WO2019026992A1 - クロルヘキシジンを含有する医薬組成物 - Google Patents
クロルヘキシジンを含有する医薬組成物 Download PDFInfo
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- WO2019026992A1 WO2019026992A1 PCT/JP2018/029011 JP2018029011W WO2019026992A1 WO 2019026992 A1 WO2019026992 A1 WO 2019026992A1 JP 2018029011 W JP2018029011 W JP 2018029011W WO 2019026992 A1 WO2019026992 A1 WO 2019026992A1
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- Prior art keywords
- pharmaceutical composition
- salt
- chlorhexidine
- ethylene oxide
- present
- Prior art date
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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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0094—Gaseous substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/20—Gaseous substances, e.g. vapours
-
- 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
Definitions
- the present invention relates to a pharmaceutical composition containing chlorhexidine or a salt thereof placed in a container sterilized with ethylene oxide gas (hereinafter also referred to as EOG).
- EOG ethylene oxide gas
- eye drops in particular, are strictly required to be sterile until eye drop, in order to be administered directly to the eye. Therefore, when producing eye drops, it is necessary to sterilize the container, and sterilization treatments such as gamma ray sterilization, electron beam sterilization, EOG sterilization, hydrogen peroxide solution sterilization, high-pressure steam sterilization and the like are performed.
- sterilization treatments such as gamma ray sterilization, electron beam sterilization, EOG sterilization, hydrogen peroxide solution sterilization, high-pressure steam sterilization and the like are performed.
- preservatives such as benzalkonium chloride and chlorhexidine are usually added to eye drops.
- chlorhexidine or a salt thereof in the pharmaceutical composition decreases with time.
- An object of the present invention is to provide a pharmaceutical composition which is stable over the long term and which is safe while suppressing the temporal decrease in the content of chlorhexidine or a salt thereof in the pharmaceutical composition.
- the inventors of the present invention have found as a result of intensive studies that when the pharmaceutical composition containing chlorhexidine or a salt thereof is placed in an electron beam-sterilized container, the content of chlorhexidine or a salt thereof decreases with time. Furthermore, when the pharmaceutical composition containing chlorhexidine or a salt thereof is placed in an ethylene oxide gas sterilization container, it has been found that the temporal decrease in the content of chlorhexidine or a salt thereof due to heat or light can be suppressed, and the present invention has been completed. . Specifically, the present invention provides the following.
- composition according to (1) or (2) further comprising edetic acid or a salt thereof.
- composition according to any one of (1) to (4) which further comprises bimatoprost, latanoprost or travoprost.
- a method for producing a pharmaceutical comprising sterilizing a container with ethylene oxide gas and containing therein a pharmaceutical composition containing chlorhexidine or a salt thereof.
- the invention further relates to the following.
- a pharmaceutical composition for treatment and / or prevention of eye diseases which is contained in an ethylene oxide gas sterilization container and contains chlorhexidine or a salt thereof.
- a method for treating and / or preventing ocular diseases which comprises administering an effective amount of a pharmaceutical composition containing chlorhexidine or a salt thereof and contained in an ethylene oxide gas sterilization container to a subject in need thereof How to do that.
- each structure of said (1) to (19) can select 2 or more arbitrarily, and can combine them.
- the pharmaceutical composition of the present invention is a pharmaceutical composition containing chlorhexidine or a salt thereof placed in an ethylene oxide gas sterilization container.
- Chlorhexidine contained in the pharmaceutical composition of the present invention may be a salt of chlorhexidine and is not particularly limited as long as it is a pharmaceutically acceptable salt.
- chlorhexidine salts include salts with inorganic acids and salts with organic acids.
- those upper limits and lower limits can be used in combination as appropriate.
- the range can be set to 0.007% (w / v), 0.002 to 0.006% (w / v), and 0.002 to 0.005% (w / v).
- the content of chlorhexidine or a salt thereof is, for example, preferably 0.0001 to 0.1% (w / v), preferably 0.0005 to 0.01% (w / v).
