspect of the present invention is characterized by containing carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

 As described above, carboxymethylcellulose is an additive that has both effects of suppressing sedimentation and deposition of acyclovir and suppressing the crystal transition of acyclovir.

Accordingly, by adding carboxymethylcellulose to the suspension of aciclovir, it is possible to obtain an ophthalmic suspension of acyclovir capable of simultaneously suppressing both sedimentation and crystal transformation of acyclovir. The pharmaceutically acceptable salts of the above-mentioned various additives are not particularly limited, but, for example, sodium salts, potassium salts, calcium salts and the like can be easily obtained.

 As the above-mentioned salt of carboxymethyl cellulose, carboxymethyl senorellose sodium is preferable. Canoleboximethy / resenololose sodium can suppress sedimentation and crystal transformation well.

 The concentration of sodium carboxymethyl cellulose in the suspension of acyclovir in the present invention needs to be a certain concentration in order to simultaneously suppress both sedimentation and crystal transformation of acyclovir during storage. If the concentration is high, the viscosity of the eye drops increases, and resuspension by light shaking becomes difficult, which is not preferable. The viscosity is preferably l O OmPas or less, and the lower is more preferable. On the other hand, the effect of increasing the concentration of carboxymethylcellulose sodium is more effective in suppressing crystal transition, and is preferably 0.5 w / v% or more, more preferably 1 w / v% or more. Therefore, it is preferable to use sodium carboxymethylcellulose having a 2 w / V% viscosity of 5 OmPa as or less (25 ° C.). 2 wZ V% Viscosities of 5 OmPa · s or less (25 ° C) are commercially available carboxymethyl senorelose sodium, for example, Cellogen F-7A, F-8A, PR_S, And F-SL (all manufactured by Daiichi Kogyo Seiyaku Co., Ltd.).

 Among the additives used in the present invention, carboxymethyl cellulose is known to be used as a thickener in aqueous preparations. However, there has been no report that carboxymethylcellulose was used with Ashikuguchi Building.

 It is also known that propyloxymethylcellulose has an action of suppressing the crystal transfer of certain compounds in an aqueous suspension. That is, it has been reported that carboxymethylcellulose inhibits the crystal transition of chlorotetracycline hydrochloride (CTC-HC1) in an aqueous suspension (Chem. Pharm. Bu11. (1 97 6), 24 (9), 20 94—2 101).

On the other hand, it is known that carboxymethylcellulose has an effect of promoting crystal transition for other kinds of compounds. That is, carboxymethylcellulose promotes the crystalline transition of sulfamethoxazole, a long-acting sulfa drug, in an aqueous suspension. (Pha rm. Ind. (1 982), 44 (10), 107 1—10 74). It has been reported that carboxymethylcellulose temporarily suppresses the crystal transition of sulfamethoxydiazine in an aqueous suspension, but its inhibitory effect decreases with time (J. Pharm. Pharma). col. (1 9 7 3), 25 (1), 1 3—20).

 Therefore, the effect of carboxymethylcellulose on the crystal transition of a compound in an aqueous suspension is different depending on the compound.

 The acyclovir suspension ophthalmic solution of the present invention may further appropriately contain a preservative, an isotonic agent, a buffering agent, and the like which are usually used in eye drops.

 Examples of the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and chlorhexidine dalconate; phenolic phenols such as chlorobutanol, fueno, retinoleanolonecone, and benzinoleanoloneole; Examples include parabens such as methinoleparaben, ethylparaben, propylparaben, and butylparaben; organic acids such as sodium dehydroacetate, sorbic acid, and sorbic acid potassium and salts thereof; and mercury-based preservatives such as thimerosal. These may be used alone or in combination of two or more. In addition, a surfactant or a chelating agent can be appropriately added.

 When the ophthalmic oral suspension of the present invention contains carboxymethylcellulose sodium, chlorobutanol and parabens are suitably used as the preservative.

 These components are generally used in the range of about 0.001 to 2 wZv%, preferably about 0.002 to 1 wV%.

