WO2022113970A1 - 涙液層破壊時間短縮型ドライアイ治療剤および該治療剤を含む点眼剤 - Google Patents
涙液層破壊時間短縮型ドライアイ治療剤および該治療剤を含む点眼剤 Download PDFInfo
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- WO2022113970A1 WO2022113970A1 PCT/JP2021/042900 JP2021042900W WO2022113970A1 WO 2022113970 A1 WO2022113970 A1 WO 2022113970A1 JP 2021042900 W JP2021042900 W JP 2021042900W WO 2022113970 A1 WO2022113970 A1 WO 2022113970A1
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- Prior art keywords
- dry eye
- copolymer
- structural unit
- therapeutic agent
- unit represented
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- 239000008213 purified water Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 229950004535 rebamipide Drugs 0.000 description 1
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- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
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- 239000000600 sorbitol Substances 0.000 description 1
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- ATZHWSYYKQKSSY-UHFFFAOYSA-N tetradecyl 2-methylprop-2-enoate Chemical group CCCCCCCCCCCCCCOC(=O)C(C)=C ATZHWSYYKQKSSY-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Images
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
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
-
- 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 invention relates to a tear layer breaking time (Tear Break Up Time, TBUT) shortening dry eye therapeutic agent containing a copolymer having a specific structure, and an eye drop containing the therapeutic agent.
- Tea Break Up Time, TBUT Tea Break Up Time
- the pathology of dry eye is diverse, for example, (1) tear-reducing dry eye, (2) evaporation-promoting dry eye, and (3) tear layer destruction time-shortening dry eye. It can be classified into three types of eyes (hereinafter, also referred to as "TBUT shortened dry eye").
- Non-Patent Document 1 With tear-reducing dry eye, the amount of tears secreted decreases in the first place, so artificial tears and hyaluronic acid In many cases, tears are replenished using ophthalmic solution and treatment is performed to prevent tear reduction by using a punctal plug or the like (Non-Patent Document 1). (2) In the evaporation-enhanced dry eye, the oil layer component of the mucin layer, the water layer and the oil layer constituting the tear fluid is reduced, and the evaporation of the water layer is promoted to obtain dry eye (). Non-Patent Document 2).
- the present invention provides a TBUT shortened dry eye therapeutic agent having an excellent dry eye therapeutic effect, and an eye drop containing the same.
- the present inventors have sufficiently prepared a corneal surface with a TBUT shortened dry eye therapeutic agent containing a copolymer having three different constituent units in a specific ratio and water. It moisturizes and retains water, thereby inducing the promotion of mutin production on the surface of the cornea, and has been found to be effective for the treatment of dry eye, and has completed the present invention.
- the TBUT shortened dry eye therapeutic agent of the present invention and the eye drops containing the same are as follows.
- a copolymer (P) having a structural unit represented by the following general formulas (1a) to (1c) and having a weight average molecular weight of 5,000 to 2,000,000 is contained, and the copolymer (P) is contained.
- a dry eye therapeutic agent for shortening the tear layer destruction time which is 400/2 to 50.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- a dry eye remedy that shortens the tear film destruction time 3.
- Type dry eye remedy 4.
- Dry eye treatment method for shortening tear layer destruction time including the following steps, It has a structural unit represented by the following general formulas (1a) to (1c), has a weight average molecular weight of 5,000 to 2,000,000, and has a molar ratio of the structural unit [(1a) / (1b).
- ) / (1c)] is a composition of 100/10 to 400/2 to 50, in which the concentration of the copolymer (P) or the copolymer (P) is 0.001 to 1.0 w / v%.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- the above item 5 wherein the copolymer (P) is composed of a structural unit represented by the general formula (1a), a structural unit represented by the (1b), and a structural unit represented by the (1c). A dry eye treatment method that shortens the tear film destruction time. 7.
- Type dry eye treatment method. 8 It has a structural unit represented by the following general formulas (1a) to (1c), has a weight average molecular weight of 5,000 to 2,000,000, and has a molar ratio of the structural unit [(1a) / (1b). ) / (1c)] is a composition of 100/10 to 400/2 to 50, in which the concentration of the copolymer (P) or the copolymer (P) is 0.001 to 1.0 w / v%.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- the copolymer (P) is composed of a structural unit represented by the general formula (1a), a structural unit represented by the (1b), and a structural unit represented by the (1c).
- a manufacturing agent for dry eye treatment that shortens the tear film destruction time.
- the TBUT shortened dry eye therapeutic agent of the present invention can sufficiently moisturize and retain water on the corneal surface and induce the promotion of mucin production on the corneal surface. Further, the eye drop containing the TBUT shortened dry eye therapeutic agent of the present invention can provide an eye drop having an excellent TBUT shortened dry eye therapeutic effect.
- the effect of the treatment of the copolymer (P) on the water retention time of the removed rabbit cornea is shown.
- A shows the observation result of the appearance of the removed rabbit cornea
- B shows the change over time in the weight of the removed rabbit cornea.
