JP5563745B2 - Eye drops - Google Patents

Description

  The present invention relates to eye drops, and more particularly to eye drops effective for the treatment of dry eye and the like, which contain specific components as emulsions.

  Dry eye is a disease in which damage (scratches) occur on the surface of the eye when the amount of tears is insufficient or the components of tears change. This dry eye is accompanied by symptoms such as painful eyes, difficulty in opening eyes, difficulty in viewing, loss of contact lenses, and infection of the eyes.

  Conventionally, this treatment of dry eye has been performed using eye drops such as artificial tears. As such eye drops, those containing castor oil, liquid paraffin, lanolin, petrolatum, etc. (Patent Documents 1 to 3), methacryloyloxyethyl phosphorylcholine (MPC), methacryloyloxyethyl phosphorylethanolamine (MPE), methacryloyloxy Known are those in which a water-soluble polymer containing a phospholipid-like substance such as ethylphosphorylcholine 2-hydroxyethyl methacrylate (HEMA) as a structural unit is blended (Patent Documents 4 to 6). Of these, lanolin and petrolatum have been conventionally used as a base for eye ointments.

  However, eye drops containing these oils have a poor feeling of use because they contain a large amount of oil. Furthermore, since these oils do not dissolve in artificial tears, they can be used by shaking or using surfactants. There was a problem that it had to be dispersed with an agent. In addition, it is known that eye drops containing a water-soluble polymer have a moisturizing effect and can replenish moisture, but the effect of replenishing an oil layer (oil) which is one of the constituents of tears is insufficient. There was a problem.

  Moreover, as an eye drop for dry eye treatment for replenishing oil, castor oil emulsified with lecithin and blended as an aqueous eye drop (Patent Document 7) is also known.

  However, this emulsion is effective for dry eyes because the emulsion is broken down by the salts and proteins in tears, and as a result, castor oil is separated and dispersed on the ocular surface. When the concentration is high, castor oil is separated before instillation, and there is a problem that the effect is not exhibited.

JP-A-10-218760 JP 2000-159659 A Special table 2007-528897 gazette JP 7-166154 A Japanese Patent Laid-Open No. 10-324634 International Publication No. WO99 / 26637 Pamphlet International Publication No. WO2006 / 9112 Pamphlet

  Accordingly, an object of the present invention is to provide an ophthalmic solution that can efficiently treat dry eye and the like, and has no limitation on the concentration of a component such as a salt, and is stable and easy to use.

  As a result of diligent research to solve the above-mentioned problems, the inventors of the present invention incorporated oils such as castor oil, liquid paraffin, lanolin, petrolatum, etc., and a specific water-soluble polymer into an emulsion, thereby blending each of them independently. As a result, the present inventors have found that a therapeutic effect such as dry eye can be obtained that is far superior to that of the above case.

  That is, the present invention provides an oily substance selected from the group consisting of castor oil, liquid paraffin, lanolin and petrolatum, and a water-soluble polymer which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate, in the form of an emulsion. It is an eye drop characterized by containing in.

  The eye drop of the present invention comprises castor oil, liquid paraffin, lanolin or petrolatum and a water-soluble polymer which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate in the form of an emulsion. Therefore, the treatment effect of dry eye is high, and since the amount of castor oil, liquid paraffin, lanolin or petrolatum in the eye drops is small, the feeling of use is excellent. Furthermore, since this ophthalmic solution is not particularly limited as to the components that are stable and can be blended, it can be made into an artificial tear suitable for the ratio of salt in tears and the physical properties of tears.

  In addition, since the eye drop of the present invention is not particularly limited in the components that can be blended, not only the above-mentioned dry eye treatment use, but also general eye drops formulated with various active ingredients according to the purpose, A multi-dose ophthalmic solution can be prepared by blending a preservative benzalkonium chloride and various drugs.

  Oils such as castor oil, liquid paraffin, lanolin and petrolatum (hereinafter referred to as “oil”) contained in the eye drops of the present invention have been conventionally used as components of eye drops such as artificial tears as described above. Any known one can be used. More specifically, any of castor oil, liquid paraffin, lanolin or petrolatum can be used as long as it is compatible with the Japanese Pharmacopoeia.

  Further, a water-soluble polymer (hereinafter referred to as “MPC polymer”), which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine (hereinafter referred to as “MPC”) and butyl (meth) acrylate, blended in the present invention, MPC is polymerized by the method described in WO99 / 26637, for example. That is, 2-methacryloyloxyethyl phosphorylcholine monomer and butyl (meth) acrylate monomer are subjected to degassing conditions in the presence of a radical polymerization initiator, or nitrogen gas, argon gas, helium gas, carbon dioxide gas. It can be produced by polymerization by heating or irradiating light in a solvent such as water, methanol, ethanol in an inert gas substitution or atmosphere. Examples of MPC polymers that can be easily obtained include Lipidure (registered trademark: manufactured by Nippon Oil & Fats Co., Ltd.). Among these, aqueous solutions containing lipida are commercially available from Nippon Oil & Fat Co., Ltd. under the trade names such as Lipidure-PMB. This may be used.