 Examples of the tonicity agent include salts such as sodium chloride and sodium phosphate; sugars such as glucose; alcohols such as glycerin, sorbitol, propylene glycol, and polyethylene glycol, and D-mannite. . These may be used alone or in combination of two or more.

When the ophthalmic oral building suspension ophthalmic solution of the present invention contains carboxymethylcellulose sodium and chlorobutanol is used as the preservative, the tonicity agent may be sodium chloride, glycerin, D-man. Knit or propylene grease A call is preferably used.

 When the ophthalmic oral building suspension ophthalmic solution of the present invention contains carboxymethylcellulose sodium and parabens are used as the preservative, propylene glycol is preferably used as the tonicity agent.

 When the acyclovir suspension ophthalmic solution of the present invention contains sodium carboxymethylcellulose and thimerosal is used as the preservative, the tonicity agent may be sodium chloride, glycerin, D-mannitol, or propylene glycol. Is preferably used.

 Examples of the buffer include alkali metal salts of acids such as phosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid, and carbonic acid; amino acids such as glutamic acid, ε-aminocaproic acid, aspartic acid, glycine, arginine, and lysine; And trishydroxymethylamino methane. These may be used alone or in combination of two or more.

 The ρΗ of the ophthalmic oral suspension of the present invention is not particularly limited as long as it is within the range normally accepted as an eye drop, but is preferably Η4.5 to 8.3, more preferably ρΗ5 5 to 8.0, and more preferably ρΗ6.0 to 8.0.

 The content of the oral mouth building in the oral mouth building suspension of the present invention may be appropriately determined depending on the disease state, age, etc., and is preferably 1 to 3 wZv%, more preferably. 2-3 wZv%.

 The number of times of administration of the oral ophthalmic suspension of the present invention may be appropriately determined according to the concentration of oak oral building in the ophthalmic suspension, the disease state, the age, etc., and is preferably about 5 times a day. . BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples.

(Example 1-3, Comparative Example 16-19, 23) Distilled water was added to 0.5 g of ε-aminocaproic acid and dissolved. Next, 2 g of acyclovir was added and the mixture was stirred well until it became homogeneous. Further, while stirring, a predetermined amount of a solution obtained by heating and dissolving the additives listed below with a small amount of distilled water was added. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 5.5, and distilled water was added to make 10 OmL.

Additives: sodium alginate, sodium carboxymethylcellulose (sodium CMC), sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, gellan gum, sodium hyaluronate (Example 4, Comparative Examples 11-15, 24)

 Distilled water was added to 0.5 g of ε-aminocaproic acid and dissolved. Next, 2 g of acyclovir was added and the mixture was stirred well until it became homogeneous. Further, while stirring, a predetermined amount of a solution obtained by dissolving the following additives with a small amount of distilled water was added. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 5.5, and distilled water was added to make up to 10 OmL. Additives: Carboxyvinyl polymer, aluminum potassium sulfate (alum), aluminum sulfate, aluminum chloride, magnesium chloride, calcium chloride, sodium EDTA, polysorbate 80, polyoxyethylene hydrogenated castor oil & 0 (HCO-60), stearin Acid polyoxynole 40, lauromacrogone, D-mannitol, glycerin, propylene glycol, polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG 4000), sodium chondroitin sulfate

(Comparative Example 20)

f-Aminocaproic acid was dissolved in 0.5 g of distilled water. Next, 2 g of cyclovinyl was added, and the mixture was stirred well until it became uniform. Further, while stirring, a predetermined amount of a solution obtained by cooling and dissolving Pluronic F127 with a small amount of distilled water was added. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 5.5, and distilled water was added to make 10 OmL. (Comparative Example 21-2)

 f-Aminocaproic acid was dissolved in 0.5 g of distilled water. Next, 2 g of acyclovir was added and the mixture was stirred well until it became homogeneous. Further, the following additives were dispersed in a small amount of hot water, and then cooled. A predetermined amount of the clear solution was added with stirring. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 5.5, and distilled water was added to make 100 mL.

