WO2015137326A1 - ジブチルヒドロキシトルエンの安定化方法 - Google Patents
ジブチルヒドロキシトルエンの安定化方法 Download PDFInfo
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- WO2015137326A1 WO2015137326A1 PCT/JP2015/056985 JP2015056985W WO2015137326A1 WO 2015137326 A1 WO2015137326 A1 WO 2015137326A1 JP 2015056985 W JP2015056985 W JP 2015056985W WO 2015137326 A1 WO2015137326 A1 WO 2015137326A1
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- Prior art keywords
- dibutylhydroxytoluene
- container
- pouring
- liquid agent
- wall surface
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
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- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/1412—Containers with closing means, e.g. caps
- A61J1/1418—Threaded type
Definitions
- the present invention relates to a product that can stably maintain dibutylhydroxytoluene in a liquid agent containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof. Furthermore, the present invention relates to a method for stabilizing a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof.
- dibutylhydroxytoluene (BHT) is known as a representative compound of a fat-soluble antioxidant.
- BHT dibutylhydroxytoluene
- tocopherol and butylhydroxyanisole are also known, but dibutylhydroxytoluene has a stronger antioxidant effect than other fat-soluble antioxidants, such as pharmaceuticals, foods, and cosmetics. Widely used in the field.
- Patent Document 1 pays attention to the stability of pranoprofen and / or a salt thereof, and does not discuss the stability of dibutylhydroxytoluene.
- Patent Document 2 also pays attention to suppression of yellowing of the aqueous composition, and the stability of dibutylhydroxytoluene itself has not been studied.
- Patent Document 2 improves the stability to heat of an aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene by incorporating a sulfa agent, and suppresses yellowing of the aqueous composition.
- Patent Document 2 discloses a technique for improving the thermal stability of dibutylhydroxytoluene itself. It is not a thing.
- the amount of dibutylhydroxytoluene added can be increased to compensate for a decrease in the content over time.
- An increase in the amount added is not realistic because it causes irritation in the case of liquid preparations applied to mucous membranes such as eye drops. Therefore, development of the technique which can suppress the fall of content of dibutylhydroxytoluene in the liquid agent containing dibutylhydroxytoluene and pranoprofen and / or its salt is required.
- an object of the present invention is to provide a technique for suppressing a decrease in the content of dibutylhydroxytoluene over time in a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof.
- the liquid agent containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof contains cromoglycic acid, allantoin, glycyrrhizic acid, chlorpheniramine, and the like.
- this invention provides the dibutylhydroxytoluene containing product of the aspect hung up below, and the stabilization method.
- Item 1. (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof, (C) at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizic acid, chlorpheniramine, and pharmaceutically acceptable salts thereof; Is a product containing dibutylhydroxytoluene contained in a container,
- the container includes a container main body portion that stores the liquid agent, a pouring portion that has a spout for pouring the liquid agent accommodated in the container main body portion, and a lid portion that blocks the spout.
- a product containing dibutylhydroxytoluene characterized in that at least one of a wall surface of the internal space of the pouring part and a wall surface facing the pouring port in the lid part is made of a resin containing polybutylene terephthalate.
- Item 2. The dibutylhydroxytoluene-containing product according to Item 1, wherein the pouring part is a nozzle for pouring the liquid agent in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing polybutylene terephthalate. .
- Item 4. Item 4. The dibutylhydroxytoluene-containing product according to any one of Items 1 to 3, wherein the solution further contains a borate buffer.
- the component (A) is 0.00001 to 0.005 w / v%
- the component (B) is 0.005 to 0.5 w / v%
- the component (C) is 0.0005 to 5 w.
- Item 6. Item 6.
- the dibutylhydroxytoluene-containing product according to any one of Items 1 to 5, wherein the solution is an eye drop.