- "Vehickle” is a group of saline solution eye drops for normal rabbits that do not develop dry eye
- MPC MPC polymer (copolymer (P) 0) for normal rabbits that do not develop dry eye. .1w / v% -containing solution)
- the instillation group is shown.
- the effects of the copolymer (P) treatment on the tear volume (A), mucin volume (B), and tear layer destruction (C and D) of the dry eye rabbit model are shown.
- None is a non-eye drop group for rabbits with dry eye
- Polymer is a saline instillation group for rabbits with dry eye
- MPC is dry eye.
- the group of eye drops of MPC polymer solution containing 0.1 w / v% of copolymer (P)) is shown for rabbits.
- the size of the scale bar indicates 1 mm.
- C shows a magnified view of the rabbit cornea.
- the black part in the figure is the dry eye spot, which indicates the part where the tear film is broken or broken.
- the TBUT shortened dry eye therapeutic agent of the present invention has a structural unit represented by the following general formulas (1a) to (1c) and has a weight average molecular weight of 5,000 to 2,000,000.
- (P) and water are included. Further, the concentration of the copolymer (P) is 0.001 to 1.0 w / v%. In addition, the molar ratio [(1a) / (1b) / (1c)] of the structural unit in the copolymer (P) is 100/10 to 400/2 to 50.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- (meth) acrylate means “acrylate or methacrylate", and the same applies to other similar terms.
- a preferable numerical range for example, a range of concentration and weight average molecular weight
- each lower limit value and upper limit value can be independently combined.
- preferably 10 or more, more preferably 20 or more, and preferably 100 or less, more preferably 90 or less “preferable lower limit value: 10” and “more preferable upper limit value: 90” are combined. Therefore, it can be set to "10 or more and 90 or less”. Further, for example, even in the description of "preferably 10 to 100, more preferably 20 to 90", it can be similarly set to "10 to 90".
- the copolymer (P) used (included) in the TBUT shortened dry eye therapeutic agent of the present invention has the general formulas (1a) to (1c) as constituent units and has a weight average molecular weight of 5,000 to 2,000. It is a copolymer of 000.
- the copolymer (P) used in the present invention has a structural unit represented by the following general formula (1a), that is, a structural unit having a phosphorylcholine structure (hereinafter, also referred to as “PC structural unit”). Since the copolymer (P) has a PC constituent unit, hydrophilicity is imparted to the copolymer (P), and an excellent moisturizing effect and water-retaining effect on the corneal surface can be exhibited.
- PC structural unit a structural unit having a phosphorylcholine structure
- R 1 represents a hydrogen atom or a methyl group.
- the PC constituent unit can be obtained by copolymerizing a monomer represented by the following general formula (1a') (hereinafter, also referred to as "PC monomer").
- the PC monomer is preferably 2- ((meth) acryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, and more preferably represented by the following (1a').
- 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate hereinafter, also referred to as "2-methacryloyloxyethyl phosphorylcholine”).
- the content of the PC constituent unit in the copolymer (P) is preferably 10 mol% or more, more preferably 20 mol% or more, still more preferably 20 mol% or more, from the viewpoint of exhibiting excellent moisturizing and water-retaining effects on the corneal surface. It is 25 mol% or more, preferably 80 mol% or less, more preferably 75 mol% or less, still more preferably 70 mol% or less.
- the copolymer (P) used in the present invention has a structural unit represented by the following general formula (1b) (hereinafter, also referred to as “amide structural unit”).
- amide structural unit By increasing the molecular weight of the copolymer (P) with the amide constituent unit, the retention of the copolymer (P) on the corneal surface can be improved.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- the amide constituent unit is obtained by copolymerizing a (meth) acrylamide or a (meth) acrylamide derivative, which is a monomer represented by the following general formula (1b') (hereinafter, also referred to as “amide monomer”). Obtainable.
- the monomer represented by the formula (1b') include N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-acryloyl morpholine and the like.
- the ratio [(1a) / (1b)] of the number of PC constituent units (1a) to the number of amide constituent units (1b) is 100 /, where the number of PC constituent units is 100. It is 10 to 400, preferably 100/30 to 250, more preferably 100/50 to 150, still more preferably 100/70 to 120, still more preferably 100/80 to 110, and even more preferably 100/80 to. It is 100. If the ratio of the number of amide constituent units to the number of PC constituent units is too large, aseptic filtration performed when producing the solution of the present invention may be difficult. On the other hand, if the ratio is too small, the high molecular weight of the copolymer (P) may be insufficient, and the retention effect of the copolymer (P) on the corneal surface may be insufficient.
- the copolymer (P) used in the present invention has a structural unit represented by the following general formula (1c) (hereinafter, also referred to as “hydrophobic structural unit”). Since the copolymer (P) has a hydrophobic constituent unit, the adhesiveness of the copolymer (P) to the surface of the corneal membrane can be improved, and the ability of the copolymer (P) to form a physically crosslinked gel due to the hydrophobic interaction is enhanced. The water-retaining action and moisturizing effect of the polymer (P) can be further enhanced.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- R 6 in the general formula (1c) is a hydrocarbon group having 12 to 24 carbon atoms, and may be linear or branched, but is preferably linear.
