Classifications

• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • 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
  • A61P27/02—Ophthalmic agents

Definitions

• the present disclosure relates to an ophthalmic composition containing dorzolamide.
• Ophthalmic compositions intended to treat glaucoma are known to slow the progression of glaucoma by lowering the intraocular pressure in the patient's eye.
• eye drops that have an intraocular pressure lowering effect.
• dorzolamide hydrochloride eye drop which has a carbonic anhydrase inhibitory effect.
• Patent Document 1 discloses dorzolamide hydrochloride eye drops with an adjusted pH of 6.5 to 8.5. Patent Document 1 states that eye irritation can be reduced by adjusting the pH to the neutral range.
• Patent Document 2 discloses an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof, cyclodextrin, and latanoprost, and adjusted to a pH of 5.8 to 6.5. Patent Document 2 describes that the stability of a composition containing dorzolamide can be improved by using hydroxypropyl- ⁇ -cyclodextrin.
• the present disclosure therefore aims to extend the shelf life of ophthalmic compositions containing dorzolamide.
• the ophthalmic composition disclosed herein contains dorzolamide and/or a pharmacologically acceptable salt of dorzolamide as an active ingredient, sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin, and polyoxyethylene hydrogenated castor oil, and has a pH of 6.5 to 8.5.
• the inventors have surprisingly discovered that the combination of sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin and polyoxyethylene hydrogenated castor oil significantly extends the shelf life of ophthalmic compositions containing dorzolamide.
• This effect is expected to be due to the fact that the generation of dorzolamide-related substances can be suppressed while maintaining the pH in the neutral range.
• the ophthalmic composition having the above-mentioned configuration can extend the shelf life of ophthalmic compositions containing dorzolamide.
• the pharmacologically acceptable salt of dorzolamide is dorzolamide hydrochloride.
• dorzolamide hydrochloride is easy to handle as an active ingredient in the ophthalmic composition and is preferably used.
• the ophthalmic composition of one embodiment disclosed herein contains 0.5 g to 20.0 g of the sulfobutyl ether- ⁇ -cyclodextrin when the total volume of the ophthalmic composition is 100 mL. This makes it possible to more effectively suppress the generation of dorzolamide-related substances.
• the polymerization number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is 20 or more and 100 or less. This makes it possible to more reliably suppress the generation of dorzolamide-related substances.
• the ophthalmic composition of one embodiment disclosed herein contains 0.1 g to 10.0 g of the polyoxyethylene hydrogenated castor oil 60 when the total volume of the ophthalmic composition is 100 mL. This makes it possible to more reliably maintain long-term stability and extend the expiration date of the composition.
• the ophthalmic composition of one embodiment disclosed herein is used as an eye drop. This makes it suitable for use in the prevention or treatment of glaucoma or ocular hypertension.
• the above dorzolamide and/or a pharmacologically acceptable salt of dorzolamide is contained in an amount of 0.1 g to 5.0 g. This makes it more suitable for use in preventing or treating glaucoma or ocular hypertension.
• One embodiment of the method disclosed herein for suppressing the generation of dorzolamide-related substances in an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof is to include sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin and polyoxyethylene hydrogenated castor oil in the ophthalmic composition having a pH of 6.5 to 8.5. This makes it possible to suppress the generation of dorzolamide-related substances in the ophthalmic composition and extend its expiration date.
• ophthalmic composition refers to a composition administered to the eye for the prevention or treatment of eye diseases, and is applied to ocular tissues such as the conjunctival sac.
• the dosage form of the ophthalmic composition is not particularly limited, and includes liquid (including concentrated solutions that are diluted before use), semi-solid, or solid preparations that are dissolved or suspended before use.
• ophthalmic compositions include eye drops (synonymous with eye drops or eye drops), artificial tears, eye washes, eye drops for contact lenses, eye ointments, etc., and also include forms administered by local injection into the eye.
• the ophthalmic composition of the present disclosure is preferably an aqueous composition, and is preferably, for example, an eye drop.
• expiration date refers to the final date of validity during which the efficacy and safety of the ophthalmic composition are maintained and the stability of its quality over a long period is guaranteed.
