WO2019216395A1 - Composition ophtalmique - Google Patents

Composition ophtalmique Download PDF

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Publication number
WO2019216395A1
WO2019216395A1 PCT/JP2019/018658 JP2019018658W WO2019216395A1 WO 2019216395 A1 WO2019216395 A1 WO 2019216395A1 JP 2019018658 W JP2019018658 W JP 2019018658W WO 2019216395 A1 WO2019216395 A1 WO 2019216395A1
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salt
ophthalmic composition
concentration
phosphoric acid
brimonidine
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PCT/JP2019/018658
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English (en)
Japanese (ja)
Inventor
憲晃 西田
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千寿製薬株式会社
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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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an ophthalmic composition
  • an ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and capable of suppressing the generation of decomposition products due to storage.
  • Brimonidine and its salts are known as adrenergic ⁇ 2 receptor agonists, and reduce intraocular pressure by promoting the outflow of aqueous humor through the uveoscleral outflow tract along with suppression of production of aqueous humor. In the past, it has been used to treat glaucoma and ocular hypertension.
  • Timolol and its salts are known as ⁇ receptor blockers, have the effect of reducing intraocular pressure by suppressing the production of aqueous humor, and are conventionally used for the treatment of glaucoma and ocular hypertension. .
  • Patent Document 1 discloses that an ophthalmic pharmaceutical composition containing brimonidine and timolol is safe and has an excellent effect of reducing intraocular pressure compared to the case where brimonidine or timolol is used alone. ing.
  • Patent Document 2 discloses that a composition containing about 1 to 4.5 mM brimonidine, about 2 to 15.8 mM timolol, and about 150 to 250 ppm benzalkonium chloride is used to treat glaucoma and ocular hypertension. Is disclosed to be effective.
  • Patent Document 3 discloses that a composition containing 0.1 w / v% brimonidine tartrate and 0.68 w / v% timolol maleate is effective in treating glaucoma and ocular hypertension, and has side effects. It is disclosed that it can be reduced.
  • the present invention provides a novel ophthalmic composition
  • a novel ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof.
  • the present inventors have found that in an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, phosphoric acid and / or It has been found that the production of decomposition products can be effectively suppressed by reducing the concentration of the salt. Furthermore, in the ophthalmic composition, the concentration of phosphoric acid and / or a salt thereof can be reduced, and the addition of edetic acid and / or a salt thereof can suppress the generation of decomposition products more effectively. I found it. The present invention has been completed by further studies based on these findings.
  • Item 1 Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof, An ophthalmic composition wherein the concentration of phosphoric acid and / or a salt thereof is 32 mM or less.
  • Item 2. Item 4. The ophthalmic composition according to Item 1, further comprising edetic acid and / or a salt thereof.
  • Item 3. Item 3.
  • Item 5. The ophthalmic composition according to Item 4, comprising disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof.
  • Item 6. Item 6. The ophthalmic composition according to any one of Items 1 to 5, wherein the concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM.
  • Item 8. The ophthalmic composition according to any one of Items 1 to 7, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 16 mM.
  • Item 9. The ophthalmic composition according to any one of Items 1 to 8, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 6.3 mM.
  • Item 10. The ophthalmic composition according to any one of Items 1 to 9, wherein the concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v%.
  • Item 11. Item 11.
  • Item 15. The ophthalmic composition according to any one of Items 1 to 14, wherein the concentration of timolol and / or a salt thereof is 0.68 w / v%.
  • Item 16. Item 3. The ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or a salt thereof is 0.0001 to 0.2 w / v%.
  • the ophthalmic composition according to Item 2 wherein the concentration of edetic acid and / or a salt thereof is 0.001 to 0.03 w / v%.
  • Item 3. The ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or a salt thereof is 0.01 w / v%.
  • Item 19. The concentration of brimonidine and / or its salt is 0.1 w / v%, the concentration of timolol and / or its salt is 0.68 w / v%, and the concentration of phosphoric acid and / or its salt is 0.3 to Item 3.
  • the ophthalmic composition according to Item 2 wherein the composition is 32 mM and the concentration of edetic acid and / or a salt thereof is 0.01 w / v%.