- w / v) is more preferable, 0.0007 to 0.007% (w / v) is further more preferable, 0.001 to 0.006% (w / v) is particularly preferable, 0.002 to 0.005 % (W / v) is most preferred.
- these values are contents based on the mass of the salt.
- % (w / v) means the mass (g) of the object component (here, chlorhexidine) contained in 100 mL of the pharmaceutical composition of the present invention.
- the target component is an additive such as surfactant, etc.
- these values are the content based on the mass of the salt or hydrate It is.
- the pharmaceutical composition of the present invention can optionally contain an additive.
- additives include surfactants, buffering agents, tonicity agents, stabilizers, preservatives, antioxidants, thickening agents, pH adjusters and the like.
- a surfactant which can be used as a pharmaceutical additive can be appropriately blended, and for example, an anionic surfactant, a cationic surfactant or a nonionic surfactant is blended. be able to.
- anionic surfactants include phospholipids and the like, and phospholipids include lecithin and the like.
- the content of the surfactant in the case of incorporating the surfactant into the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of surfactant etc., but 0.001 to 10% (w / v) Preferably, 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.
- Examples of phosphates include sodium phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, anhydrous sodium monohydrogen phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate And potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like
- examples of boric acid salts include borax, sodium borate, potassium borate and the like
- examples of citrates Examples include citric acid monohydrate, sodium citrate, disodium citrate and the like, and examples of acetate include sodium acetate, potassium acetate and the like, and examples of carbonate include sodium carbonate and carbonate
- Examples of the tartrate include sodium tartrate, potassium tartrate and the like.
- an isotonicity agent which can be used as an additive of a medicine can be appropriately blended.
- tonicity agents include ionic tonicity agents and nonionic tonicity agents.
- ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like, with sodium chloride being preferred.
- non-ionic tonicity agent include glycerin, propylene glycol, sorbitol, mannitol and the like, with preference given to mannitol.
- the content of the stabilizer in the case of incorporating the stabilizer into the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of the stabilizer etc., but 0.0001 to 3% (w / v) Preferably, 0.0005 to 1% (w / v) is more preferable, 0.001 to 0.1% (w / v) is more preferable, and 0.01 to 0.05% (w / v) is most preferable. .
- a preservative usable as an additive of a pharmaceutical can be appropriately blended in the pharmaceutical composition of the present invention.
- preservatives include benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol and the like.
- the content of the preservative in the case of incorporating the preservative into the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of preservative, etc., but preferably 0.0001 to 3% (w / v), 0 .0005 to 2% (w / v) is more preferable, 0.0007 to 1% (w / v) is more preferable, and 0.001 to 0.1% (w / v) is most preferable.
- an antioxidant which can be used as an additive of a medicine can be appropriately blended.
- antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
- the content of the antioxidant in the case of incorporating the antioxidant into the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of the antioxidant etc., but 0.0001 to 1% (w / v) Preferably, 0.0005 to 0.5% (w / v) is more preferable, 0.01 to 0.1% (w / v) is more preferable, and 0.001 to 0.01% (w / v) is preferable Most preferred.
- the content thereof can be appropriately adjusted depending on the type of the thickening agent and the like.
- the lower limit of the content of the thickening agent is, for example, 0.001% (w / v), preferably 0.0015% (w / v), more preferably 0.005 % (W / v), more preferably 0.01% (w / v), particularly preferably 0.1% (w / v), most preferably 0.3% (w / v),
- the upper limit thereof is, for example, 5% (w / v), preferably 4% (w / v), more preferably 3% (w / v), still more preferably 2% (w / v), particularly preferably 1% (W / v), most preferably 0.9% (w / v).