• the ophthalmic composition of the present disclosure is an ophthalmic composition containing dorzolamide and/or a pharmacologically acceptable salt of dorzolamide as an active ingredient.
• the ophthalmic composition also contains sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin, and polyoxyethylene hydrogenated castor oil.
• the ophthalmic composition of the present disclosure has a pH of 6.5 to 8.5. Each element will be described in detail below.
• dorzolamide is (4S,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide7,7-dioxide, and is a compound represented by the following chemical formula (I).
• Dorzolamide can be synthesized by a known method or can be obtained as a commercially available product.
• the dorzolamide contained may be a salt.
• the salt of dorzolamide there are no particular limitations on the salt of dorzolamide as long as it is a pharmacologically acceptable salt.
• salts of dorzolamide include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts.
• salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, etc.
• salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, etc.
• salts with alkali metals include salts with lithium, sodium, potassium, etc.
• salts with alkaline earth metals include salts with calcium, magnesium, etc.
• metal salts include salts with iron, zinc, etc.
• the SBE- ⁇ -CD contained may be a salt.
• the salt of SBE- ⁇ -CD there are no particular limitations on the salt of SBE- ⁇ -CD, so long as it is a pharmacologically acceptable salt.
• salts of SBE- ⁇ -CD include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts.
• salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, and the like.
• Salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, and the like.
• Salts with alkali metals include salts with lithium, sodium, potassium, and the like.
• Examples of salts with alkaline earth metals include salts with calcium, magnesium, etc.
• metal salts include salts with iron, zinc, etc.
• salts with organic amines examples include quaternary ammonium salts, salts with halogen ions, and salts with organic amines.
• the monosodium salt sodium SBE- ⁇ -CD is particularly preferred as a salt of SBE- ⁇ -CD.
• the content of SBE- ⁇ -CD or a salt of SBE- ⁇ -CD is not particularly limited as long as it is an amount that is acceptable to the living body.
• the lower limit may be 0.5 w/v% or more, preferably 1.0 w/v% or more, more preferably 5.5 w/v% or more, even more preferably 6.0 w/v% or more, and most preferably 8.0 w/v% or more.
• the upper limit may be 20.0 w/v% or less, 15.0 w/v% or less, or 11.0 w/v% or less.
• the ophthalmic composition of the present disclosure contains polyoxyethylene hydrogenated castor oil, which is a nonionic surfactant, as a solubilizing agent.
• polyoxyethylene hydrogenated castor oil various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used.
• the polymerization number of ethylene oxide is not particularly limited. From the viewpoint of stabilizing dorzolamide, the lower limit of the polymerization number is preferably 20 or more, more preferably 30 or more, and most preferably 40 or more.
• the upper limit is preferably 100 or less, more preferably 80 or less, and most preferably 60 or less.
• polyoxyethylene hydrogenated castor oil examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 80. From the viewpoint of more significantly enhancing the effect of the present disclosure, polyoxyethylene hydrogenated castor oil 60 is most preferable. In addition, the content of polyoxyethylene hydrogenated castor oil is not particularly limited as long as it is an amount acceptable to the living body.
• the lower limit is preferably 0.1 w/v% or more, more preferably 0.5 w/v% or more, and most preferably 1.0 w/v% or more, and the upper limit may be 10.0 w/v% or less, 5.0 w/v% or less, or 3.0 w/v% or less.
• the ophthalmic composition of the present disclosure has a pH of 6.5 to 8.5 (neutral range).
• the pH of the aqueous solution becomes acidic (e.g., pH 5.5 to 5.9), so a pH adjuster is added to adjust the pH to 6.5 to 8.5.
• Ophthalmic compositions containing dorzolamide as an active ingredient have strong eye irritation. However, by adjusting the pH to a neutral range, eye irritation can be reduced, making it easier for patients to continue treatment by following the dosage instructions.
• pH adjusters examples include sodium hydroxide or calcium hydroxide, alkaline aqueous solutions of potassium hydroxide, etc., and acidic aqueous solutions of hydrochloric acid, citric acid, etc.
• the pH of the aqueous solution becomes acidic, so it is preferable to use sodium hydroxide to make it neutral.