  • Item 20 The ophthalmic composition according to Item 20.
  • Item 21 The ophthalmic composition according to any one of Items 1 to 20, which is an eye drop.
  • Item 23 The ophthalmic composition according to Item 23.
  • An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally containing edetic acid and / or a salt thereof,
  • the concentration of phosphoric acid and / or its salt is 0.01-32 mM
  • the concentration of brimonidine and / or its salt is 0.01-1 w / v%
  • the concentration of timolol and / or its salt is 0.1 to 1.5 w / v%
  • the concentration of edetic acid and / or its salt optionally contained is 0.0001 to 0.2 w / v%, Ophthalmic composition. Item 24.
  • Brimonidine and / or salt thereof timolol and / or salt thereof, phosphoric acid and / or salt thereof, and optionally edetic acid and / or salt thereof, having a pH of 7.1 to 7.3
  • An ophthalmic composition comprising: The concentration of phosphoric acid and / or its salt is 0.01-32 mM, The concentration of brimonidine and / or its salt is 0.01-1 w / v%, The concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, The concentration of edetic acid and / or its salt optionally contained is 0.0001 to 0.2 w / v%, Ophthalmic composition. Item 25.
  • Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof, preservative, optionally edetic acid and / or salt thereof, pH 7.1 to 7 .3 an ophthalmic composition The concentration of phosphoric acid and / or its salt is 0.01-32 mM, The concentration of brimonidine and / or its salt is 0.01-1 w / v%, The concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, The concentration of the preservative is 0.0001 to 0.1 w / v%, The concentration of edetic acid and / or its salt optionally contained is 0.0001 to 0.2 w / v%, Ophthalmic composition.
  • Item 26 The ophthalmic composition according to any one of Items 23 to 25, wherein the brimonidine salt is brimonidine tartrate and / or the timolol salt is timolol maleate. Item 27.
  • An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally containing edetic acid and / or a salt thereof,
  • the concentration of brimonidine and / or its salt is 0.1 w / v%
  • the concentration of timolol and / or its salt is 0.68 w / v%
  • the concentration of phosphoric acid and / or salt thereof is 6.3 mM
  • the concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%, Ophthalmic composition. Item 28.
  • An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally containing edetic acid and / or a salt thereof,
  • the concentration of brimonidine and / or its salt is 0.1 w / v%
  • the concentration of timolol and / or its salt is 0.68 w / v%
  • the concentration of phosphoric acid and / or salt thereof is 6.3 mM
  • the concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%
  • pH is 7.1
  • Ophthalmic composition Item 29.
  • An ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and benzalkonium chloride, and optionally containing edetic acid and / or a salt thereof.
  • the concentration of brimonidine and / or its salt is 0.1 w / v%, The concentration of timolol and / or its salt is 0.68 w / v%, The concentration of phosphoric acid and / or salt thereof is 6.3 mM, The concentration of benzalkonium chloride is 0.002 w / v%, The concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%, pH is 7.1, Ophthalmic composition.
  • Brimonidine tartrate, salt of timolol includes timolol maleate, disodium hydrogen phosphate and sodium dihydrogen phosphate, benzalkonium chloride, and may optionally contain edetic acid and / or its salt
  • the concentration of brimonidine tartrate is 0.1 w / v%
  • the concentration of timolol maleate is 0.68 w / v%
  • the total concentration of disodium hydrogen phosphate and sodium dihydrogen phosphate is 6.3 mM
  • the concentration of benzalkonium chloride is 0.002 w / v%
  • the concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%
  • pH is 7.1, Ophthalmic composition.
  • the present invention provides the following inventions.
  • Term A1 A method for suppressing degradation products in an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, A step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, The concentration of the phosphoric acid and / or salt thereof is 32 mM or less.
  • Method for suppressing decomposition products Term A2.
  • the suppression method of the decomposition product of term A1 which makes edetic acid and / or its salt coexist in an ophthalmic composition.
  • the present invention provides the following inventions.
  • Term B1. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, A step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition; The concentration of the phosphoric acid and / or salt thereof is 32 mM or less. How to improve storage stability.