Additives: Methynoresozerolorose, Hydroxypropinolemethinoresenolerose (HPMC) 5 mL of each of the obtained pacific mouth building suspensions was filled into a test tube and shaken well. They were allowed to stand at 25 ° C and the floculation effect of the additives was examined. The flocculation effect was examined by comparing the height of the sedimentation surface one week later with the control. A control prepared in the same manner as in Example 1 except that no additive was added was used as a control. The results are shown in Table 1.

Suppression effect of sedimentation surface decrease after one week (vs. control)

 1 1.E-01 1.E-02 lE-03 1.E-04 1.E-05 Example 1 Sodium Alginate 〇 XXXX One Example 2 Sodium CMC 〇 XXX — Example 3 Sodium Polyacrylate 〇 o XXX — Example 4 Carboxyvinyl polymer 〇 XXX 铰 ミ 铰 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

 Comparative Example 3 Aluminum chloride X X X X X — Comparative Example 4 Magnesium chloride X X X X X

 Comparative Example 5 Calcium chloride X X X X X

 Comparative Example 6 Sodium EDTA X X X X X

 Comparative Example 7 Polysorbate 80 X X X X X

 Comparative Example 8 HCO60 X X X X X

 Comparative Example 9 Polystearate / Polyester 40 X X X X X

 Ratio shelf 10 Lauro Macro Gonore X X X X X

 Comparative Example 11 D-mannite

 Comparative Example 12 Glycerin X X X X X

 Comparative Example 13 Propylene Glyco / X X X X X X

 Comparative Example 14 PEG400 X X X X X

 Comparative Example 15 PEG4000 X X X X X

 Comparative Example 16 Polyvinyl alcohol X X X X X

 Comparative Example 17 Polybutylpyrrolidone K25 X X X X X

 Comparative Example 18 Gelatin X X X X X

 Comparative Example 19 Gellan Gum X X X X X Comparative Example 20 Pluronic F127 X X X X X

 Comparative Example 21

 Comparative Example 22 HP C X X X X X

 Comparative Example 23 Sodium Hyaluronate X X X X X

 Comparative Example 24 Sodium Chondroitin Sulfate X X X X X

 〇: Effective X: No effect or below control 1: Not tested

As shown in Table 1, various compounds were used as additives, and flocculation was studied.As shown in Comparative Examples 11 to 24, many additives were However, flocculation did not occur at all, or flocculation did not persist for a long time, and settled to about the same level as the control after one week, or formed a hard cake. On the other hand, all of the additives used in Examples 14 to 14 showed continuous flocculation, and did not cause hard caking. In addition, this effect occurred in a concentration range specific to each compound, and the compound could be easily redispersed by falling.

From the above, sodium alginate, sodium CMC, sodium polyacrylate Each additive of the polymer and carboxyvinyl polymer has a specific concentration for each compound (sodium alginate 1% or more; sodium CMC 0.1% or more; sodium polyacrylate 0.1% or more; carboxyvinyl Polymer (0.01% or more) produced flocculation of suspended particles of acyclovir, thereby preventing the formation of cake. The effect was also shown to last for a long time.

(Example 5-7)

2 g of acyclovir and additives (sodium CMC, sodium polyacrylate, carboxyvinyl polymer) were thoroughly ground and mixed in a mortar until uniform. Then, a small amount of a 0.5 g aqueous solution of _ε -aminocaproic acid (hereinafter referred to as buffer A), which had been adjusted to pH 5.5 in advance, was added, and the mixture was kneaded well to form a paste. The kneading process was repeated several times while gradually adding buffer A until about half of the total amount was added. The resulting slurry was transferred to a beaker, and the sample remaining in the mortar was rinsed with buffer A and mixed well with the slurry. To this solution, 0.11 11 hydrochloric acid or 0.1 N sodium hydroxide solution was added little by little to adjust the pH to 5.5, and distilled water was added to make 10 OmL.