  In order to make the oil and MPC polymer into the form of an emulsion, these components may be vigorously stirred according to a conventional method without using an emulsifier. That is, a solution in which MPC polymer is dissolved in a solvent such as water is heated, and an oil component is added thereto, and then vigorously stirred. In addition, since an example of the method for obtaining an emulsion using MPC polymer is described also in Unexamined-Japanese-Patent No. 10-109029, you may obtain an emulsion based on this description.

  A more specific example for obtaining the emulsion is as follows. First, an aqueous solution in which the MPC polymer is dissolved in an amount of 0.0001 to 40% by mass (hereinafter simply referred to as “%”), preferably 0.001 to 10%, more preferably 0.01 to 5%, Preferably it heats to 65-75 degreeC. Next, oil is added to 0.01-5 parts by mass, preferably 0.1-1 part by mass with respect to 1 part by mass of the MPC polymer, and then a magnetic stirrer or homogenizer (Hiscotron (trade name): Hitachi, Ltd.) Etc.) to obtain a preliminary emulsion. Furthermore, this pre-emulsified product is about 60 to 150 MPa, preferably about 80 to 120 MPa, about 5 to 50 times, preferably about 5 to 50 times using a high-pressure homogenizer (PANDA 2K type: manufactured by Niro Soavi S. p. A). The fine emulsion is obtained by processing about 10 to 30 times. The average particle size of the fine emulsion is 50 to 300 nm, preferably about 200 nm.

  The eye drop of the present invention is produced by adding the above-mentioned emulsion to a suitable solvent and the like according to a conventional method, further adjusting the pH, osmotic pressure, etc., and further sterilizing.

  The content of the emulsion in the eye drop of the present invention is not particularly limited. For example, the oil content is 0.001 to 10%, preferably 0.01 to 1% with respect to the whole eye drop. What is necessary is just to mix | blend. Moreover, what is necessary is just to mix | blend MPC polymer content so that it may become 0.0001 to 40% with respect to the whole eyedrops, Preferably it is 0.001 to 10%, More preferably, it is 0.01 to 5%.

  In addition to the above emulsion, the eyedrops of the present invention can be blended with conventionally known optional components within a range that does not impair the effects of the invention in the eyedrops. Examples of such optional components include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; thickeners such as hydroxyethyl cellulose; sugars such as glucose; polyhydric alcohols such as glycerin; and hyperemia such as naphazoline hydrochloride. Removal components, focus regulators such as neostigmine methyl sulfate, anti-inflammatory components such as epsilon-aminocaproic acid, antihistamines such as chlorpheniramine maleate, vitamins such as cyanocobalamin and pyridoxine hydrochloride, taurine, aspartate, etc. Amino acids, sulfa drugs such as sulfamethoxazole, antiallergic ingredients such as cromoglycates, surfactants such as polyoxyethylene eorubitan monooleate, essential oils such as menthol and camphor, boric acid, citric acid Buffers such as salts, chlorobutanol, benzalkonium chloride, preservatives such as paraben, stabilizers such as edetate salts.

  The ophthalmic solution of the present invention thus obtained is suitable for treatment of dry eye as it is, and since there are no particular restrictions on the components that can be blended, the ratio of salt in tears, physical properties of tears In addition, artificial tears containing inorganic salts and the like, and general eye drops containing various kinds of active ingredients according to the purpose can be obtained. Furthermore, since additives such as preservatives can be appropriately blended according to the purpose, they can be used for treating various diseases of the eye as conventional multi-dose type eye drops.

  Hereinafter, the present invention will be described in detail with reference to production examples, examples and test examples, but the present invention is not limited to these examples.

Manufacturing example 1
Preparation of Emulsion 1:
200 parts by weight of a 5% aqueous solution (Lipidure-PMB (trade name) manufactured by NOF Corporation) of a water-soluble polymer that is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate was added to about 70 ° C. Warm up. 10 parts by weight of castor oil (Japanese Pharmacopoeia compatible product) was added thereto and stirred vigorously with a magnetic stirrer for about 10 minutes to obtain a preliminary emulsion. This pre-emulsion was processed 20 times at a pressure of about 120 MPa using a desktop high-pressure homogenizer (PANDA 2K type: manufactured by Niro Soavi S. p. A) to obtain a fine emulsion. When the particle size of this emulsion was measured with a particle size distribution analyzer (NICOMP380ZLS: manufactured by Particle Sizing System), the average particle size was 285 nm.

Manufacturing example 2
Preparation of Emulsion 2:
An emulsion was prepared in the same manner as in Production Example 1 except that castor oil was liquid paraffin (Japanese Pharmacopoeia compatible product: High Coal M-202 (trade name): manufactured by Kaneda Corporation). The average particle size of this emulsion was 239 nm.