  • Term B2. Furthermore, the storage stability improvement method according to Item B1, wherein edetic acid and / or a salt thereof is allowed to coexist in the ophthalmic composition.
  • the present invention provides the following inventions.
  • Term C1 Production of an ophthalmic composition of a composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, wherein the concentration of phosphoric acid and / or a salt thereof is 32 mM or less.
  • Term C2. The use according to Item C1, wherein the composition further comprises edetic acid and / or a salt thereof.
  • the concentration of phosphoric acid and / or a salt thereof is a predetermined value or less.
  • an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, when the concentration of phosphoric acid and / or a salt thereof is set to a predetermined value or less, although there exists a tendency for another decomposition product to arise, in this invention, the production amount of the said decomposition product can also be suppressed by containing edetic acid and / or its salt further. As a result, the storage stability of the ophthalmic composition can be further improved.
  • ophthalmic compositions such as eye drops are administered directly to the ocular mucosa, it is necessary to ensure high safety, and it is necessary to suppress the generation of degradation products due to storage.
  • concentration of decomposition products generated by storage under specified conditions exceeds a certain amount, it is mandatory to identify the structure of the decomposition products and report safety. (Regarding revision of guidelines on drug impurities in pharmaceutical products containing new active ingredients No. 0624001), in developing eye drops, the concentration of degradation products usually exceeds 1.0% This obligation arises in some cases. For this reason, in the preparation of eye drops, it is necessary to sufficiently suppress the generation of degradation products caused by storage.
  • Patent Documents 1 to 4 include, as a specific example of a preparation containing brimonidine or a salt thereof and timolol or a salt thereof, an embodiment containing phosphoric acid and / or a salt thereof in a calculated concentration of 96.1 to 111.4 mM. It is shown. Accordingly, the present inventors have made studies to verify the stability of the preparations specifically disclosed in Patent Documents 1 to 4, and in such preparations, degradation products (described later) are stored by storage. It has been found that there is a problem that decomposition products A1, A2, and A3) are generated.
  • the inventors of the present invention use an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof at a concentration of 32 mM phosphoric acid and / or a salt thereof. It discovered that the production
  • the concentration of phosphoric acid and / or a salt thereof is set to 32 mM or less as described above, the generation amount of the decomposition products A1, A2, and A3 can be reduced, but another decomposition product ( It was confirmed that the decomposition product B) described later increases. Therefore, the inventors have made further studies, and in the ophthalmic composition, the concentration of phosphoric acid and / or its salt is set to 32 mM or less, and edetic acid and / or its salt is contained. Thus, it was found that the generation of the decomposition products A1, A2, and A3 can be suppressed while the generation of the decomposition product B can be effectively suppressed.
  • ophthalmic composition means a pharmaceutical composition for ophthalmic use.
  • brimonidine is a compound known as an adrenergic ⁇ 2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.
  • thymolol is a compound known as a ⁇ receptor blocker, and is (2S) -1- (tert-butylamino) -3- (4-morpholino-1,2,5-thiadiazole. -3-yloxy) -2-propanol.
  • phosphoric acid is one of phosphorus oxo acids and refers to an inorganic acid having the chemical formula H 3 PO 4 .
  • edetic acid refers to a known compound that is also called ethylenediaminetetraacetic acid.
  • degradation product A1 refers to brimonidine and / or a salt thereof, timolol and / or a salt thereof, and an ophthalmic composition containing phosphoric acid and / or a salt thereof, It is a substance corresponding to a peak that is observed at a retention time of about 2.6 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”.
  • “Decomposition product A1” is a decomposition product produced by the interaction of brimonidine and / or its salt with timolol and / or its salt.
  • the “decomposition product A2” means that after storing an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, “( It is a substance corresponding to a peak observed at a time when the retention time is about 7.8 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”. “Decomposition product A2” is a decomposition product caused by brimonidine and / or a salt thereof.
  • degradation product A3 refers to brimonidine and / or a salt thereof, timolol and / or a salt thereof, and an ophthalmic composition containing phosphoric acid and / or a salt thereof, It is a substance corresponding to a peak observed at a time when the retention time is about 14.0 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”.
  • “Decomposition product A3” is a decomposition product caused by brimonidine and / or a salt thereof.