 Each of the thus-obtained oral-mouth building suspension preparations was filled into a test tube in an amount of 5 mL and shaken well. They were allowed to stand at 25 ° C., and the flocculation effect of each cauldron was examined. The flocculation effect was examined by comparing the height of the sedimentation surface after 2 weeks with the control. A control prepared in the same manner as in each example except that no additive was added was used. The results are shown in Table 2. The sedimentation surface reduction rate shown in the table indicates the degree of reduction of the sedimentation surface when the sedimentation surface height is the same as the control and the sedimentation surface height is 100% when the sedimentation surface height is the same as the control. The following formula was used to calculate the rate of sinking surface reduction. Settling surface reduction rate (%)

= (Sinking surface reduction ratio in each sample) Sinking surface reduction ratio in control) X 100 Sedimentation surface decrease rate after 2 weeks (%)

 Additive concentration (%)

 2 1.5 1 0.8 0.6 0.5 0.4 0.2 0.1 0.08 0.06 0.04 0.02 0.01 l.E-03 1.E-04 l.E-05 Example 5 Sodium CMC 0 0 0 — — 0 — — 32.8 —

Example 6 Sodium polyacrylate 0 0 0-4.6 18.8 60.8-131.2

Example 7 Carboxyvinyl / Repolymer-0 0 0 32.8 65.6 79.6 107.6 103.0 103.0 I: Not tested

· · —

. o From Examples 5 and 6 in Table 2, it was shown that when the additive was sodium CMC or sodium polyacrylate, flocculation occurred when the additive amount was 0.1% or more. At a concentration of 0.5% or more for sodium CMC and 0.2% or more for sodium polyacrylate, extremely high effects were observed. Further, in Example 7, when the additive was a carboxyvinyl polymer, the effect was exhibited even at a lower concentration of 0.01% or more. When a carboxyvinyl polymer was added, an extremely high effect was observed at an addition amount of 0.06% or more.

 As described above, although the concentration for producing floculation is different for each additive, the higher the concentration, the higher the effect. In the case of the carboxy butyl polymer, the effect was exhibited even with the addition amount of 0.01%.

(Examples 8-9, Comparative Examples 25-26)

 2 g of acyclovir and additives (sodium CMC, methylcellulose, sodium polyacrylate, carboxyvinyl polymer) were thoroughly ground and mixed in a mortar until uniform. To this was added a small amount of an aqueous solution of 0.5 g of ε-aminocaproic acid (hereinafter referred to as buffer A), which had been adjusted to pH 5.5 in advance, and kneaded well to form a paste. The kneading process was repeated several times while gradually adding buffer A until about half of the total amount was added. The resulting slurry was transferred to a beaker, and the sample remaining in the mortar was rinsed with buffer A and mixed well with the slurry. To this solution, 0.1 N hydrochloric acid or 0.1 N sodium hydroxide 'solution was added little by little to adjust the pH to 5.5, and distilled water was added to make 100 mL.

(Comparative Example 27)

An acyclovir suspension preparation was prepared in the same manner as in Example 8, except that no additive was added. Each of the resulting suspensions of acyclovir was filled into a 5 mL PP bottle. Under constant temperature conditions of 25 ° C or 5 ° C, or 40 ° C (1W) → 5 ° C (1W) or 25 ° C (1W) → 5 ° C (1W) Storage under cycling conditions Was examined. The crystal transition was confirmed by direct observation of the crystals under a microscope and analysis by TGZDTA of the filtered crystals. Table 3 shows the storage results. Here, the storage conditions of 40 ° C (1 W) → 5 ° C (1 W) and 25 ° C (1 W) → 5 ° C (1 W) are 40 ° C and 25 ° C, respectively. This indicates that the cells were stored at 5 ° C for one week after storage at C for one week, and this two-week storage period was regarded as one cycle. After the second cycle, this process was repeated for preservation.