- the hydrocarbon group having 12 to 24 carbon atoms include a lauryl group, a myristyl group, a cetyl group, a stearyl group, an oleyl group, and a behenyl group.
- R 6 is preferably a hydrocarbon group having 12 to 20 carbon atoms, and more preferably a hydrocarbon having 12 to 18 carbon atoms, from the viewpoint of improving the adhesiveness of the copolymer (P) to the surface of the cornea. It is a group, specifically, a lauryl group and a stearyl group.
- the hydrophobic structural unit can be obtained by copolymerizing a monomer represented by the following formula (1c') (hereinafter, also referred to as "hydrophobic monomer").
- hydrophobic monomer represented by the general formula (1c') examples include lauryl (meth) acrylate, myristyl (meth) acrylate, cetyl (meth) acrylate, stearyl (meth) acrylate, and oleyl (meth) acrylate. , And linear alkyl (meth) acrylates such as behenyl (meth) acrylates.
- the hydrophobic monomer represented by the general formula (1c') is preferably a lauryl (meth) acrylate or myristyl (meth) from the viewpoint of improving the adhesiveness of the copolymer (P) to the corneal surface.
- the ratio [(1a) / (1c)] of the number of PC constituent units (1a) to the number of hydrophobic constituent units (1c) is 100, where the number of PC constituent units is 100. It is / 2 to 50, preferably 100/5 to 25, more preferably 100/7 to 20, and even more preferably 100/8 to 15. If the ratio of the number of hydrophobic constituent units to the number of PC constituent units is too small, the adhesion of the copolymer (P) to the corneal surface may be insufficient.
- the molar ratio [(1a) / (1b) / (1c)] of the constituent unit in the copolymer (P) is the moisturizing / water-retaining action of the copolymer (P) and the corneal surface. From the viewpoint of adhesiveness, it is 100/10 to 400/2 to 50, preferably 100/30 to 250/5 to 25, more preferably 100/50 to 150/5 to 25, and even more preferably 100/70 to. It is 120/5 to 25, more preferably 100/80 to 110/7 to 20, and even more preferably 100/80 to 100/8 to 15.
- the copolymer (P) used in the present invention may have at least one PC constituent unit, an amide constituent unit, and a hydrophobic constituent unit, and may contain, for example, a plurality of types of PC constituent units. good.
- the weight average molecular weight of the copolymer (P) is 5,000 to 2,000,000, preferably 10,000 or more, more preferably 20,000 or more, still more preferably 50,000 or more, still more preferably. 700,000 or more, and preferably 1,800,000 or less, more preferably 1,600,000 or less, still more preferably 1,500,000 or less, still more preferably 1,300,000 or less, and more. More preferably, it is 1,100,000 or less. If the weight average molecular weight is less than 5,000, the adhesion of the copolymer (P) to the corneal surface may be insufficient, and the TBUT shortened dry eye therapeutic effect may not be expected. If the weight average molecular weight exceeds 2,000,000, the viscosity may increase and handling may become difficult.
- the weight average molecular weight of the copolymer (P) is a value measured by gel permeation chromatography (GPC). Specifically, it refers to the molecular weight in terms of polyethylene glycol measured using any of chloroform, dimethylformamide, tetrahydrofuran, methanol, and a combination of these solvents as the eluent.
- the copolymer (P) can be prepared, for example, by copolymerizing the monomers according to the method described in International Publication No. 2013/128633.
- it is usually a random copolymer, it may be an alternating copolymer or a block copolymer in which each structural unit is regularly arranged, or it may have a partially grafted structure.
- the TBUT shortened dry eye therapeutic agent of the present invention has a copolymer (P) concentration of 0.001 w / v% or more, preferably 0.002 w / v% or more, and more preferably 0.003 w / v%. Above, more preferably 0.005 w / v% or more, and 1.0 w / v% or less, preferably 0.8 w / v% or less, more preferably 0.6 w / v% or less, still more preferable. Is 0.5 w / v% or less.
- w / v% represents the mass of a certain component in 100 ml of solution in grams (g).
- the solution of the present invention contains 1.0 w / v% copolymer (P)
- 100 ml of the solution contains 1.0 g of the copolymer (P). do.
- the TBUT shortened dry eye therapeutic agent of the present invention can use water as a solvent.
- water used for the TBUT shortened dry eye therapeutic agent of the present invention water used for manufacturing pharmaceuticals and medical devices can be usually used. Specifically, ion-exchanged water, purified water, sterile purified water, distilled water, water for injection and the like can be used.
- the TBUT shortened dry eye therapeutic agent of the present invention may further contain the following additives in addition to the copolymer (P), if necessary.