- the content of the thickening agent is, for example, 0.001 to 5% (w / v), and 0.0015 to 4% (w / v) Is preferable, 0.005 to 3% (w / v) is more preferable, 0.01 to 2% (w / v) is more preferable, 0.1 to 1% (w / v) is particularly preferable, 0. 3 to 0.9% (w / v) is most preferred.
- the pharmaceutical composition of the present invention may not contain a thickening agent.
- a pH adjuster which can be used as a pharmaceutical additive can be appropriately blended.
- pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, with hydrochloric acid, sodium hydroxide and citric acid being preferred.
- the pH of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharmaceutically acceptable pH, preferably 4.0 to 8.5, more preferably 4.5 to 8.0, and 5.0 to 7 .8 is more preferred, and 5.5 to 7.5 is most preferred.
- the pharmaceutical composition of the invention may contain one or more, preferably one to three, more preferably one or two drugs.
- the drug include steroids such as fluorometholone, hydrocortisone, triamcinolone, fluocinolone, dexamethasone, betamethasone, prostaglandin derivatives such as isopropyl unoprostone, latanoprost, bimatoprost, travoprost, cyclosporin, sirolimus, FK506 etc.
- antiallergic agents such as olopatadine and azelastine
- non-steroidal anti-inflammatory agents such as indomethacin, bromfenac and diclofenac
- carbonic anhydrase inhibitors such as dorzolamide and brinzolamide
- ⁇ receptor blockers such as timolol and carteolol, etc.
- the pharmaceutical composition of the present invention may preferably further comprise an ophthalmic drug, more preferably a prostaglandin derivative, even more preferably bimatoprost, latanoprost or travoprost.
- the content can be appropriately adjusted according to the type of drug etc., but 0.00001 to 10% (w / v) is preferable, 0.0005 to 5 % (W / v) is more preferable, 0.001 to 3% (w / v) is more preferable, and 0.001 to 2% (w / v) is most preferable.
- the pharmaceutical composition of the present invention is placed in an ethylene oxide gas sterilization container. After placing the pharmaceutical composition of the present invention in an ethylene oxide gas sterilization container, the ethylene oxide gas sterilization container can be sealed in a conventional manner.
- the ethylene oxide gas sterilization container is not particularly limited as long as it is a container sterilized using ethylene oxide gas, and examples include an eye drop container, preferably a multi-dose type eye drop container.
- a multi-dose type eye drop container is an eye drop container in which opening and closing of a cap or the like can be freely performed for the purpose of multiple use. You may place in a PFMD (Preservative Free Multi Dose) eye drop container having a special structure for exerting a preservative effect such as a backflow prevention function.
- the eye drop container may be formed of a single member or a plurality of members, and may be any of a 1 piece eye drop container, a 2 piece eye drop container, or a 3 piece eye drop container.
- the material of the ethylene oxide gas sterilization container is not particularly limited, and a resin can be used, for example, polyethylene (PE), polypropylene (PP), polypropylene-polyethylene copolymer, polyethylene terephthalate (PET) And polybutylene terephthalate (PBT), polyvinyl chloride, acrylic resin, polystyrene and the like.
- polyethylene is classified according to its density and includes low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE) and the like.
- polyethylene, polypropylene, propylene-ethylene copolymer, polyethylene terephthalate and the like and particularly preferred are polypropylene, propylene-ethylene copolymer and the like.
- the propylene-ethylene copolymer is not particularly limited as long as it is a propylene polymer containing an ethylene component, but is preferably a propylene polymer containing 10 mol% or less of an ethylene component.
- the ethylene oxide gas sterilization container has a residual ethylene oxide concentration of, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, still more preferably 0 to 0.5 ppm or less. Is most preferred. It can be measured according to the Japan Medical Plastics Association "Method for determining residual ethylene oxide of medical devices".
- ethylene oxide gas sterilization is not particularly limited as long as the container can be sterilized using ethylene oxide gas, but for example, the container is exposed to ethylene oxide gas under a predetermined temperature and a predetermined relative humidity for a predetermined time. Thus, it can be sterilized and then aerated to remove ethylene oxide gas as required.