\ ο

Crystal transition ♦ Prevent growth

 Narrow mouth agent 1 VJII cycle test (2 cycles)

 25 C 25 → 5V Example 8 CMC sodium 〇 〇 o 〇 Example 9 Methyzresenorelose (1%) 〇 XX Comparative Example 25 Sodium polyacrylate (0.1%). XXXX Comparative Example 26 Carboxyvinylol polymer One (0.01%) XXXX Comparative example 27 XXXX

 〇: No crystal transition X: Crystal transition (needle-shaped crystal)

Dimension

o

As shown in Comparative Example 27 of Table 3, when the suspension of acyclovir to which no additive was added was stored, a transition from the original plate-like crystals to needle-like crystals was observed. If the crystal is transferred, there is a possibility that the intraocular transferability and the medicinal effect of the oral mouth building may be changed, which is not preferable. Therefore, as a result of the examination, as shown in Examples 8 and 9, when sodium CMC and methylcellulose were used as additives, the crystal under storage at a certain temperature (25 ° C, 5 ° C) Metastasis was prevented. However, drugs are usually stored at room temperature, and the temperature of the sample changes as the temperature changes naturally. Assuming that phenomenon, the samples were stored under cycle conditions of 40 ° C (1 W) → 5 ° C (1 W) and 25 ° C (1 W) → 5 ° C (1 W). CMC sodium in Fig. 8 showed an effect of preventing crystal transition, but when methylcellulose was added, crystal transition was observed during storage under cycle conditions. In addition, the sodium polyacrylate and carboxyvinyl polymer of Comparative Examples 25 and 26 caused crystal transition under any conditions of constant temperature and cycle test, and no effect of preventing crystal transition was observed.

 From the above, methylcellulose and sodium CMC were found to have an effect of suppressing crystal transition, and in particular, sodium CMC was found to have an effect of suppressing crystal transition even under storage conditions accompanied by temperature changes.

(Examples 10 to 18; Comparative Examples 28 to 30)

 Distilled water was added to and dissolved in 0.2 g of boric acid. Next, 1 g of CMC sodium, a preservative and a tonicity agent were added in predetermined amounts and dissolved. Further, 3 g of acyclovir was added, and the mixture was stirred well until it became homogeneous. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 7.0, and distilled water was added to make 100 mL.

Preservatives: chlorobutanol, methylparaben 'propylparaben, thimerosal Isotonizing agent: sodium chloride, glycerin, D-mannitol, propylene glycol

The obtained acyclovir suspension preparation was filled into a 5 mL PP bottle. They were stored at the cycle conditions of 40 ° C (1 W) → 5 ° C (1 W), and the crystal transition was examined. The crystal transition was confirmed by direct observation of the crystals under a microscope. The storage results are shown in Table 4. oo crystal transition

 Cycle paste (40 → 5) 25 C Preservative Isotonizing agent 5 cycle 1 year Comparative example 28 Methyl paraben (0.026%) + propyl paraben (0.014%) Sodium chloride (0.9%) X (Crystal growth) — Comparative example 29 Methyl para z-ben (0.026%) + propylpara'-ben (0.014%) glycerin (2.4%)

Comparative Example 30 Methynoreno "? Laven (0.026%) + Bropylparaben (0.014%) D-mannitol (4.4%), day / ^ ノ · ノ

Example 10 Methyl paraben (0.026%) + propyl para'ben (0.014%) Prohylene kulkonore (2.0%) ηo Example 11 chlorobutanol (0.5%) Sodium chloride (0.9%) π o Example 12 chlorobutanol (0.5%) Glycerin (2.4%) 〇 〇 Example 13 Chlorobutanol (0.5%) D-mant (4.4%)

Example 14 Chlorobutanol (0.5%) Propylene glycol (2.0%) πExample 15 Thimerosal (0. (H¾) Sodium chloride (0.9%)