- additives examples include those used for conventional eye drops, such as vitamins, amino acids, sugars, refreshing agents, inorganic salts, organic acid salts, acids, bases, and antioxidants. Agents, stabilizers, preservatives and the like can be mentioned.
- vitamins examples include flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, sodium pantothenate, calcium pantothenate and the like.
- amino acids examples include aspartic acid and salts thereof, aminoethyl sulfonic acid and the like.
- saccharides examples include glucose, mannitol, sorbitol, xylitol, trehalose and the like.
- Examples of the refreshing agent include menthol and camphor.
- inorganic salts examples include sodium chloride, potassium chloride and the like.
- organic acid salt examples include sodium citrate and the like.
- Examples of the acid include phosphoric acid, citric acid, sulfuric acid, acetic acid and the like.
- Examples of the base include trishydroxymethylaminomethane, monoethanolamine and the like.
- antioxidant examples include tocopherol acetate, dibutylhydroxytoluene and the like.
- Examples of the stabilizer include sodium edetate, glycine and the like.
- preservative examples include benzalkonium chloride, chlorhexidine gluconate, potassium sorbate, polyhexanide hydrochloride and the like.
- the eye drop containing the TBUT shortened dry eye therapeutic agent of the present invention is produced by a general method for producing an eye drop, in which the copolymer (P), water, and if necessary, other components are mixed and stirred. can do.
- the obtained eye drops may be subjected to an operation such as aseptic filtration, if necessary.
- the present invention also includes a method for treating dry eye with a shortened tear layer destruction time, which comprises the following steps. It has a structural unit represented by the following general formulas (1a) to (1c), has a weight average molecular weight of 5,000 to 2,000,000, and has a molar ratio of the structural unit [(1a) / (1b). ) / (1c)] is a composition in which the concentration of the copolymer (P) is 100/10 to 400/2 to 50 and the concentration of the copolymer (P) is 0.001 to 1.0 w / v%.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- the method for treating tear layer destruction time-reducing dry eye of the present invention is not particularly limited, and for example, 0.01 to 0.2 mL of the tear layer destruction time-reducing dry eye therapeutic agent of the present invention is applied per day. It can be dropped on the eye (eyeball) from any angle 1 to 10 times, 1 to 8 times, 1 to 6 times, 1 to 4 times, 1 to 3 times (preferably morning, noon, and evening).
- the target of treatment is not particularly limited, but is limited to mammals including humans, and preferably targets patients in need of prevention, alleviation, improvement, or treatment of dry eye with shortened tear layer destruction time.
- the present invention also includes the use of the copolymer (P) as a therapeutic agent for reducing the tear layer destruction time.
- It has a structural unit represented by the following general formulas (1a) to (1c), has a weight average molecular weight of 5,000 to 2,000,000, and has a molar ratio of the structural unit [(1a) / (1b). ) / (1c)] is a composition of 100/10 to 400/2 to 50, in which the concentration of the copolymer (P) or the copolymer (P) is 0.001 to 1.0 w / v%.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group.
- R 3 and R 4 each independently represent a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents a hydrocarbon group having 12 to 24 carbon atoms.
- the following can be exemplified as the copolymer (P) used in the tear film layer destruction time shortening type dry eye therapeutic agent or the tear film layer destruction time shortening type dry eye therapeutic method of the present invention.
- the structural unit represented by (1a) is 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, and the structural unit represented by (1b) is N, N-dimethylacrylamide.
- the structural unit represented by (1c) above is stearyl methacrylate.
- the structural unit represented by (1a) is 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, and the structural unit represented by (1b) is N, N-dimethylacrylamide.
- the structural unit represented by (1c) above is lauryl methacrylate.
- the structural unit represented by (1a) is 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, and the structural unit represented by (1b) is N, N-dimethylacrylamide.
- the structural unit represented by (1c) above is myristyl methacrylate.
- the weight average molecular weight of the copolymer (P) was measured by dissolving 5 mg of each obtained copolymer in a methanol / chloroform mixed solution (80/20) to prepare a sample solution under the following analytical conditions.
- Calculation method of weight average molecular weight Molecular weight calculation program (GCP program for SC-8020)
- Flow rate 1 mL / min
- Injection volume 100 ⁇ L
- Column oven Constant temperature around 40 ° C
- Example or comparative example shown below 50 ⁇ L eye drops were administered once a day for 2 days. (6) After that, the dry eye state was measured again by the procedure shown in (4) (2 days). (7) For the solution of Example or Comparative Example, 50 ⁇ L eye drops were administered once a day for 3 days. (8) After that, the dry eye state was measured again by the procedure shown in (4) (5 days).
- a mucin amount measurement test was carried out according to the following procedure.
- N-Acetylcysteine was dissolved in physiological saline (sodium chloride: 0.9%, water: balance) to prepare a 10 w / v% solution.
- Tear fluid was collected for 5 minutes with a Sylmel test paper, and the amount of mucin contained in the tear fluid was measured using a tear fluid mucin measurement kit (manufactured by Cosmo Bio) and used as the initial value.