- Item 7. (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof, A method for stabilizing dibutylhydroxytoluene in a solution containing A container main body that contains (C) at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizic acid, chlorpheniramine, and pharmaceutically acceptable salts thereof, and contains the liquid A pouring part having a pouring port for pouring out the liquid agent accommodated in the container main body part, a lid part blocking the pouring port, and a wall surface of the internal space of the pouring part, and the lid part In which at least one of the wall surfaces facing the spout is contained in a container made of a resin containing polybutylene terephthalate, the liquid agent is contained, St
- Item 8. The stabilization method according to Item 7, wherein the dispensing unit is a nozzle that dispenses the liquid agent in the form of droplets, and a wall surface of the internal space of the nozzle is made of a resin containing polybutylene terephthalate.
- Item 9. Item 9. The stabilization method according to Item 7 or 8, wherein the container body is made of a resin containing polyethylene terephthalate.
- Item 10. Item 10. The stabilization method according to any one of Items 7 to 9, wherein the liquid agent further contains a borate buffer.
- the component (A) is 0.00001 to 0.005 w / v%
- the component (B) is 0.005 to 0.5 w / v%
- the component (C) is 0.0005 to 5 w.
- Item 11 The stabilization method according to any one of Items 7 to 10, which is contained in an amount of / v%.
- Item 12. The stabilization method according to any one of Items 7 to 11, wherein the solution is an eye drop.
- the present invention while containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof, it is possible to improve the thermal stability of dibutylhydroxytoluene and to suppress adsorption to the container, and to contain dibutylhydroxytoluene. The amount can be kept stable.
- dibutylhydroxytoluene is set to a low content close to the threshold amount required for exhibiting the antioxidant action.
- pranoprofen and / or its Under the coexistence with the salt the thermal stability of dibutylhydroxytoluene was remarkably impaired, and the loss of the antioxidant effect due to the decrease in its content tended to be remarkable.
- according to the present invention overcoming the drawbacks of the prior art, co-existing dibutylhydroxytoluene and pranoprofen and / or a salt thereof in liquid preparations such as eye drops and nasal drops. Even in this case, it is possible to effectively suppress the decrease in the content and to effectively maintain the antioxidant action in the liquid agent.
- FIG. 1 shows a cross-sectional view of an embodiment of an eye drop container used in the present invention.
- FIG. 2 shows a partially enlarged cross-sectional view of the eye drop container shown in FIG.
- FIG. 3 shows a cross-sectional view of an example of an eye drop container used in the present invention.
- FIG. 4 shows a cross-sectional view of an example of an eye drop container used in the present invention.
- FIG. 5 shows a partially enlarged sectional view of the eye drop container shown in FIG.
- FIG. 6 shows a cross-sectional view of one example of an eyewash container used in the present invention.
- stabilization or “stability” of dibutylhydroxytoluene suppresses a decrease in the content of the liquid agent over time due to decomposition of dibutylhydroxytoluene or adsorption to a container, It means to keep the content stable or its characteristics.
- thermal stability of dibutylhydroxytoluene means a property of suppressing decomposition of dibutylhydroxytoluene by heat.
- dibutylhydroxytoluene-containing product means a product in which a liquid agent containing the components (A) to (C) described later is contained in a container, and “BHT-containing product” Sometimes abbreviated.
- the unit “w / v%” refers to a mass-to-volume percentage in the 16th revised Japanese Pharmacopoeia, and is synonymous with g / 100 mL.
- BHT-containing product The BHT-containing product of the present invention comprises (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof, (C) cromoglycic acid, allantoin, glycyrrhizic acid, chloro
- a liquid preparation containing at least one selected from the group consisting of pheniramine and pharmaceutically acceptable salts thereof is provided on the wall surface and / or the lid portion of the inner space of the pouring portion, The opposing wall surfaces are accommodated in a container made of a resin containing polybutylene terephthalate.
- the liquid agent accommodated in the container contains dibutylhydroxytoluene (sometimes referred to as (A) component).
- Dibutylhydroxytoluene is also called 2,6-di-tert-butyl-4-methylphenol, BHT, DBPC, and is a known compound as an antioxidant.