Example 16 Thimerosal (0.01%) Glycerin (2.4%) 〇

Example 17 Thimerosal (0.01%) D-Mannit (4.4%) 〇

Example 18 Thimerosal (0.01%) Propylene Darcol (2.0%) 〇

O: No crystal transition X: Crystal transition (acicular), with growth

As shown in the comparative example in Table 4, when acyclovir suspension containing paraben as a preservative and sodium chloride, glycerin, and D-mannitol as isotonic agents was stored under cycle conditions, A transition from the original plate-like crystal to a needle-like crystal and crystal growth were observed. On the other hand, as shown in Examples 10 to 14, chlorobutanol was used as a preservative, and sodium chloride, glycerin, D-mannite, and propylene glycol were added as isotonic agents, respectively. Did not show any change in crystals during storage under cyclic conditions. In addition, no change in crystals was observed in the suspension of the building with mouth opening in which paraben was used as a preservative and propylene dalicol was added as an isotonic agent. From the above, when paraben is used as a preservative, propylene glycol is used in combination with propylene glycol as an isotonic agent, and when chlorobutanol is used as a preservative, sodium chloride, glycerin, D-mannitol, and propylene glycol are used. It was found that the combination with any of the above tonicity-imparting agents did not hinder the effect of CMC sodium on crystal transfer suppression.

 On the other hand, regarding the flocculation, no change was observed in any of the examples.

After 4 weeks, it was confirmed that the floculation effect was maintained. Even with acyclovir suspension containing thimerosal as a preservative and sodium chloride, glycerin, D-mannitol, and propylene glycol as isotonic agents, no crystal change was observed during storage under cycle conditions.

 On the other hand, regarding flocculation, no change was observed when thimerosal was used as a preservative, and it was confirmed that the flocculation effect was maintained even after 2 weeks.

 When a long-term storage test was performed for one year, no crystal transition or growth was observed when stored at 25 ° C, as shown in Examples 10 to 14, indicating that the material was stable for a long time near room temperature. confirmed.

(Reference example [Sample No. 1-1 2])

Distilled water was added to and dissolved in 0.2 g of boric acid. Next, predetermined amounts of sodium CMC, a preservative and a tonicity agent were added and dissolved. Further, 3 g of acyclovir was added and stirred well until the mixture became homogeneous. 0.1 N hydrochloric acid was added to this solution little by little to adjust the pH to 7.0. And distilled water was added to make 100 mL.

 CMC sodium: Cellogen F-7A, F-810A, F-815A, FAG

(These are manufactured by Daiichi Kogyo Pharmaceutical Co., Ltd.)

Preservative: chlorobutanol (0.5%)

Tonicity agent: Propylene glycol (2.0%)

(Reference example [Sample No. 13-24])

 Distilled water was added to and dissolved in 0.2 g of boric acid. Next, predetermined amounts of sodium CMC, a preservative and a tonicity agent were added and dissolved. Further, 3 g of acyclovir was added and stirred well until the mixture became homogeneous. To this solution, 0.1 N hydrochloric acid was added little by little to adjust the pH to 7.0, and distilled water was added to make 10 OmL.

 CMC sodium: cellogen F-7A, F-8A, PR-S, F-SL (all manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)

Preservative: chlorobutanol (0.5%)

Isotonizing agent: Propylene glycol (2.0%)

 The obtained acyclovir suspension preparation was filled into a 5 mL PP bottle. They were stored under the cycle conditions of 40 ° C → 5 ° C, and the crystal transition was examined. The crystal transition was confirmed by direct observation of the crystals with a microscope.

The storage results are shown in Tables 5 and 6.