- aqueous solution containing 1 w / v% of the copolymer (P) is prepared in advance, and 0.1 mL thereof and a physiological saline solution (sodium chloride: 0.9%, water: balance) are used to prepare a copolymer (P). ) was prepared and used as the solution of the example.
- a physiological saline solution sodium chloride: 0.9%, water: balance was used as the solution of the comparative example.
- the TBUT shortened dry eye therapeutic agent of the present invention can sufficiently moisturize and retain water on the surface of the cornea, and can exhibit an excellent TBUT shortened dry eye therapeutic effect by inducing the production of mucin. can.
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Abstract
Description
本出願は、参照によりここに援用されるところの日本出願特願2020-197735号優先権を請求する。
1.下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000である共重合体(P)を含み、該共重合体(P)の濃度が0.001~1.0w/v%であり、該共重合体(P)における前記構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、涙液層破壊時間短縮型ドライアイ治療剤。
2.前記共重合体(P)が、前記一般式(1a)で表される構成単位、前記(1b)で表される構成単位及び前記(1c)で表される構成単位からなる、前項1に記載の涙液層破壊時間短縮型ドライアイ治療剤。
3.前記(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がステアリルメタクリレートである、前項1又は2に記載の涙液層破壊時間短縮型ドライアイ治療剤。
4.前項1~3のいずれか1に記載の涙液層破壊時間短縮型ドライアイ治療剤を含有する点眼剤。
5.以下の工程を含む、涙液層破壊時間短縮型ドライアイ治療方法、
下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000であり、かつ該構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、共重合体(P)又は該共重合体(P)の濃度が0.001~1.0w/v%である組成物を、ヒトを含む哺乳類に投与する工程。
6.前記共重合体(P)が、前記一般式(1a)で表される構成単位、前記(1b)で表される構成単位及び前記(1c)で表される構成単位からなる、前項5に記載の涙液層破壊時間短縮型ドライアイ治療方法。
7.前記(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がステアリルメタクリレートである、前項6又は7に記載の涙液層破壊時間短縮型ドライアイ治療方法。
8.下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000であり、かつ前記構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、共重合体(P)又は該共重合体(P)の濃度が0.001~1.0w/v%である組成物の涙液層破壊時間短縮型ドライアイ治療剤の製造としての使用。
9.前記共重合体(P)が、前記一般式(1a)で表される構成単位、前記(1b)で表される構成単位及び前記(1c)で表される構成単位からなる、前項8に記載の涙液層破壊時間短縮型ドライアイ治療剤の製造としての使用。
10.前記(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がステアリルメタクリレートである、前項8又は9に記載の涙液層破壊時間短縮型ドライアイ治療剤の製造としての使用。
本発明のTBUT短縮型ドライアイ治療剤は、下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000である共重合体(P)及び水を含む。さらに、前記共重合体(P)の濃度が0.001~1.0w/v%である。加えて、前記共重合体(P)における前記構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である。
なお、本明細書において、「(メタ)アクリレート」とは、「アクリレート又はメタクリレート」を意味し、他の類似用語についても同様である。
また、本明細書において、好ましい数値範囲(例えば、濃度や重量平均分子量の範囲)を段階的に記載した場合、各下限値及び上限値は、それぞれ独立して組み合わせることができる。例えば、「好ましくは10以上、より好ましくは20以上、そして、好ましくは100以下、より好ましくは90以下」という記載において、「好ましい下限値:10」と「より好ましい上限値:90」とを組み合わせて、「10以上90以下」とすることができる。また、例えば、「好ましくは10~100、より好ましくは20~90」という記載においても、同様に「10~90」とすることができる。