- BHT 2,6-di-tert-butyl-4-methylphenol
- DBPC 2,6-di-tert-butyl-4-methylphenol
- dibutylhydroxytoluene improves the thermal stability of pranoprofen and / or its salt and exhibits an antioxidant effect in the solution, such as pharmacological components and additives that are added as necessary. It is a component that contributes to the improvement of stability.
- the content of the component (A) in the liquid is not particularly limited and may be appropriately set according to the use of the liquid, etc., for example, 0.00001 to 0.005 w / v%, preferably 0. 00005 to 0.005 w / v%, more preferably 0.0001 to 0.005 w / v%.
- the liquid preparation used in the present invention further contains pranoprofen and / or a salt thereof (may be referred to as (B) component).
- pranoprofen and / or a salt thereof may be referred to as (B) component.
- pranoprofen and / or a salt thereof is improved in light stability by dibutylhydroxytoluene.
- Planoprofen is also known as ⁇ -methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, and is a known compound known to have an anti-inflammatory action in the ophthalmic field. is there.
- the salt of pranoprofen is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt; triethylamine salt, diethylamine And organic base salts such as salts, morpholine salts, piperazine salts and the like. These pranoprofen salts may be used alone or in combination of two or more.
- the component (B) one kind selected from pranoprofen and a salt thereof may be used alone, or two or more kinds may be used in combination. .
- pranoprofen is preferable.
- the content of the component (B) in the liquid is not particularly limited and may be appropriately set according to the use of the liquid, etc., for example, 0.005 to 0.5 w / v%, preferably 0. 05 to 0.1 w / v%, more preferably 0.05 w / v%.
- the liquid agent used in the present invention further includes cromoglycic acid, allantoin, glycyrrhizic acid, It contains at least one selected from the group consisting of chlorpheniramine and pharmaceutically acceptable salts thereof (sometimes referred to as (C) component).
- C pharmaceutically acceptable salts thereof
- the content of dibutylhydroxytoluene caused in the presence of pranoprofen and / or a salt thereof by blending the component (C) and storing it in a specific container described later Can be effectively suppressed.
- Cromoglycic acid is also referred to as 5,5 ′-[(2-hydroxy-1,3-propanediyl) bisoxy) bis (4-oxo-4H-1-benzopyran-2-carboxylic acid), cromolyn, DSCG. It is a known compound that is also used for purposes such as allergies and anti-inflammation.
- the salt of cromoglycic acid is not particularly limited as long as it is pharmaceutically acceptable.
- examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. It is done.
- alkali metal salts such as sodium salts and potassium salts
- alkaline earth metal salts such as calcium salts and magnesium salts. It is done.
- an alkali metal salt is preferable, and a sodium salt is more preferable.
- These salts of cromoglycic acid may be used alone or in combination of two or more.
- cromoglycic acid and / or its salt can be used in the form of a hydrate.
- Allantoin is also known as 5-ureidohydantoin and is a known compound that is also used for the purpose of anti-allergy, anti-inflammation, granulation formation promotion, tissue repair promotion and the like.
- the salt of allantoin is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include allantoindihydroxyaluminum and allantoinchlorohydroxyaluminum. These allantoin salts may be used alone or in combination of two or more.
- Glycyrrhizic acid is 3 ⁇ -[[2-O- (6-O-potacio- ⁇ -D-glucopyranuronosyl) -6-O-potacio- ⁇ -D-glucopyranuronosyl] oxy]- It is also known as 11-oxooleana-12-ene-30-acid, and is a known compound that is also used for antiallergic and anti-inflammatory purposes.
- the salt of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically acceptable; for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt Is mentioned.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt Is mentioned a glycyrrhizic acid salts
- an alkali metal salt is preferable, and a potassium salt is more preferable.
- These glycyrrhizic acid salts may be used alone or in combination of two or more.
- Chlorpheniramine is also known as 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin-2-yl-propan-1-amine and is a known compound that is also used for purposes such as antihistamine. is there.
- the salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically acceptable.
- examples thereof include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate, and the like. Can be mentioned.
- these chlorpheniramine salts maleate is preferable.