• the lower limit of the pH of the ophthalmic composition of the present disclosure is preferably 6.5 or more, more preferably 6.7 or more.
• the upper limit is preferably 8.5 or less, more preferably 8.2 or less, and even more preferably 7.8 or less.
• the above-mentioned ophthalmic composition suppresses the generation of dorzolamide analogues and can extend the expiration date of the ophthalmic composition containing dorzolamide up to three years. Since the efficacy and toxicity of this dorzolamide analogue to the human body are unknown when the standard value is exceeded, safety cannot be maintained and the expiration date is shortened.
• dorzolamide analogues are generated, and the expiration date is limited to 1.5 years.
• one form of dorzolamide analogues is (4R,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide7,7-dioxide. This compound is represented by the following chemical formula (II).
• the ophthalmic composition of the present disclosure may contain other components that can be used as additives for pharmaceuticals, as long as the effects of the technology of the present disclosure are not significantly impaired.
• Such components may include active ingredients expected to have medicinal effects used in known ophthalmic compositions, additives required for formulation design, etc.
• known buffers, pH adjusters, thickeners, isotonicity agents, chelating agents, humectants, fragrances or refreshing agents, medicines, antibacterial agents, preservatives/bactericides, etc. may be blended in one or a combination of two or more.
• the ophthalmic composition of the present disclosure may further contain other different ingredients that can be used as active ingredients in pharmaceuticals.
• the other active ingredients are preferably those that have an intraocular pressure-reducing effect and are useful for treating glaucoma or ocular hypertension.
• other active ingredients include ⁇ 2 receptor agonists such as brimonidine, ⁇ -receptor blockers such as befunolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, and prostaglandin F derivatives such as latanoprost, travoprost, and bimatoprost.
• timolol has the advantage of being useful for treating ocular hypertension and is therefore preferred.
• timolol is (2S)-1-[(1,1-dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)propan-2-ol, and is represented by the following chemical formula (IV). Timolol can be synthesized by known methods or is available as a commercially available product.
• the timolol, etc. contained therein may be a salt.
• the salt of timolol, etc. include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts.
• salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, etc.
• salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, etc.
• salts with alkali metals include salts with lithium, sodium, potassium, etc.
• salts with alkaline earth metals include salts with calcium, magnesium, etc.
• metal salts include salts with iron, zinc, etc.
• Other examples include quaternary ammonium salts, salts with halogen ions, and salts with organic amines.
• the most preferred salt of timolol is monomaleate (timolol maleate).
• the timolol, etc., and the salt of timolol, etc., contained therein may be in the form of a hydrate or solvate.
• the ophthalmic composition of the present disclosure may contain timolol or a pharmacologically acceptable salt thereof. This allows prevention or treatment of glaucoma or ocular hypertension through a mechanism different from that of dorzolamide, thereby improving the effectiveness.
• the content of timolol or a salt thereof is not particularly limited as long as it is a pharmacologically acceptable amount.
• the lower limit is preferably 0.1 w/v% or more, more preferably 0.2 w/v% or more, and most preferably 0.3 w/v% or more.
• the upper limit is preferably 3.0 w/v% or less, more preferably 2.0 w/v% or less, and most preferably 1.0 w/v% or less.
• buffering agents examples include phosphoric acid, citric acid, acetic acid, tartaric acid, carbonic acid, boric acid and their salts, trometamol, etc.
• boric acid or its salts are preferred because they have the advantage of having a bacteriostatic effect.
• phosphoric acid when used, it has the advantage of having a buffering capacity in the neutral pH range, which further increases the stability of the composition of the present disclosure.
• thickening agents examples include hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and their salts, polyvinylpyrrolidone, macrogol, etc.
• isotonicity agents examples include sugars such as sorbitol, glucose, and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol, and salts such as sodium chloride and potassium chloride.
• preservatives and disinfectants examples include polyhexanide hydrochloride, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, paraoxybenzoic acid esters (parabens), benzyl alcohol, etc. Glaucoma and ocular hypertension require long-term treatment, and it is preferable for the ophthalmic composition to contain a preservative and disinfectant to prevent contamination. From the standpoint of safety and preservative efficacy, benzalkonium chloride is preferred.