本発明のTBUT短縮型ドライアイ治療剤に用いられる(含まれる)共重合体(P)は、一般式(1a)~(1c)を構成単位とし、重量平均分子量が5,000~2,000,000である共重合体である。
本発明で用いられる共重合体(P)は、下記一般式(1a)で表される構成単位、すなわち、ホスホリルコリン構造を有する構成単位(以下、「PC構成単位」ともいう。)を有する。共重合体(P)がPC構成単位を有することにより、共重合体(P)に親水性が付与され、角膜表面上への優れた保湿作用・保水効果を発現することができる。
本発明で用いられる共重合体(P)は、下記一般式(1b)で表される構成単位(以下、「アミド構成単位」ともいう。)を有する。共重合体(P)をアミド構成単位によって高分子量化することにより、共重合体(P)の角膜表面上への滞留性を向上させることができる。
本発明で用いられる共重合体(P)は、下記一般式(1c)で表される構成単位(以下、「疎水性構成単位」ともいう。)を有する。共重合体(P)が疎水性構成単位を有することにより、共重合体(P)の角膜表面に対する接着性を向上させることができると共に、疎水性相互作用による物理架橋ゲル形成能を高め、共重合体(P)の保水作用・保湿効果をさらに高めることができる。
R6はこれらの中でも共重合体(P)の角膜表面への接着性を向上させる観点から、好ましくは炭素数12~20の炭化水素基であり、より好ましくは炭素数12~18の炭化水素基であり、具体的には、好ましくはラウリル基、及びステアリル基である。
一般式(1c’)で表される疎水性単量体は、これらの中でも、共重合体(P)の角膜表面への接着性を向上させる観点から、好ましくはラウリル(メタ)アクリレート、ミリスチル(メタ)アクリレート、及びステアリル(メタ)アクリレートであり、より好ましくはラウリルメタクリレート、及びステアリルメタクリレートであり、より好ましくはステアリルメタクリレートである。
共重合体(P)の重量平均分子量は5,000~2,000,000であり、好ましくは10,000以上、より好ましくは20,000以上、更に好ましくは50,000以上、より更に好ましくは700,000以上であり、そして、好ましくは1,800,000以下、より好ましくは1,600,000以下、更に好ましくは1,500,000以下、より更に好ましくは1,300,000以下、より更に好ましくは1,100,000以下である。
重量平均分子量が5,000未満の場合、共重合体(P)の角膜表面への接着性が不十分となる恐れがあり、TBUT短縮型ドライアイ治療効果を見込めない恐れがある。重量平均分子量が2,000,000を超える場合は、粘度が増大して取扱いが困難となるおそれがある。
共重合体(P)は、例えば、国際公開第2013/128633号に記載されている方法に従って前記単量体の共重合を行うことにより調製することができる。加えて、通常はランダム共重合体であるが、各構成単位が規則的に配列された交互共重合体やブロック共重合体であってもよく、一部にグラフト構造を有してもよい。
本発明のTBUT短縮型ドライアイ治療剤は、共重合体(P)の濃度が0.001w/v%以上であり、好ましくは0.002w/v%以上、より好ましくは0.003w/v%以上、更に好ましくは0.005w/v%以上であり、そして、1.0w/v%以下であり、好ましくは0.8w/v%以下、より好ましくは0.6w/v%以下、更に好ましくは0.5w/v%以下である。共重合体(P)の濃度が0.001w/v%未満であると、十分なTBUT短縮型ドライアイ治療効果が得られない。1.0w/v%を超えると、配合量に見合った効果が得られないために経済的に不利である。
なお、本発明において、「w/v%」は、100mlの溶液中のある成分の質量をグラム(g)で表したものである。例えば、「本発明の溶液が1.0w/v%の共重合体(P)を含有する」とは、100mlの溶液が1.0gの共重合体(P)を含有していることを意味する。
本発明のTBUT短縮型ドライアイ治療剤は溶媒として水を用いることができる。
本発明のTBUT短縮型ドライアイ治療剤に用いる水は、通常、医薬品や医療機器の製造に用いられる水を用いることができる。具体的には、イオン交換水、精製水、滅菌精製水、蒸留水、及び注射用水等を用いることができる。
本発明のTBUT短縮型ドライアイ治療剤は、共重合体(P)以外に更に必要に応じて以下の添加剤を含有してもよい。
本発明のTBUT短縮型ドライアイ治療剤を含む点眼剤は、共重合体(P)、水、及び必要に応じてその他の成分を混合して攪拌する、一般的な点眼剤の製造方法により製造することができる。なお、得られた点眼剤は必要に応じて無菌ろ過等の操作を行ってもよい。
本発明は、以下の工程を含む、涙液層破壊時間短縮型ドライアイ治療方法も含む。
下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000であり、かつ該構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、共重合体(P)又は該共重合体(P)の濃度が0.001~1.0w/v%である組成物を、ヒトを含む哺乳類に投与する工程。
治療の対象は、特に限定されないが、ヒトを含む哺乳類であり、好ましくは涙液層破壊時間短縮型ドライアイの予防、緩和、改善、または治療が必要な患者を対象とする。
本発明は、共重合体(P)の涙液層破壊時間短縮型ドライアイ治療剤の製造としての使用も含む。
下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000であり、かつ前記構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、共重合体(P)又は該共重合体(P)の濃度が0.001~1.0w/v%である組成物の涙液層破壊時間短縮型ドライアイ治療剤の製造としての使用。