- the gas used in ethylene oxide gas sterilization may be ethylene oxide gas alone or mixed gas with carbon dioxide or the like.
- the ratio of ethylene oxide gas to the other gases is, for example, 5:95 to 50:50, preferably 10:90 to 40:60, and 15:85 to 30:70 in volume ratio. Is more preferred, and 20:80 is most preferred.
- the temperature of ethylene oxide gas sterilization is, for example, 20 to 80 ° C., preferably 30 to 60 ° C.
- the relative humidity of ethylene oxide gas sterilization is, for example, 20 to 90%, preferably 30 to 80%.
- the time of ethylene oxide gas sterilization is, for example, 1 to 10 hours, preferably 2 to 5 hours.
- aeration does not necessarily have to be carried out, but when carrying out aeration, for example, air, nitrogen, argon, carbon dioxide can be used, and the aeration time is preferably It is 8 hours or more, more preferably 12 hours or more, and most preferably 24 hours or more.
- the storage temperature is preferably ⁇ 30 ° C. or more and 30 ° C. or less, more preferably ⁇ 25 ° C. or more and 25 ° C. or less, and still more preferably ⁇ 15 ° C. or more and 15 ° C. or less.
- the pharmaceutical composition of the present invention maintains a concentration of at least 60% of chlorhexidine or a salt thereof after a storage period relative to the time when it is prepared (ie, when the remaining rate is 60% or more) ), It can be said that it is a pharmaceutically stable preparation.
- the concentration of chlorhexidine or its salt in the pharmaceutical composition is 60 to 100% after a certain storage period, as compared to the amount of chlorhexidine or its salt at the time of preparation of the pharmaceutical composition.
- the pharmaceutical composition of the present invention is stable over the storage period of 1 week to 5 years, preferably 1 month to 4 years, more preferably 3 months to 3 years, most preferably 6 months to 2 years.
- the dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical, and it is, for example, an eye drop and can be manufactured according to a conventional method in the art.
- the pharmaceutical composition of the present invention may be, for example, a solution or a suspension or an emulsion, and the solvent or dispersion medium is preferably water, and most preferably an aqueous solution.
- the present invention provides a pharmaceutical product comprising a pharmaceutical composition containing chlorhexidine or a salt thereof in an ethylene oxide gas sterilization container.
- the present invention also provides a pharmaceutical product comprising a pharmaceutical composition containing chlorhexidine or a salt thereof, and an ethylene oxide gas sterilization container containing the pharmaceutical composition.
- the present invention also provides a pharmaceutical product, wherein a pharmaceutical composition containing chlorhexidine or a salt thereof is contained in an ethylene oxide gas sterilization container.
- the pharmaceutical product of the present invention is one in which the pharmaceutical composition containing chlorhexidine or a salt thereof is contained in an ethylene oxide gas sterilization container.
- the pharmaceutical product is preferably an ophthalmic product, an otolaryngological product, or a dermatological product, and more preferably an ophthalmic product.
- ophthalmic products include products such as eye drops, injections, eye ointments, inserts and the like.
- composition of the present invention is a method of stabilizing chlorhexidine of the present invention or a salt thereof, a method of producing a medicament, use of a medicament, a pharmaceutical composition, treatment and / or prevention of eye diseases
- the method also applies to pharmaceutical products.
- the stability of chlorhexidine or a salt thereof in a pharmaceutical composition is maintained, and the reduction of the content thereof is controlled.
- the method of producing the medicament of the present invention comprises sterilizing the container with ethylene oxide gas and placing therein the pharmaceutical composition containing chlorhexidine or a salt thereof.
- Formulation Examples Representative formulation examples of the present invention are shown below.
- the compounding quantity of each component is a content in 1 mL of formulation in the following formulation example.