- chlorpheniramine and / or a salt thereof may be in the form of a solvate such as a hydrate, and may be either d-form or dl-form.
- component (C) one kind selected from cromoglycic acid, allantoin, glycyrrhizic acid, chlorpheniramine, and pharmaceutically acceptable salts thereof is used alone. You may use it in combination of 2 or more types.
- cromoglycic acid, allantoin, glycyrrhizic acid preferably from the viewpoint of exhibiting an excellent antiallergic action while effectively suppressing a decrease in the content of dibutylhydroxytoluene.
- pharmaceutically acceptable salts thereof more preferably cromoglycic acid, and pharmaceutically acceptable salts thereof, more preferably pharmaceutically acceptable salts of cromoglycic acid, particularly preferably sodium cromoglycate. It is done.
- Examples of the content of the component (C) in the liquid used in the present invention include 0.0005 to 5 w / v%, preferably 0.001 to 2 w / v%. More specifically, the content of each type of component (C) includes the following ranges.
- cromoglycic acid and / or a salt thereof preferably 0.1 to 5 w / v%, more preferably 0.5 to 3 w / v%, particularly preferably 1 to 2 w / v%.
- allantoin and / or a salt thereof is used: preferably 0.01 to 1 w / v%, more preferably 0.03 to 0.5 w / v%, particularly preferably 0.06 to 0.3 w / v%.
- glycyrrhizic acid and / or a salt thereof preferably 0.005 to 1 w / v%, more preferably 0.01 to 0.5 w / v%, particularly preferably 0.05 to 0.25 w / v% .
- chlorpheniramine and / or a salt thereof is used: preferably 0.0005 to 1 w / v%, more preferably 0.001 to 0.1 w / v%, particularly preferably 0.006 to 0.03 w / v. %.
- the liquid agent used in the present invention may contain a buffering agent for providing a buffering action.
- a buffering agent for example, a boric acid buffer, a phosphate buffer, a citrate buffer, a tartaric acid buffer, an acetic acid buffer, a Tris buffer, an amino acid (glutamic acid etc.) etc. are mentioned.
- These buffering agents may be used alone or in combination of two or more.
- the borate buffer has a buffer capacity in a pH range where pranoprofen and / or a salt thereof can be dissolved, and is preferably used in the present invention.
- the content of the buffering agent in the liquid used in the present invention may be appropriately set within a range in which a desired buffering action can be imparted depending on the type of the buffering agent used. For example, 0.001 to 5 w / v%, preferably 0.05 to 3 w / v%, more preferably 0.1 to 2 w / v%.
- liquid agent used in the present invention may contain a chelating agent in addition to the above components.
- a chelating agent By containing a chelating agent, it becomes possible to suppress the fall of content of dibutylhydroxytoluene more effectively.
- chelating agents include edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametalin.
- acids and pharmaceutically acceptable salts thereof include acids and pharmaceutically acceptable salts thereof.
- These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
- edetic acid and pharmaceutically acceptable salts thereof are preferable from the viewpoint of more effectively suppressing a decrease in the content of dibutylhydroxytoluene.
- the pharmaceutically acceptable salt of edetic acid include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt.
- the content may be appropriately set according to the use of the liquid, etc., for example, 0.0005 to 0.5 w / v%, preferably Is 0.001 to 0.2 w / v%, more preferably 0.005 to 0.13 w / v%.
- the liquid agent used in the present invention can contain a pharmacological component in addition to the above components, depending on the use of the liquid agent.
- the pharmacological component used is not particularly limited.
- a preparation used in the ophthalmic or otolaryngological field such as eye drops, eye wash, nasal drops, ear drops, etc.
- ketorolactolome Anti-histamines such as diphenhydramine hydrochloride
- ketotifen fumarate, acitazanolast, amlexanox, pemiro Antiallergic agents such as last potassium, tranilast, ibudilast
- antibacterial agents such as norfloxacin, ofloxacin, lomefloxacin, levofloxacin, gentamicin, gatifloxacin
- ascorbic acid flavin adenine dinucleotide sodium
- cyanoco Vitamins such as lamin, pyridoxine hydrochloride, tocopherol acetate, retinol acetate, retinol palmitate, panthenol, calcium panto
- the content of these pharmacological components is appropriately set according to the type of pharmacological component and the use of the liquid agent.