  • composition product B includes brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and includes edetic acid and / or a salt thereof.
  • “Decomposition product B” is a decomposition product resulting from brimonidine and / or a salt thereof.
  • FIG. 1 after storing an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, they are described in the column of “(HPLC measurement conditions)”. Shows a chromatogram obtained by HPLC measurement under different conditions. In the chromatogram, peaks corresponding to the decomposition products A1, A2, A3, and B are clearly shown.
  • the degradation product A1 contains phosphoric acid and / or a salt thereof and is not detected even when an ophthalmic composition containing only brimonidine and / or a salt thereof, or timolol and / or a salt thereof is stored. Is detected by storing an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof together with phosphoric acid and / or a salt thereof. Note that the decomposition product A1 is not detected immediately after the ophthalmic composition is prepared. Therefore, it has been confirmed that the degradation product A1 is a degradation product produced by the involvement of at least brimonidine and / or its salt and timolol and / or its salt by storage of the ophthalmic composition.
  • the decomposition products A2, A3, and B are decomposition products produced by the involvement of at least brimonidine and / or a salt thereof upon storage of the ophthalmic composition.
  • the decomposition products A1, A2, and A3 can suppress the production by setting the concentration of phosphoric acid and / or its salt in the ophthalmic composition to 32 mM or less. It becomes possible.
  • Decomposition product B is a substance whose production amount increases when the concentration of phosphoric acid and / or its salt in the ophthalmic composition is set to 32 mM or less, and its production is suppressed by edetic acid and / or its salt. It becomes possible to do.
  • “suppression of decomposition products” includes not only reducing the production amount of decomposition products but also suppressing generation completely.
  • the “method for suppressing decomposition products” is a method for reducing the generation amount of decomposition products generated by storage of an ophthalmic composition or completely suppressing the generation thereof.
  • the degree of the “decomposition product suppression method” can be indicated by the amount of decomposition product produced when stored at 60 ° C. for 4 weeks.
  • “storage stability” means that the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof is reduced by suppressing the generation of degradation products generated by storage of an ophthalmic composition. It means the degree not to let it.
  • the “method for improving storage stability” is to reduce the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof by suppressing the generation of decomposition products generated by storage of an ophthalmic composition. It is a method of suppressing.
  • the degree of “storage stability” can be indicated by the amount of decomposition products generated when stored at 60 ° C. for 4 weeks.
  • Ophthalmic composition As one embodiment of the present invention, brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof are included, and the concentration of phosphoric acid and / or a salt thereof is 32 mM or less.
  • An ophthalmic composition is provided. According to the ophthalmic composition of this aspect, it is possible to solve the problem of suppressing the decomposition products A1, A2, and A3.
  • brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof of 32 mM or less, and edetic acid and / or a salt thereof are contained.
  • An ophthalmic composition is provided. According to the ophthalmic composition of this aspect, it is possible to solve the problem of suppressing the decomposition product B as well as the decomposition products A1, A2, and A3.
  • brimonidine salt is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride and the like. Further, brimonidine and / or a salt thereof may be in the form of a solvate such as a hydrate.
  • brimonidine or a salt thereof may be used alone or in combination.
  • brimonidine and its salt brimonidine tartrate is preferable.
  • the concentration of brimonidine and / or a salt thereof is not particularly limited, and may be appropriately set according to the degree of symptom of the patient to be applied, the amount applied per time, and the like. Is, for example, 0.01 to 1 w / v%. From the viewpoint of suppressing the concentration of each decomposition product to 1.0% or less, it is preferably 0.05 to 0.3 w / v%, more preferably 0.1 to 0.2 w / v%, particularly preferably 0.8. 1 w / v% is mentioned.
  • the concentration of brimonidine and / or a salt thereof means a concentration converted to brimonidine tartrate.
  • timolol and / or its salt The salt of timolol is not particularly limited as long as it is pharmaceutically acceptable. Specifically, maleate, fumarate, acetate, tartrate, citrate, succinate, mesylate Examples thereof include organic acid salts such as salts, besylate salts and tosylate salts; inorganic acid salts such as hydrochloride salts, nitrate salts, sulfate salts, hydrobromide salts and hydroiodide salts. Further, timolol and / or a salt thereof may be in the form of a solvate such as a hydrate.