- Formulation example 1 Sodium citrate monohydrate 0.2 mg Chlorhexidine gluconate 0.01 mg Edetate disodium dihydrate 0.1 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
- Formulation example 2 Hydrogen phosphate disodium dodecahydrate 5 mg Chlorhexidine gluconate 0.03 mg D-mannitol 30 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.5
- Formulation example 3 Bimatoprost 30 mg Sodium citrate monohydrate 0.2 mg Chlorhexidine gluconate 0.01 mg Edetate disodium dihydrate 0.1 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
- Formulation example 4 Travoprost 4 mg Hydrogen phosphate disodium dodecahydrate 5 mg Chlorhexidine gluconate 0.03 mg D-mannitol 30 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.5
- Comparative Example The same as Examples 1 to 26 except that ethylene oxide gas sterilization was changed to electron beam sterilization (accelerating voltage 4.0 MV, electron current 20 mA, 18 kGy) for the preparations of Comparative Examples 1 to 5.
- the content of chlorhexidine was calculated by
- Test Results and Discussion The test results are shown in Tables 1-7.
- Example 27 to 29 containing chlorhexidine as a preservative are comparative examples 6 containing SofZia (registered trademark) (a preservative system consisting of boric acid, propylene glycol, D-sorbitol, zinc chloride). It showed much higher cell viability than the preparation of From the above results, it was found that the pharmaceutical composition of the present invention has low cytotoxicity and can be safely used as a pharmaceutical.
- SofZia registered trademark
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Abstract
Description
で表される化合物であり、化学名1-[amino-[6-[amino-[amino-(4-chlorophenyl)amino-methylidene]amino-methylidene]aminohexylimino]methyl]imino-N-(4-chlorophenyl)-methanediamine等で表される化合物である。
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤1mL中の含量である。
クエン酸ナトリウム一水和物 0.2mg
クロルヘキシジングルコン酸塩 0.01mg
エデト酸二ナトリウム二水和物 0.1mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 6.5
リン酸水素二ナトリウム十二水和物 5mg
クロルヘキシジングルコン酸塩 0.03mg
D-マンニトール 30mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 7.5
ビマトプロスト 30mg
クエン酸ナトリウム一水和物 0.2mg
クロルヘキシジングルコン酸塩 0.01mg
エデト酸二ナトリウム二水和物 0.1mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 6.5
トラボプロスト 4mg
リン酸水素二ナトリウム十二水和物 5mg
クロルヘキシジングルコン酸塩 0.03mg
D-マンニトール 30mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 7.5
1.被験製剤の調製