- liquid agent used in the present invention contains, as necessary, isotonic agents, solubilizers, viscous bases, cooling agents, pH adjusters, preservatives, stabilizers. Further, additives such as surfactants may be contained.
- isotonic agent examples include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid and the like. These isotonic agents may be used alone or in combination of two or more.
- solubilizer examples include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, and pluronic; polyhydric alcohols such as glycerin and macrogol. These solubilizers may be used alone or in combination of two or more.
- viscous base examples include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, sodium chondroitin sulfate, alginic acid or a salt thereof, sodium hyaluronate; hypromellose, hydroxyethylcellulose, methylcellulose, Examples thereof include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
- These viscous bases may be used individually by 1 type, and may be used in combination of 2 or more type.
- Examples of the refreshing agent include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.
- Examples of the pH adjuster include alkalis such as sodium hydroxide, potassium hydroxide and borax; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid, tartaric acid and boric acid.
- preservatives examples include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid or a salt thereof Benzalkonium chloride, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, polyhexamethylene biguanide and the like. These preservatives may be used individually by 1 type, and may be used in combination of 2 or more type.
- stabilizer examples include polyvinyl pyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, tocopherol and the like. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.
- surfactant examples include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol; alkyldiaminoethylglycine, Amphoteric surfactants such as lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfate, N-acyl taurate, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate; alkyl pyridinium salts; And cationic surfactants such as alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.
- nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty
- the concentration of these additives is appropriately set according to the type of additive and the use of the liquid agent.
- the form of the liquid used in the present invention is not limited as long as it contains water as a base.
- it may be in the form of an aqueous solution, a suspension, an emulsion, etc. Can be mentioned.
- the pH of the liquid used in the present invention is not particularly limited and may be appropriately set according to the use of the liquid, etc., for example, 5.0 to 9.0, preferably 6.5 to 8. .5.
- liquid agent used in the present invention is not particularly limited, and examples thereof include pharmaceuticals and contact lens care products.
- pharmaceuticals include ophthalmic solutions such as eye drops (including eye drops for contact lenses that can be instilled even when wearing contact lenses), eye wash, etc .; ophthalmic and nasal solutions such as nasal drops and ear drops An internal preparation, an injection, an external preparation and the like.
- contact lens care products include contact lens mounting liquids, contact lens multipurpose solutions, and the like. Among the uses of these solutions, preferably, ophthalmic solutions, otolaryngological solutions, and contact lens care products, and more preferably eye drops.
- liquid agent used in the present invention may be filled in a multi-dose type container that is used in multiple doses and used repeatedly, or filled in a single dose and used up once.
- a unit dose type container may be filled.
- the liquid agent used in the present invention may be produced according to a known preparation method according to the form, use, etc., for example, by blending each component with an aqueous base such as water or physiological saline. it can.
- an aqueous base such as water or physiological saline. it can.
- it can be produced using the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
- the container in order to accommodate the liquid agent, includes a container main body part, a pouring part, and a lid part.
- a container having a wall surface facing the spout made of a resin containing polybutylene terephthalate is used.
- the container main body part which comprises the said container is a site
- the shape and size of the container main body are not particularly limited, and are appropriately set according to the type and volume of the liquid agent to be stored.
- the pouring part constituting the container has an internal space that communicates between the container main body part and the outside of the container, and includes a pouring outlet for pouring the liquid agent contained in the container main body part.
- the outlet is provided so as to communicate with the opening of the container main body, and the liquid agent accommodated in the container main body is poured out (discharged) from the spout to the outside of the container through the internal space.
- the structure of the dispensing unit is not particularly limited as long as the liquid agent accommodated in the container main body part can be poured out of the container from the spout, and for example, the liquid agent is in the form of droplets.