  • timolol or a salt thereof may be used alone, or a combination thereof may be used.
  • timolol and its salt timolol maleate is preferable.
  • the concentration of timolol and / or a salt thereof is not particularly limited, and may be set as appropriate according to the degree of symptom of the patient to be applied, the amount applied per time, and the like. Is, for example, 0.1 to 1.5 w / v%. From the viewpoint of further suppressing the generation amount of the decomposition product B, it is preferably 0.3 to 1.1 w / v%, more preferably 0.5 to 0.9 w / v%, particularly preferably 0.68 w / v. %.
  • the concentration of timolol and / or a salt thereof means a concentration converted to timolol maleate.
  • the ophthalmic composition of the present invention contains phosphoric acid and / or a salt thereof, and the concentration of phosphoric acid and / or a salt thereof is set to 32 mM or less.
  • concentration of phosphoric acid and / or a salt thereof is set to a predetermined value or less.
  • the salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable.
  • a dialkali metal phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate
  • sodium dihydrogen phosphate And alkali metal dihydrogen phosphates such as potassium dihydrogen phosphate
  • trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate.
  • the salt of phosphoric acid may be in the form of a solvate such as a hydrate.
  • a solvate such as a hydrate.
  • disodium hydrogen phosphate the form of dodecahydrate, sodium dihydrogen phosphate, In some cases, it may be in the form of a dihydrate.
  • one of phosphoric acid and its salt may be selected and used alone, or two or more may be used in combination.
  • a dialkali metal hydrogen phosphate A combination of a salt and an alkali metal dihydrogen phosphate, more preferably a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • the ratio of these is not particularly limited, but for example, dihydrogen phosphate per mole of hydrogen alkali metal phosphate is used.
  • the alkali metal hydrogen salt include 0.005 to 1.0 mol. From the viewpoint of further stabilizing the pH, it is preferably 0.01 to 0.4 mol, more preferably 0.05 to 0.5 mol, and particularly preferably 0.26.
  • the concentration of phosphoric acid and / or its salt is set to 32 mM or less.
  • the concentration of phosphoric acid and / or a salt thereof is preferably 16 mM or less, more preferably 13 mM or less, particularly preferably 6.3 mM. The following are mentioned.
  • the lower limit value of the concentration of phosphoric acid and / or a salt thereof is not particularly limited, and examples thereof include 0.01 mM or more.
  • an ophthalmic composition that does not contain edetic acid and / or a salt thereof from the viewpoint of reducing the amount of decomposition product B produced, it is preferably 0.3 mM or more, more preferably 3.2 mM or more, particularly preferably 6 .3 mM or more.
  • a specific range of the concentration of phosphoric acid and / or a salt thereof is, for example, 0.01 to 32 mM. From the viewpoint of further suppressing the total amount of decomposition products, 0.3 to 32 mM is preferable, 0.3 to 16 mM is more preferable, and 0.3 to 6.3 mM is particularly preferable.
  • the ophthalmic composition of the present invention may contain edetic acid and / or a salt thereof in addition to the above components.
  • a decomposition product when the concentration of phosphoric acid and / or a salt thereof is set within the above range
  • the production amounts of A1, A2 and A3 are reduced, the production amount of the decomposition product B tends to increase.
  • the amount of decomposition product B can be effectively reduced by further containing edetic acid and / or a salt thereof. Become.
  • the salt of edetic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sodium edetate such as monosodium edetate, disodium edetate (EDTA), and tetrasodium edetate. .
  • the salt of edetic acid may be in the form of a solvate such as a hydrate such as a dihydrate.
  • the ophthalmic composition of the present invention contains edetic acid and / or a salt thereof, one may be selected from edetic acid and a salt thereof and used alone or in combination of two or more. May be.
  • edetic acids and salts thereof from the viewpoint of more effectively reducing the amount of decomposition product B produced, a salt of edetic acid is preferable, and disodium edetate (EDTA) is more preferable.
  • the concentration is, for example, 0.0001 to 0.2 w / v%.