• the ophthalmic composition of the present disclosure can be contained in a unit-dose container or a multi-dose container, and from the viewpoint of long-term treatment, it is preferable to contain the ophthalmic composition in a multi-dose container.
• a unit-dose container is a container intended for single use, i.e., for single use.
• a multi-dose container is a container intended for multiple use, which can be freely opened and closed with a cap or the like.
• the ophthalmic composition of the present disclosure may also be contained in a special container that exhibits an antiseptic effect by a backflow prevention function, a filter, or the like.
• the material of the container is not particularly limited, and for example, polyethylene, polypropylene, polystyrene, polyethylene terephthalate, etc. can be used for the container.
• the dosage form of the ophthalmic composition disclosed herein is not particularly limited as long as it can be used as a pharmaceutical, but eye drops are particularly preferred, and can be manufactured according to conventional methods in the art.
• the ophthalmic composition of the present disclosure is useful as a preventive and/or therapeutic agent for ophthalmology, in particular as a preventive and/or therapeutic agent for glaucoma or ocular hypertension.
• the dosage is preferably one drop administered twice a day.
• the dosage is not necessarily limited to this and can be changed as appropriate.
• the ophthalmic composition has a pH in the neutral range of 6.5 or more, and contains dorzolamide or a pharmacologically acceptable salt thereof, sulfobutylether- ⁇ -cyclodextrin or a pharmacologically acceptable salt thereof, and polyoxyethylene hydrogenated castor oil, thereby significantly suppressing the generation of dorzolamide analogues, maintaining long-term stability, and extending the expiration date.
• a method for suppressing the generation of dorzolamide analogues by allowing sulfobutylether- ⁇ -cyclodextrin and polyoxyethylene hydrogenated castor oil to coexist in an ophthalmic composition having a pH of 6.5 to 8.5 and containing dorzolamide or a pharmacologically acceptable salt thereof as an active ingredient.
• ⁇ Test example: Acceleration test> The ophthalmic solutions of Examples 1 and 2 and Comparative Examples 1 to 6 were stored at 40°C, and the dorzolamide analogues contained in each ophthalmic solution were measured 2, 4, and 6 months after the start of storage.
• the accelerated test performed under the above-mentioned 40°C condition can predict chemical changes that occur when a pharmaceutical is stored for a long period of time, and can also evaluate the effects of short-term deviations from the above-mentioned storage method that may occur during distribution.
• storage for 2 months, 4 months, and 6 months at 40°C corresponds to storage for 1 year, 2 years, and 3 years at room temperature (25°C).
• Item 1 An ophthalmic composition containing dorzolamide and/or a pharmacologically acceptable salt of dorzolamide as an active ingredient, which contains sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin and polyoxyethylene hydrogenated castor oil, and has a pH of 6.5 to 8.5.
• Item 2 The ophthalmic composition according to Item 1, wherein the pharmacologically acceptable salt of dorzolamide is dorzolamide hydrochloride.
• Item 3 The ophthalmic composition according to item 1 or 2, which contains 0.5 g to 20.0 g of the sulfobutyl ether- ⁇ -cyclodextrin when the total volume of the ophthalmic composition is 100 mL.
• Item 5 The ophthalmic composition according to Item 4, containing 0.1 g to 10.0 g of the polyoxyethylene hydrogenated castor oil 60 when the total volume of the ophthalmic composition is 100 mL.
• Item 6 An ophthalmic composition according to any one of items 1 to 5, which is used as an eye drop.
• Item 7 The ophthalmic composition according to Item 6, containing 0.1 g to 5.0 g of the dorzolamide and/or pharmacologically acceptable dorzolamide when the total volume of the eye drop is 100 mL.
• Item 8 A method for suppressing the generation of dorzolamide-related substances in an ophthalmic composition, comprising adding sulfobutylether- ⁇ -cyclodextrin and/or a pharmacologically acceptable salt of sulfobutylether- ⁇ -cyclodextrin, and polyoxyethylene hydrogenated castor oil to an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof and having a pH of 6.5 to 8.5.

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  • 2024-05-15 JP JP2025529498A patent/JPWO2025004579A1/ja active Pending
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