ビマトプロスト0.06g、リン酸水素二ナトリウム十二水和物0.716g、クエン酸一水和物0.028g、エデト酸二ナトリウム二水和物0.02g、塩化ナトリウム1.66g、水で0.2%に希釈したクロルヘキシジングルコン酸塩液2mLを水180mLに溶解し、水酸化ナトリウム/希塩酸を加えてpHを調整した後に全量を200mLとし、実施例1の製剤を調製した。また、同様の方法により、実施例2~26及び比較例1~5の製剤を調製した。
・実施例
5mL用の樹脂製容器(ポリエチレン、東ソー製ペトロセン)にエチレンオキサイドガス滅菌処理(エチレンオキサイド/二酸化炭素濃度20%/80%(V/V)、温度40℃、相対湿度50%、3時間滅菌)を施した後、同容器に実施例1~26の製剤5mLを入れて、打栓をし、キャップを装栓した。温度;60℃又は50℃、湿度:成り行き、及び遮光下の条件、又は、温度:約25℃、湿度:成り行き、及び1000lx/hrの条件で表2~7に記載した期間保存した後に、高速液体クロマトグラフィー法にて製剤中のクロルヘキシジンの濃度を測定し、保存開始時の濃度を基準(100%)としてクロルヘキシジンの残存率を算出した。その結果を表1~7に示す。高速液体クロマトグラフィー法は、Waters社製UPLCを用いて、次の条件により測定した。カラム AQCUITY BEH C18 (100mmx2.1mm,粒子径1.7μm)を50℃付近の一定温度に保ち、pH2.5のトリエチルアミン・過塩素酸溶液/アセトニトリルを約0.5mL毎分の流量でグラジエント機能により、アセトニトリルの割合を制御して測定を行った。
比較例1~5の製剤につき、エチレンオキサイドガス滅菌処理を電子線滅菌処理(加速電圧4.0MV、電子流20mA、18kGy)に変えた点を除いて、実施例1~26と同様の操作でクロルヘキシジンの含有率を算出した。
試験結果を表1~7に示す。
1.被験製剤の調製
実施例1の製剤と同様の方法により、実施例27~29及び比較例6の製剤を調製した。
SV40不死化ヒト角膜上皮細胞(HCE-T:理化学研究所 バイオリソースセンター、Cell No.:RCB2280)を96ウエルプレートに播種(1×104細胞/ウエル)し、10%FBS含有D-MEM/F12培地で2日間培養した。培地をDMEM/F-12、または実施例27~29、または比較例6の製剤に交換した後、前記角膜上皮細胞を30分間または60分間培養した。Cell Proliferation Assay Kit(Promega社製、カタログ番号:G3580)を用いて、生細胞数(490nmの吸光度に相当する)を測定した。DMEM/F-12群に対する各実施例および比較例の吸光度値の百分率を算出し、細胞生存率(%)とした。
試験結果を表8に示す。
Claims (14)
- エチレンオキサイドガス滅菌容器に入れられた、クロルヘキシジン又はその塩を含有する医薬組成物。
- クロルヘキシジン又はその塩の含有量が、0.0001~0.1%(w/v)である、請求項1に記載の医薬組成物。
- エデト酸又はその塩をさらに含有する、請求項1又は2に記載の医薬組成物。
- エデト酸又はその塩の含有量が、0.0001~3%(w/v)である、請求項3に記載の医薬組成物。
- ビマトプロスト、ラタノプロスト又はトラボプロストをさらに含有する、請求項1~4のいずれか一項に記載の医薬組成物。
- ビマトプロストの含有量が、0.01~0.05%(w/v)である、請求項5に記載の医薬組成物。
- ラタノプロスト又はトラボプロストの含有量が、0.001~0.01%(w/v)である、請求項5に記載の医薬組成物。
- 容器が、ポリエチレン製又はポリプロピレン製である、請求項1~7のいずれか一項に記載の医薬組成物。
- エチレンオキサイドガス滅菌容器の残留エチレンオキサイド濃度が、0~10ppmである、請求項1~8のいずれか一項に記載の医薬組成物。
- 点眼剤である、請求項1~9のいずれか一項に記載の医薬組成物。
- 水溶液である、請求項1~10のいずれか一項に記載の医薬組成物。
- クロルヘキシジン又はその塩を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に入れることによる、クロルヘキシジン又はその塩を安定化する方法。
- 容器をエチレンオキサイドガスで滅菌し、その中にクロルヘキシジン又はその塩を含有する医薬組成物を入れることを含む、医薬品を製造する方法。
- クロルヘキシジン又はその塩を含有する医薬組成物がエチレンオキサイドガス滅菌容器に入れられた、医薬用製品。
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WO2021166274A1 (ja) * | 2020-02-19 | 2021-08-26 | 千寿製薬株式会社 | 医薬製品 |
JP2021130649A (ja) * | 2020-02-19 | 2021-09-09 | 千寿製薬株式会社 | 医薬製品 |
WO2024010039A1 (ja) * | 2022-07-06 | 2024-01-11 | ロート製薬株式会社 | 眼科組成物 |
WO2024010044A1 (ja) * | 2022-07-06 | 2024-01-11 | ロート製薬株式会社 | 眼科組成物 |
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WO2024010044A1 (ja) * | 2022-07-06 | 2024-01-11 | ロート製薬株式会社 | 眼科組成物 |
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