1)(1a)で表される構成単位が2-(メタクリロイルオキシ)エチル2-(トリメチルアンモニオ)エチルホスファート、(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がステアリルメタクリレート。
2)(1a)で表される構成単位が2-(メタクリロイルオキシ)エチル2-(トリメチルアンモニオ)エチルホスファート、(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がラウリルメタクリレート。
3)(1a)で表される構成単位が2-(メタクリロイルオキシ)エチル2-(トリメチルアンモニオ)エチルホスファート、(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がミリスチルメタクリレート。
共重合体(P)は以下に示す共重合体(1)を用いた。共重合体(1)は国際公開第2013/128633号の実施例に記載されている方法によって調製した。
PC単量体として一般式(1a’)で表される2-(メタクリロイルオキシ)エチル2-(トリメチルアンモニオ)エチルホスファート(2-メタクリロイルオキシエチルホスホリルコリン)、アミド単量体としてN,N-ジメチルアクリルアミド、及び疎水性単量体としてステアリルメタクリレートを用いた共重合体
構成単位のモル比[(1a)/(1b)/(1c)]=100/90/10
重量平均分子量:1,000,000
カラム:PLgel-mixed-C
標準物質:ポリエチレングリコール
検出器:示差屈折計RI-8020(東ソー(株)製)
重量平均分子量の算出法:分子量計算プログラム(SC-8020用GCPプログラム)
流量:毎分1mL
注入量:100μL
カラムオーブン:40℃付近の一定温度
以下の手順(参考文献Pharmaceutics 2020, 12, 155)に従い、涙液層破壊時間短縮型ドライアイ治療効果を確認するために各種の測定を行った。
(1)N-アセチルシステインを生理食塩液(塩化ナトリウム:0.9%、水:残部)で溶かして、10w/v%溶液を調製した。
(2)(1)にて調製した溶液を使用して、雄性日本白色種家兎へ、1回あたり50μLを2時間間隔で合計6回点眼投与した。
(3)点眼投与後の翌日、雄性日本白色種家兎のドライアイ状態を確認した後、涙液層破壊時間短縮型ドライアイを発症したドライアイモデルとした。
(4)ドライアイモデルにつき、ドライアイ測定装置(DR-1α、興和)にて観察を行い、そのドライアイ状態を測定した(TBUTを測定)。
(5)以下で示す実施例もしくは比較例の溶液につき、1日1回50μL点眼投与を2日間行った。
(6)この後、(4)に示す手順にて、再度、ドライアイ状態を測定した(2days)。
(7)実施例もしくは比較例の溶液につき、1日1回50μL点眼投与を3日間行った。
(8)この後、(4)に示す手順にて、再度、ドライアイ状態を測定した(5days)。
シルマー試験紙を用いて涙液量を測定した。
以下の手順に従い、ムチン量測定試験を実施した。
(1)N-アセチルシステインを生理食塩液(塩化ナトリウム:0.9%、水:残部)で溶かして、10w/v%溶液を調製した。
(2)シルメル試験紙にて涙液を5分間採取、涙液ムチン測定キット(コスモ・バイオ製)を用いて涙液中に含まれるムチン量を測定し、初期値とした。
(3)(1)にて調製した溶液を使用して、雄性日本白色種家兎へ、1回あたり50μLを2時間間隔で合計6回点眼投与した。
(4)点眼投与後の翌日、雄性日本白色種家兎のドライアイ状態を確認した後、涙液層破壊時間短縮型ドライアイを発症したドライアイモデルとした。
(5)ドライアイモデルもしくは正常ウサギにつき、(2)に示す手順により、ムチン量を測定した。
(6)実施例もしくは比較例の溶液につき、1日1回50μL点眼投与を合計5日間行った。
(7)この後、(2)に示す手順にて、再度、ムチン量を測定した。
初期値と5日後との比較を行い、これを百分率へと変換して、Mucin level(%)を算出した。
ドライアイモデル(ウサギ)を作製した時点で、TBUTを測定した後に、画像を取得した。この取得した画像を、画像処理ソフトImage Jで取り込み、涙液が破断した面積を算出した(初期値)。ドライアイモデルへVehicle点眼、MPC点眼、又は無点眼を5日間の繰り返しを行い、5日後に、再度、TBUTを測定した後に、画像を取得した。この取得した画像をImage Jで取り込み、涙液が破断した面積を算出した(5日後)。
初日の涙液が破断した面積と5日後の涙液が破断した面積との比較を行い、これを百分率へと変換して、Tearfilm breakup level(%)を算出した。
涙液層破壊時間測定で使用したウサギから摘出した角膜を以下で示す実施例の溶液又は比較例の生理食塩液(塩化ナトリウム:0.9%、水:残部)に浸漬し、取り出し後150分間静置し、複数時点で重量を測定し、重量の経時変化を調べた。また、取り出し直後(0分後)及び60分後の外観の画像をデジタルカメラにて取得した。
共重合体(P)を1w/v%含む水溶液を予め調製し、これを0.1mLと、生理食塩液(塩化ナトリウム:0.9%、水:残部)とを用いて共重合体(P)を0.1w/v%含む溶液を調製し、実施例の溶液とした。なお、比較例の溶液として生理食塩液(塩化ナトリウム:0.9%、水:残部)を使用した。
実施例の溶液(図1中:「MPC」)又は生理食塩液(塩化ナトリウム:0.9%、水:残部、図1中「Vehicle(比較例)」)を正常ウサギへ点眼処理し、涙液量及びTBUTの測定を実施した。なお、参考例として、ドライアイを発症していない正常ウサギへの無点眼群のTBUTの測定を実施した。結果を図1に示す。