- the pouring part is preferably a nozzle configured to pour out the liquid agent in the form of droplets.
- pouring part may be provided with the inside stopper like an inside stopper nozzle or a perforated inside stopper, for example.
- a part or all of the pouring part may be integrally formed with the container body part. Moreover, the said extraction
- pouring part may be attached to the lumen
- the lid part constituting the container is a part that closes the spout.
- the said cover part should just be equipped with the structure fitted with the container main-body part and / or the spout. More specifically, when the BHT-containing product of the present invention is a multi-dose type, it may be a structure that can be detachably fitted to the container body and / or the spout, and the BHT-containing product of the present invention is also included. When the product is a unit dose type, it may have a structure that is detachably fitted from the container body and / or the spout.
- a lid that is detachably attached to the container main body and / or the pouring part by screw fitting.
- the lid part and the container body part and / or the pouring part are detachably attached by screw fitting, the lid part is provided with a screw part that is screwed with the thread part of the container body part and / or the pouring part. It only has to be done.
- the shape of the container is appropriately set according to the application of the BHT-containing product to be accommodated. Specifically, an eye drop container, an eye wash container, an nasal drop container, etc. are mentioned.
- FIGS. 1-10 Examples of specific embodiments of containers used in the present invention are shown in FIGS.
- FIG. 1 is a cross-sectional view of an embodiment of an eye drop container
- FIG. 2 is a partially enlarged cross-sectional view of the eye drop container shown in FIG.
- a dispensing part 2 capable of dispensing the liquid agent in the form of droplets is inserted into the lumen of the opening of the container body part 1
- the lid part 3 further comprises a container body part. 1 is detachably attached by screw fitting, and the spout of the spout 2 is blocked.
- the liquid agent accommodated in the container main body 1 is poured out of the container through the internal space 4 of the dispensing part 2 from the spout.
- the eye drop container shown in FIG. 1 may be used for accommodating a unit dose type liquid agent, but is preferably used for accommodating a multi dose type liquid agent.
- FIG. 3 is a cross-sectional view of an embodiment of an eye drop container.
- the container main body 1 and the pouring part 2 are integrally formed of the same material regardless of bonding or mechanical joining, and the internal space 4 of the pouring part 2 is interposed.
- the liquid agent can be poured out from the spout into the outside of the container.
- the lid is omitted and a virtual line (dotted line) is inserted for convenience.
- the container member below the imaginary line corresponds to the container main body 1
- the container member above the imaginary line corresponds to the dispensing part 2.
- the eye drop container shown in FIG. 3 may be used for accommodating a unit dose type liquid agent, but is preferably used for accommodating a multi dose type liquid agent.
- FIG. 4 is a cross-sectional view of an embodiment of an eye drop container
- FIG. 5 is a partially enlarged cross-sectional view of the eye drop container shown in FIG.
- the container main body portion 1, the extraction portion 2, and the lid portion 3 are integrally molded.
- the pouring part 2 and the lid part 3 are connected, the liquid agent accommodated in the container main body part 1 is poured through the internal space 4 of the pouring part 2 by separating them when used. It becomes possible to pour out the container from the outlet. 4 and 5, a virtual line (dotted line) is inserted for convenience. 4 and 5, the container member between two virtual lines corresponds to the extraction part 2, and the space between the two virtual lines corresponds to the internal space 4 of the extraction part 2.
- the eye drop container shown in FIG. 4 is suitably used for housing a unit dose type liquid agent.
- FIG. 6 is a cross-sectional view of the eyewash container.
- a part of the container main body 1 and the extraction part 2 are integrally formed.
- the said liquid agent accommodated in the container main-body part 1 is poured out of a container from the spout through the internal space 4 of the extraction
- FIG. 6 a virtual line (dotted line) is inserted for convenience.
- FIG. 1 to 6 show specific embodiments of the eye drop container and the eye wash container.
- the present invention is not limited to these structures and shapes, and a container other than the eye drop container and the eye wash container may be used. It can be used as long as it has the features of
- the “wall surface facing the spout in the lid” corresponds to an inner wall portion of the lid that covers the spout when the lid is attached to the container main body and / or the extraction portion.