t t

 0 P-7A Λ

 3 0.03% X 〇 〇 〇

 4 Lily

 5 F-810A 0.2% o X o 〇

 6 0.02% X o 〇 〇

 7 2.0% 〇 〇 〇 〇

 8 F-815A 0.2% 〇 〇 〇 〇

 9 0.02% X 〇 〇

 10.0.5% 〇 〇 〇 〇

 11 F-AG 0.05¾ 〇 o 〇 〇

 12 0.005% X mm X 〇

Of sedimentation> 〇: good X: caking

 <Agglomerate> 〇: None particularly

 <Crystallinity> 〇: Stable X: Changes such as generation of needle crystals

CMC sodium> 2% viscosity (25 ° 〇, 11 ^ & '5) Degree of etherification

 F-7A 12-18 0.70-0.80

 F-810A 50 ~ 150 0.75 ~ 0.85

 F-815A 50 ~ 150 0.80 ~ 0.90

 F-AG 900-1500 0.85-0.95

Five

 21 0.5% 〇 〇 〇 〇

 22 2.0% 〇 〇 〇 〇

 23 F-SL 1.0% 〇 〇 〇 〇

 24 0.5% 〇 〇 〇 〇

 j Width X: Caking

 , Δ: Slightly aggregated X: Aggregation is noticeable Crystallinity:> 〇: Stable X: Changes such as generation of needle-like crystals

 CMC sodium> 2% viscosity (25 ° C mPa's) Degree of etherification

 F-7A 12 18 0.70 0.80

 F-8A 30 50 0.70 -0.80

 PR-S 20 40 0.70 0.85

 F-SL 20 40 0.80 0.95

≠ 6 As shown in Nos. 1, 4, 7, and 10 in Table 5, the storage at the cycle mouth condition for the suspension of the ash mouth building to which CMC sodium was added so that the viscosity was about lO OmPas No crystal change was observed. No crystal change was observed in Nos. 5, 8, and 11 in which sodium CMC at a concentration of 1Z10 was added, but crystal aggregation was observed in the lowest viscosity F-7A. And the formation of needle-like crystals were observed (No. 2). Furthermore, at No. 3, 6, 9, and 12 with CMC sodium at a concentration of 110, the sedimentation surface could not be maintained, and the transition from the original plate-like crystals to needle-like crystals and crystal aggregation occurred. Admitted.

 Next, as shown in Table 6, all the suspensions containing the low viscosity CMC sodium at 0.5 to 2.0% were added to prevent sedimentation of suspended particles due to storage under cycle conditions. No change in the crystal was observed. Industrial applicability

 Since the present invention has the above-described constitution, in a suspended ophthalmic solution containing acyclovir as an active ingredient, sedimentation and / or crystal transition of suspended acyclovir particles can be stably suppressed over a long period of time.

Claims

The scope of the claims 1. acyclovir, and at least one compound selected from the group consisting of polyacrylic acid, carboxyvinyl polymer, carboxymethylcellulose, alginic acid, and a pharmaceutically acceptable salt thereof. An ophthalmic mouth building suspended ophthalmic solution characterized in that sedimentation is suppressed. 2. It contains at least one compound selected from the group consisting of acyclovir, methinoresenololose, carboxymethylcellulose, and pharmaceutically acceptable salts thereof, and suppresses the crystal transition of acyclovir. Acyclovir suspension ophthalmic solution characterized by: 3. Suspended acyclovir ophthalmic solution comprising acyclovir and carboxymethylcellulose or a pharmaceutically acceptable salt thereof, wherein sedimentation and crystal transition of acyclovir are suppressed. 4. Suspended eye drop for oak mouth building, comprising acyclovir and sodium carboxymethylcellulose, wherein sedimentation and crystal transformation of oak mouth building are suppressed. 5. Including at least one compound selected from the group consisting of acyclovinole, canoleboxymethinoresenole, sodium sodium, chlorobutanole, and sodium chloride, glycerin, D-mannitol, and propylene glycol, An acyclovir suspension ophthalmic solution characterized by suppressing sedimentation and crystal transition of acyclovir. 6. Suspended ophthalmic ophthalmic suspension containing acyclovir, sodium carboxymethylcellulose sodium paraben, and propylenedaricol, wherein sedimentation and crystal transition of ashokuburi are suppressed. 7. Includes acyclovir, sodium carboxymethylcellulose, thimerosal, and at least one compound selected from the group consisting of sodium chloride, glycerin, D-mannitol, and propylene glycol; An ophthalmic mouth building suspension ophthalmic solution characterized by suppressing deposition and crystal transition.