  • concentration of edetic acid and / or its salt means the density
  • an isotonic agent in addition to the above components, an isotonic agent, a polyhydric alcohol, a surfactant, a thickener, a buffer (other than phosphoric acid and its salt), a chelate, if necessary.
  • the isotonic agent is not particularly limited as long as it is pharmaceutically acceptable.
  • polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol
  • metal salts such as magnesium, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
  • These isotonic agents may be used alone or in combination of two or more.
  • the polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the surfactant is not particularly limited as long as it is pharmaceutically acceptable.
  • tyloxapol polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Nonionic surfactants such as diols; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls Anionic surfactants such as ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has a high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc.
  • Molecule Celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc. These thickeners may be used alone or in combination of two or more.
  • the buffer (other than phosphate and its salts) is not particularly limited as long as it is pharmaceutically acceptable.
  • the ophthalmic composition of the present invention provides a buffering action by including phosphoric acid and / or a salt thereof, a desired buffering action can be obtained without adding a buffering agent other than phosphoric acid and a salt thereof. Can be provided.
  • the chelating agent (other than edetic acid and its salt) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include citric acid and its salt. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
  • a chelating action is also imparted. Therefore, a desired chelating agent other than edetic acid and its salt is added. A chelating action can be provided.
  • the refreshing agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.
  • the preservative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chloro Butanol, Chlorhexidine gluconate, Chlorhexidine hydrochloride, Chlorhexidine acetate, Boric acid or its salt, Dehydroacetic acid or its salt, Benzalkonium chloride, Benzalkonium bromide, Benzethonium chloride, Benzyl alcohol, Zinc chloride, Parachlormeta Examples include xylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, and dibutylhydroxytoluene.
  • preservatives may be used individually by 1 type, and may be used in combination of 2 or more type.
  • benzalkonium chloride is particularly preferable because it increases the permeability of the preparation together with the antiseptic effect.
  • concentration of the preservative can be appropriately changed depending on the kind thereof, and examples thereof include 0.0001 to 0.1 w / v%.
  • it is 0.0005 to 0.05 w / v%, more preferably 0.001 to 0.05 w / v%, and particularly preferably 0.002 w / v%.
  • the stabilizer is not particularly limited as long as it is pharmaceutically acceptable.
  • examples of the stabilizer include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. Can be mentioned. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable.
  • acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide , Alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate.
  • alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate.
  • concentration of these additives may be appropriately set according to the type of additive to be used and the characteristics to be imparted to the ophthalmic composition.
  • ophthalmic composition of the present invention in addition to brimonidine and / or a salt thereof and timolol and / or a salt thereof, as long as it does not interfere with the effects of the present invention, glaucoma and ocular hypertension can be prevented. And a pharmacological component showing a therapeutic effect.
  • Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic drugs such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; and sympathetic nerves such as dipivefrin hydrochloride. Stimulants; ⁇ 1 blockers such as betaxolol hydrochloride; ⁇ 1 / ⁇ blockers such as nipradilol and levobanolol hydrochloride; ⁇ 1 blockers such as bunazosin hydrochloride and the like. These pharmacological components may be used alone or in combination of two or more.
  • concentration of these pharmacological components may be appropriately set according to the type of pharmacological component to be used and the medicinal effect to be imparted.
  • the pH of the ophthalmic composition of the present invention is not particularly limited as long as it is applicable to the ocular mucosa, and examples thereof include pH 6.6 to 7.6. From the viewpoint of reducing the production amount of the decomposition product B, it is preferably pH 6.7 to 7.5, more preferably pH 6.7 to 7.3, further preferably pH 7.1 to 7.3, particularly preferably. pH 7.1 is mentioned.
  • the osmotic pressure ratio of the ophthalmic composition of the present invention is not particularly limited as long as it is applicable to the ocular mucosa, and examples thereof include 0.5 to 4. From the viewpoint of reducing discomfort such as a feeling of irritation of a chemical solution, 0.7 to 1.3 is preferable, and 0.9 to 1.1 is more preferable.
  • the osmotic pressure ratio is a ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is in accordance with the “osmotic pressure method (osmolarity measurement method)” defined in the 17th revision Japanese Pharmacopoeia Measured.