実施例の溶液(図3中:「MPC」)又は生理食塩液(塩化ナトリウム:0.9%、水:残部、図3中「Vehicle(比較例)」)をドライアイウサギモデルへ点眼処理し、涙液量、ムチン量及びTear film breakupの測定を実施した。なお、参考例として、ドライアイを発症しているウサギへの無点眼群の涙液量、ムチン量及びTear film breakupの測定を実施した。結果を図3に示す。
上記評価後の正常ウサギにおいて、実施例の溶液(図2中:「MPC」)又は生理食塩液(塩化ナトリウム:0.9%、水:残部、図2中「Vehicle(比較例)」を摘出ウサギ角膜へ点眼処理し、角膜の水分保持時間を測定した。結果を図2に示す。
正常ウサギへの点眼処理の評価の結果に関し、正常ウサギへ点眼処理したところ、涙液量の増加(図1A)とTBUTの上昇(図1B)を確認した。
ドライアイウサギへの点眼処理の評価の結果に関し、図3Aのドライアイウサギモデルは図1Aの正常ウサギと比較して涙液量保持量が低下していたが、実施例の溶液の点眼により高い水分保持を確認した(図3A)。さらに、ドライアイによる角膜上ムチン量の改善を確認した(図3B)。加えて、涙液層破壊の早期修復も確認した(図3C及びD)。
摘出ウサギ角膜へ点眼処理の評価の結果に関し、摘出ウサギ角膜に実施例の溶液で点眼処理したところ、比較例の溶液よりも水分付着量が高まった(図2A及びB)。さらに、揮発するまでの時間の延長を確認した(図2A及びB)。
一方で、比較例及び参考例では、2days及び5daysの測定時においても涙液層破壊時間短縮型ドライアイ治療効果に乏しく、十分な涙液層破壊時間短縮型ドライアイ治療効果は認められなかった(図3C)。
Claims (4)
- 下記一般式(1a)~(1c)で表される構成単位を有し、重量平均分子量が5,000~2,000,000である共重合体(P)を含み、該共重合体(P)の濃度が0.001~1.0w/v%であり、該共重合体(P)における該構成単位のモル比[(1a)/(1b)/(1c)]は、100/10~400/2~50である、涙液層破壊時間短縮型ドライアイ治療剤。
- 前記共重合体(P)が、前記一般式(1a)で表される構成単位、前記(1b)で表される構成単位及び前記(1c)で表される構成単位からなる、請求項1に記載の涙液層破壊時間短縮型ドライアイ治療剤。
- 前記(1b)で表される構成単位がN,N-ジメチルアクリルアミドであり、かつ前記(1c)で表される構成単位がステアリルメタクリレートである、請求項1又は2に記載の涙液層破壊時間短縮型ドライアイ治療剤。
- 請求項1~3のいずれか1に記載の涙液層破壊時間短縮型ドライアイ治療剤を含有する点眼剤。
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WO2013128633A1 (ja) * | 2012-03-02 | 2013-09-06 | 日油株式会社 | コンタクトレンズ用ケア製剤及びパッケージング溶液 |
WO2016140242A1 (ja) * | 2015-03-03 | 2016-09-09 | 日油株式会社 | 点眼剤 |
WO2017110874A1 (ja) * | 2015-12-22 | 2017-06-29 | 日油株式会社 | 涙液油層安定化剤およびこれを含有する点眼剤 |
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WO2013128633A1 (ja) * | 2012-03-02 | 2013-09-06 | 日油株式会社 | コンタクトレンズ用ケア製剤及びパッケージング溶液 |
WO2016140242A1 (ja) * | 2015-03-03 | 2016-09-09 | 日油株式会社 | 点眼剤 |
WO2017110874A1 (ja) * | 2015-12-22 | 2017-06-29 | 日油株式会社 | 涙液油層安定化剤およびこれを含有する点眼剤 |
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KISHO NAGAI: "P49 Applicability of biocompatible polymers: MPC polymer and dry eye treatment", 45TH ANNUAL MEETING OF THE JAPANESE CORNEAL SOCIETY // THE 37TH ANNUAL MEETING OF THE JAPANESE CORNEA TRANSPLANTATION SOCIETY; FEBRUARY 11-13, 2021, vol. 45th/37th, 11 February 2021 (2021-02-11) - 13 February 2021 (2021-02-13), JP, pages 84, XP009537855 * |
MIZUKI YAMAGUCHI, RYOTARO RYOKU, AYAKA WATANABE, MIWA YUNA, MISA MINAMI, YUKO OTAKE, SHUNSUKE SAKURAI, EIJI HARADA, KISHO NAGAI: "1D-14 Preparation of novel biocompatible polymer MPCP and its applicability to dry eye treatment", PROCEEDINGS OF THE ANNUAL MEETING OF THE ACADEMY OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY; 2021-05-13~2021-05-15, vol. 36, 7 May 2021 (2021-05-07) - 15 May 2021 (2021-05-15), JP, pages 132, XP009537336 * |
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