WO2002026234A1 - Gouttes ophtalmiques contenant une suspension d'aciclovir - Google Patents

Gouttes ophtalmiques contenant une suspension d'aciclovir Download PDF

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Publication number
WO2002026234A1
WO2002026234A1 PCT/JP2001/008619 JP0108619W WO0226234A1 WO 2002026234 A1 WO2002026234 A1 WO 2002026234A1 JP 0108619 W JP0108619 W JP 0108619W WO 0226234 A1 WO0226234 A1 WO 0226234A1
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Prior art keywords
acyclovir
sodium
suspension
sedimentation
ophthalmic
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PCT/JP2001/008619
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English (en)
Japanese (ja)
Inventor
Hiroyuki Ogawa
Hidekazu Suzuki
Masanobu Takeuchi
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Wakamoto Pharmaceutical Co., Ltd.
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Priority to AU2001290328A priority Critical patent/AU2001290328A1/en
Publication of WO2002026234A1 publication Critical patent/WO2002026234A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to an ophthalmic oral ophthalmic suspension capable of suppressing the sedimentation and deposition of acyclovir suspended particles.
  • 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.
  • 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.
  • corneal infection 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.
  • 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.
  • 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. .
  • 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:
  • 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.
  • carboxymethylcellulose salt carboxymethylcellulose sodium is preferred.
  • the tonicity agent may be sodium chloride, glycerin, D-mannitol, or And propylene glycol are preferably used.
  • 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.
  • the tonicity agent may be sodium chloride, glycerin, D-mannite, or propylene. Glycol is preferably used.
  • 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.
  • 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.
  • 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.
  • 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.
  • a physically stable suspension means that the particles are uniformly dispersed throughout the dispersion.
  • 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.
  • 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.
  • polyacrylic acid 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.
  • 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.
  • 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.
  • carboxymethylcellulose is an additive that has both effects of suppressing sedimentation and deposition of acyclovir and suppressing the crystal transition of acyclovir.
  • carboxymethylcellulose added 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.
  • 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.
  • 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.
  • 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.).
  • carboxymethyl cellulose is known to be used as a thickener in aqueous preparations.
  • carboxymethylcellulose was used with Ashikuguchi Building.
  • 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).
  • CTC-HC1 chlorotetracycline hydrochloride
  • 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).
  • 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.
  • preservative examples 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.
  • quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and chlorhexidine dalconate
  • phenolic phenols such as
  • 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%.
  • tonicity agent examples 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.
  • the tonicity agent may be sodium chloride, glycerin, D-man. Knit or propylene grease A call is preferably used.
  • 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.
  • the tonicity agent may be sodium chloride, glycerin, D-mannitol, or propylene glycol. Is preferably used.
  • the buffer examples 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, ⁇ -aminocaproic acid, aspartic acid, glycine, arginine, and lysine; And trishydroxymethylamino methane. These may be used alone or in combination of two or more.
  • the ⁇ 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 ⁇ 4.5 to 8.3, more preferably ⁇ 5 5 to 8.0, and more preferably ⁇ 6.0 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. .
  • Example 1-3 Comparative Example 16-19, 23
  • Distilled water was added to 0.5 g of ⁇ -aminocaproic acid and dissolved.
  • 2 g of acyclovir was added and the mixture was stirred well until it became homogeneous.
  • a predetermined amount of a solution obtained by heating and dissolving the additives listed below with a small amount of distilled water was added.
  • 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.
  • Distilled water was added to 0.5 g of ⁇ -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.
  • 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
  • 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.
  • Example 1 Sodium Alginate ⁇ XXXX One Example 2 Sodium CMC ⁇ XXX — Example 3 Sodium Polyacrylate ⁇ o XXX — Example 4 Carboxyvinyl polymer ⁇ XXX ⁇ ⁇ ⁇ 1 1 1 1 1 1 1 1 1 1 1 1 1. 1.
  • 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.
  • acyclovir and additives sodium CMC, sodium polyacrylate, carboxyvinyl polymer
  • a small amount of a 0.5 g aqueous solution of ⁇ -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.
  • 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 (%)
  • Example 7 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.
  • acyclovir and additives sodium CMC, methylcellulose, sodium polyacrylate, carboxyvinyl polymer
  • acyclovir and additives sodium CMC, methylcellulose, sodium polyacrylate, carboxyvinyl polymer
  • buffer A an aqueous solution of 0.5 g of ⁇ -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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Distilled water was added to and dissolved in 0.2 g of boric acid.
  • 1 g of CMC sodium, a preservative and a tonicity agent were added in predetermined amounts and dissolved.
  • 3 g of acyclovir was added, and the mixture was stirred well until it became homogeneous.
  • 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%)
  • Example 10 Methyl paraben (0.026%) + propyl para'ben (0.014%) Prohylene kulkonore (2.0%) ⁇ o
  • Example 11 chlorobutanol (0.5%) Sodium chloride (0.9%) ⁇ o
  • Example 12 chlorobutanol (0.5%) Glycerin (2.4%) ⁇ ⁇
  • Example 13 Chlorobutanol (0.5%) D-mant (4.4%)
  • Example 14 Chlorobutanol (0.5%) Propylene glycol (2.0%) ⁇ Example 15 Thimerosal (0. (H3 ⁇ 4) Sodium chloride (0.9%)
  • 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
  • Tonicity agent Propylene glycol (2.0%)
  • 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.)
  • 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 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.

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Abstract

L'invention vise à fournir des gouttes ophtalmiques comprenant une suspension d'aciclovir et dans lesquelles la précipitation ou sédimentation et la transition cristalline de l'aciclovir peuvent être empêchées. L'invention concerne des gouttes ophtalmiques qui contiennent une suspension d'aciclovir constituée d'aciclovir et d'au moins un composé sélectionné dans le groupe comprenant acide polyacrylique, polymère carboxyvinylique, carboxyméthylcellulose, acide alginique et des sels pharmaceutiquement acceptables de ces composés et pouvant empêcher la précipitation ou sédimentation de l'aciclovir.
PCT/JP2001/008619 2000-09-29 2001-10-01 Gouttes ophtalmiques contenant une suspension d'aciclovir WO2002026234A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287552A (ja) * 1997-04-11 1998-10-27 Kobayashi Seiyaku Kogyo Kk 滅菌されたアシクロビル水性懸濁点眼剤及びその製造方法
WO1998051281A1 (fr) * 1997-05-14 1998-11-19 Senju Pharmaceutical Co., Ltd. Preparations a base de suspensions aqueuses possedant d'excellentes proprietes de redispersion
WO1999011239A1 (fr) * 1997-09-03 1999-03-11 Chauvin Pharmaceuticals Limited Procede de preparation de compositions pharmaceutiques
JP2000247887A (ja) * 1999-03-01 2000-09-12 Senju Pharmaceut Co Ltd 水性懸濁液剤およびその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287552A (ja) * 1997-04-11 1998-10-27 Kobayashi Seiyaku Kogyo Kk 滅菌されたアシクロビル水性懸濁点眼剤及びその製造方法
WO1998051281A1 (fr) * 1997-05-14 1998-11-19 Senju Pharmaceutical Co., Ltd. Preparations a base de suspensions aqueuses possedant d'excellentes proprietes de redispersion
WO1999011239A1 (fr) * 1997-09-03 1999-03-11 Chauvin Pharmaceuticals Limited Procede de preparation de compositions pharmaceutiques
JP2000247887A (ja) * 1999-03-01 2000-09-12 Senju Pharmaceut Co Ltd 水性懸濁液剤およびその製造方法

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