- the surface portion indicated by reference numeral 5 corresponds to the “wall surface of the internal space of the extraction portion”
- the surface portion indicated by reference numeral 6 indicates “the outlet in the lid portion.
- a wall surface facing corresponds to “a wall surface facing”.
- the resin containing polybutylene terephthalate constitutes the wall surface of the inner space of the pouring part and / or the wall surface facing the pouring port of the pouring part in the lid part, thereby allowing the specific composition employed in the liquid agent.
- the resin constituting the wall surface of the internal space of the pouring portion and / or the wall surface facing the pouring port of the pouring portion in the lid portion may be made of polybutylene terephthalate alone, and polybutylene terephthalate and It may consist of a blend polymer with another polymer.
- a blend polymer of polybutylene terephthalate and another polymer is used as the resin constituting the wall surface facing the pouring port of the pouring part in the wall surface and / or the lid part of the pouring part, the effect of the present invention is exhibited.
- the mixing ratio is not particularly limited, but polybutylene terephthalate is 50 w / w% or more, preferably 60 w / w% or more, more preferably 70 w / w% or more, based on the total amount of the blend polymer. More preferably, it occupies 80 w / w% or more, particularly preferably 90 w / w% or more.
- At least one of the wall surface of the internal space of the pouring part and the wall surface facing the pouring port of the pouring part in the lid part may contain polybutylene terephthalate.
- a pouring part for example, a nozzle configured so that the liquid agent is dropped in the form of droplets
- the content of dibutylhydroxytoluene is further reduced.
- at least the wall surface of the inner space of the pouring portion is made of a resin containing polybutylene terephthalate, and the pouring is performed on the wall surface of the inner space of the pouring portion and the lid portion.
- both the outlet and the opposite wall surface are made of a resin containing polybutylene terephthalate.
- the wall surface facing the spout port of the section is made of a resin containing polybutylene terephthalate, and both the wall surface of the inner space of the spout section and the wall surface facing the spout port of the spout section in the lid portion are made of poly. More preferably, it is made of a resin containing butylene terephthalate.
- the wall surface of the internal space of the pouring part and / or the wall surface facing the pouring port of the pouring part in the lid part is made of resin containing polybutylene terephthalate
- the portions other than these wall surfaces may be made of a resin containing polybutylene terephthalate, or may be made of a material other than polybutylene terephthalate.
- the container main body is made of the same resin as the pouring part.
- the container body may be made of glass or plastic, but preferably made of plastic.
- the type of resin forming the container body is not particularly limited.
- polyethylene terephthalate, polybutylene terephthalate, polystyrene, acrylonitrile butadiene styrene, etc. Is mentioned.
- polyethylene terephthalate can suppress adsorption of dibutylhydroxytoluene while having excellent moldability, it is suitably used as a resin for forming the container body.
- the method for stabilizing dibutylhydroxytoluene of the present invention comprises (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof, and (C) cromoglycol.
- the wall surface of the inner space of the outlet portion and / or the wall surface of the lid portion facing the outlet of the outlet portion is housed in a container made of a resin containing polybutylene terephthalate.
- the types and contents of the components (A) to (C) contained in the liquid the types and contents of other components that can be blended, the use of the liquid, etc. It is the same as that of the case of the liquid agent used.
- the container used in the stabilization method of the present invention is the same as the container used in the BHT-containing product.
- the stabilization method of the present invention improves the thermal stability of dibutylhydroxytoluene and suppresses the adsorption of dibutylhydroxytoluene to the container in a liquid agent containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof. Therefore, the content stability of dibutylhydroxytoluene can be effectively suppressed and the storage stability of dibutylhydroxytoluene can be improved. Therefore, it can also be implemented as a storage method for the solution.