  • the ophthalmic composition of the present invention When the ophthalmic composition of the present invention is locally administered to the ocular mucosa, the action of brimonidine and / or its salt and timolol and / or its salt suppresses the production of aqueous humor and reduces intraocular pressure. Therefore, it is provided as an eye drop and is suitably used for the treatment of glaucoma and ocular hypertension.
  • the container for storing the ophthalmic composition of the present invention is not particularly limited as long as it is conventionally used as an eye drop container, and may be made of glass or plastic.
  • the constituent material of the plastic container is not particularly limited.
  • polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one type of polyimide or a mixture of two or more types may be mentioned.
  • the material of the container main body is preferably polyethylene or polypropylene, More preferred is polyethylene.
  • the decomposition products A1, A2 and A3 can be suppressed. Specifically, as the degree of suppression of the decomposition products A1, A2 and A3 in the ophthalmic composition of the present invention, specifically, each of the decomposition products A1, A2 and A3 after being stored in the dark at 60 ° C. for 4 weeks. A production amount is 1.0% or less. From the viewpoint that the ophthalmic composition is more stable, it is preferably 0.9% or less, more preferably 0.85% or less.
  • the ophthalmic composition of the present invention contains edetic acid and / or a salt thereof, the decomposition product B can be suppressed.
  • the degree of inhibition of the decomposition product B in the ophthalmic composition of the present invention is 1.0% or less of the decomposition product B after being stored in a dark place at 60 ° C. for 4 weeks. From the viewpoint that the ophthalmic composition is more stable, it is preferably 0.1% or less, more preferably 0%.
  • the total amount of decomposition products A1, A2, A3, and B after being stored in a dark place at 60 ° C. for 4 weeks is 2.0% or less. From the viewpoint that the ophthalmic composition is more stable, it is preferably 1.5% or less, more preferably 1.3% or less.
  • concentrations of the decomposition products A1, A2, A3, and B are concentrations in the ophthalmic composition determined according to the HPLC measurement conditions and calculation formulas shown below.
  • the decomposition products A1, A2, A3, and B of the ophthalmic composition of the present invention are measured by liquid chromatography (HPLC: manufactured by Shimadzu Corporation; high-performance liquid chromatograph: Prominence) under the following conditions.
  • the present invention relates to a method for inhibiting degradation products of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the composition comprising: Including a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and the concentration of the phosphoric acid and / or the salt thereof is 32 mM or less.
  • a method of inhibiting degradation products of ophthalmic compositions is provided. In this invention, it becomes possible to suppress the production
  • edetic acid and / or a salt thereof may be further coexisted in the ophthalmic composition.
  • edetic acid and / or a salt thereof may be further coexisted in the ophthalmic composition.
  • brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof the type, concentration and the like thereof are described in “3.
  • Those described in the column of “Ophthalmic composition” may be used alone or in combination.
  • other components that can be blended in the ophthalmic composition, pH, osmotic pressure ratio, formulation form, container, etc. of the ophthalmic composition are also described in “3. Ophthalmic composition”. You may employ
  • the present invention improves the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof.
  • the method comprises the step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and the concentration of the phosphoric acid and / or the salt thereof is 32 mM or less.
  • a method for improving the storage stability of an ophthalmic composition is provided. In the present invention, by setting the concentration of phosphoric acid and / or a salt thereof to 32 mM or less, it is possible to suppress degradation products A1, A2, and A3 and improve the storage stability of the ophthalmic composition. .
  • edetic acid and / or a salt thereof may be further coexisted in the ophthalmic composition.
  • edetic acid and / or a salt thereof may be further coexisted in the ophthalmic composition.
  • brimonidine and / or salt thereof timolol and / or salt thereof, and phosphoric acid and / or salt thereof used in the method for improving storage stability of the present invention
  • the type, concentration and the like thereof are described in “3.
  • Those described in the column of “Ophthalmic composition” may be used alone or in combination.
  • other components that can be blended in the ophthalmic composition, pH, osmotic pressure ratio, formulation form, container, etc. of the ophthalmic composition are also described in “3.