- Test Example 1 Evaluation of change over time in content of dibutylhydroxytoluene The change over time in the content of dibutylhydroxytoluene when the solutions shown in Table 2 were prepared and stored in various containers was measured. Specifically, the liquid preparations shown in Table 2 were prepared according to a conventional method, stored in each container shown in Table 1, sealed, and stored by standing at 40 ° C., 75% RH, light-shielding conditions for 2 weeks. did. At that time, in the case of containers 2 and 3, the capacity of the liquid agent was 10 mL, and in the case of container 1, the capacity of the liquid agent was 5 mL.
- the container was left standing in an upright state so that the lid portion was the upper surface and the bottom of the container main body was the lower surface.
- Dibutylhydroxytoluene was sampled by sampling so that the liquid in the container would not come into contact with the nozzle before and after the start of storage, and measuring the content of dibutylhydroxytoluene in the liquid by HPLC.
- the thermal stability of toluene was evaluated. Specifically, the stability of dibutylhydroxytoluene was calculated as a residual ratio (%) by the ratio of the dibutylhydroxytoluene content after storage to the dibutylhydroxytoluene content before storage.
- the container 3 is an example of a conventional eye drop container. Further, it is known that glass is difficult to adsorb general drugs, and the container 1 is an example of a container that is difficult to adsorb dibutylhydroxytoluene.
- Table 2 shows the results obtained. As can be seen from the results of the control, it was revealed that when dibutylhydroxytoluene and pranoprofen were allowed to coexist in the solution, the content of dibutylhydroxytoluene was significantly reduced. In addition, when naphazoline hydrochloride or neostigmine methyl sulfate is combined with dibutylhydroxytoluene and pranoprofen, the decrease in dibutylhydroxytoluene content cannot be sufficiently suppressed, or a further decrease in dibutylhydroxytoluene content may occur. (Comparative Examples 1 and 2).
- Reference Test Example 1 Evaluation of time-dependent change in the content of dibutylhydroxytoluene
- the liquid agents shown in Tables 3 and 4 were prepared according to a conventional method, and stored in each container shown in Table 1 in the same manner as in Test Example 1. And the content of dibutylhydroxytoluene in the solution was measured by HPLC. Based on the obtained measured values, the residual rate (%) of dibutylhydroxytoluene was calculated in the same manner as in Test Example 1.
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CN201580012544.2A CN106068122B (zh) | 2014-03-10 | 2015-03-10 | 二丁基羟基甲苯的稳定化方法 |
RU2016139409A RU2690490C2 (ru) | 2014-03-10 | 2015-03-10 | Способ стабилизации дибутилгидрокситолуола |
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Cited By (4)
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WO2017043488A1 (ja) * | 2015-09-08 | 2017-03-16 | ロート製薬株式会社 | 眼科組成物 |
JPWO2015190483A1 (ja) * | 2014-06-10 | 2017-04-20 | ロート製薬株式会社 | 眼科用水性組成物 |
JP2017105752A (ja) * | 2015-08-31 | 2017-06-15 | ロート製薬株式会社 | 眼科組成物 |
WO2019230971A1 (ja) * | 2018-05-31 | 2019-12-05 | 千寿製薬株式会社 | ジブチルヒドロキシトルエンの含量低下が抑制された眼科用液剤 |
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- 2015-03-10 WO PCT/JP2015/056985 patent/WO2015137326A1/ja active Application Filing
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- 2015-03-10 RU RU2016139409A patent/RU2690490C2/ru active
- 2015-03-10 CN CN201580012544.2A patent/CN106068122B/zh active Active
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CN106068122A (zh) | 2016-11-02 |
TWI644663B (zh) | 2018-12-21 |
RU2690490C2 (ru) | 2019-06-04 |
JP6800264B2 (ja) | 2020-12-16 |
JPWO2015137326A1 (ja) | 2017-04-06 |
JP2019147802A (ja) | 2019-09-05 |
JP6509811B2 (ja) | 2019-05-08 |
RU2016139409A3 (zh) | 2018-09-26 |
TW201617056A (zh) | 2016-05-16 |
CN106068122B (zh) | 2019-04-19 |
RU2016139409A (ru) | 2018-04-10 |
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