  • Test example 1 Test solutions (eye drops) having the compositions shown in Table 3 were prepared. 5 mL of each eye drop was filled in a 5 mL polyethylene container, sealed, and stored in the dark at 60 ° C. for 4 weeks. Each test solution after storage was subjected to HPLC under the following conditions, and the amount of decomposition products was analyzed.
  • FIG. 1 shows a chromatogram obtained by subjecting the test solution of Example 1 before and after storage to HPLC.
  • FIG. 2 shows a chromatogram obtained by subjecting the test solutions of Example 1 and Comparative Example 1 after storage to HPLC.
  • Degradation products A1 (retention time of about 2.6 minutes), A2 (retention time of about 7.8 minutes), A3 (retention time of about 14.0 minutes), and B (retention time of about 15 minutes) in each test solution after storage .2 minutes) is shown in Table 3.
  • Example 1 where the phosphate concentration was 6.3 mM, the amount of decomposition products A1, A2 and A3 produced was reduced compared to Comparative Example 1 where the phosphate concentration was 126 mM.
  • the total amount of decomposition products A1, A2, A3, and B was also reduced in Example 1 compared to Comparative Example 1. From these results, in the ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the storage stability of the ophthalmic composition is improved by setting the phosphate concentration low. It was confirmed.
  • Example 1 compared with Comparative Example 1, the amount of decomposition products A1, A2, and A3 could be reduced, but the amount of decomposition product B increased.
  • Example 2 in which EDTA dihydrate was further blended, the amount of decomposition product B produced was so small that it could not be detected. That is, it was confirmed that the decomposition product B generated by lowering the phosphate concentration can be reduced by further adding EDTA dihydrate, and the storage stability can be further improved.
  • Test example 2 In an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the effect of the phosphate concentration on the amount of decomposition products was examined. Specifically, test liquids (eye drops) having the compositions shown in Tables 4 and 5 were prepared, and the storage and degradation product generation amount were measured under the same conditions as in Test Example 1.
  • Test example 3 In an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the effect of pH on the amount of decomposition products was examined. Specifically, a test solution (eye drops) having the composition shown in Table 6 was prepared and stored under the same conditions as in Test Example 1 except that a 5 mL polypropylene container was used as a container for filling the test solution. Then, the production amount of the decomposition product was measured.
  • Table 6 shows the obtained results.
  • Examples 16 and 17 in which the pH is within the range of 7.1 to 7.3, compared with Examples 13 to 15 and 18 in which the pH is outside the range of 7.1 to 7.3, the degradation The amount of product B produced was reduced. Therefore, in an ophthalmic composition containing brimonidine tartrate and timolol maleate and having a phosphate concentration set to a low concentration of 32 mM or less, the pH is set to 7.1 to 7.3, whereby decomposition is achieved. It became clear that the production amount of the product B can be suppressed more effectively and the storage stability can be further improved.
  • Formulation Examples Specific embodiments of the ophthalmic composition of the present invention include ophthalmic compositions having the components shown in Tables 7 to 10. In Tables 7 to 10, the unit of the content of each component is “w / v%”. Formulation examples 1 to 18 in the table are accommodated in polyethylene (hereinafter referred to as PE) containers, formulation examples 19 to 28 are accommodated in polypropylene (PP) containers, and formulation examples 29 to 36 are accommodated in glass containers.
  • PE polyethylene
  • PP polypropylene

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Abstract

L'objectif de la présente invention est de fournir une technique permettant d'empêcher la formation de produits de dégradation liés au stockage et d'améliorer la stabilité au stockage d'une composition ophtalmique qui contient de la brimonidine et/ou un sel correspondant, du timolol et/ou un sel correspondant, et de l'acide phosphorique et/ou un sel correspondant. La concentration en acide phosphorique et/ou en sel correspondant de la composition ophtalmique qui contient de la brimonidine et/ou un sel correspondant, du timolol et/ou un sel correspondant, et de l'acide phosphorique et/ou un sel correspondant, est de 32 mM ou moins.
PCT/JP2019/018658 2018-05-11 2019-05-10 Composition ophtalmique WO2019216395A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN117571883A (zh) * 2024-01-15 2024-02-20 四川智强医药科技开发有限公司 一种酒石酸溴莫尼定滴眼液的质量检测方法
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