Manufacturing example 3
Preparation of emulsion 3:
An emulsion was prepared in the same manner as in Production Example 1 except that castor oil was lanolin (refined lanolin; manufactured by Nippon Seika Co., Ltd.). The average particle size of this emulsion was 235 nm.

Manufacturing example 4
Preparation of emulsion 4:
An emulsion was prepared in the same manner as in Production Example 1 except that the castor oil was petrolatum (white petrolatum; manufactured by Crompton). The average particle size of this emulsion was 237 nm.

Manufacturing example 5
Preparation of emulsion 5:
An emulsion was prepared in the same manner as in Production Example 1 except that 10 parts by weight of castor oil was changed to 1.5 parts by weight of castor oil. The average particle size of this emulsion was 197 nm.

Manufacturing Example 6
Preparation of emulsion 6:
200 parts by weight of a 5% aqueous solution of a water-soluble polymer, which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate, is dissolved in water that is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate. An emulsion was prepared in the same manner as in Production Example 1 except that 180 parts by weight of purified water was added in place of 20 parts by weight of a 5% aqueous solution of the soluble polymer. The average particle size of this emulsion was 224 nm.

Manufacturing example 7
Preparation of emulsion 7:
An emulsion was prepared in the same manner as in Production Example 1 except that 10 parts by weight of castor oil was replaced with 20 parts by weight of liquid paraffin. The average particle size of this emulsion was 303 nm.

Example 1
Preparation of eye drops:
Add and dissolve 2,100 mg of Emulsion 1 prepared in Production Example 1, 1,000 mg of taurine, 560 mg of sodium chloride and 113 mg of potassium chloride in 85 mL of purified water, and adjust the pH to 7.4 with sodium hydroxide. After that, purified water was added to make the total amount to 100 mL to prepare eye drops. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 286 mOsm.

Example 2
Preparation of eye drops:
Sterile eye drops were prepared in the same manner as in Example 1 except that 2,100 mg of Emulsion 1 was changed to 2,100 mg of Emulsion 2 prepared in Production Example 2. The osmotic pressure of this eye drop was 286 mOsm.

Example 3
Preparation of eye drops:
Sterile eye drops were prepared in the same manner as in Example 1 except that 2,100 mg of Emulsion 1 was changed to 2,100 mg of Emulsion 3 prepared in Production Example 3. The osmotic pressure of this eye drop was 286 mOsm.

Example 4
Preparation of eye drops:
Sterile eye drops were prepared in the same manner as in Example 1 except that 2,100 mg of Emulsion 1 was changed to 2,100 mg of Emulsion 4 prepared in Production Example 4. The osmotic pressure of this eye drop was 286 mOsm.

Example 5
Preparation of eye drops:
A sterile eye drop was prepared in the same manner as in Example 1 except that 2,100 mg of Emulsion 1 was changed to 2,015 mg of Emulsion 5 prepared in Production Example 5. The osmotic pressure of this eye drop was 286 mOsm.

Example 6
Preparation of eye drops:
Sterile eye drops were prepared in the same manner as in Example 1 except that 2,100 mg of Emulsion 1 was changed to 21 mg of Emulsion 6 prepared in Production Example 6. The osmotic pressure of this eye drop was 286 mOsm.

Example 7
Preparation of eye drops:
Sterile eye drops were prepared in the same manner as in Example 1 except that 85 mL of purified water was changed to 50 mL and 2,100 mg of Emulsion 1 was changed to 22,000 mg of Emulsion 7 prepared in Production Example 7. The osmotic pressure of this eye drop was 286 mOsm.

Comparative Example 1
Preparation of eye drops:
In 85 mL of purified water, 2,000 mg of MPC polymer (Lipidure-PMB (trade name): manufactured by Nippon Oil & Fats Co., Ltd.), 1,000 mg of taurine, 560 mg of sodium chloride and 113 mg of potassium chloride were added and dissolved, and sodium hydroxide was added. After adjusting the pH to 7.4, purified water was added to make up a total volume of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 286 mOsm.

Comparative Example 2
Preparation of eye drops:
Add 85 mg of castor oil (Japanese Pharmacopoeia), 560 mg of sodium chloride and 113 mg of potassium chloride to 85 mL of purified water, dissolve, adjust pH to 7.2 with sodium hydroxide, add purified water To 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 286 mOsm.

Comparative Example 3
Preparation of eye drops:
To 85 mL of purified water, 1,000 mg of taurine, 560 mg of sodium chloride and 113 mg of potassium chloride were added and dissolved. After adjusting the pH to 7.4 with sodium hydroxide, purified water was added to make up a total volume of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 286 mOsm.

Test example 1
Dry eye improvement effect (moisture transpiration suppression effect) test
A male Japanese white rabbit (Kitayama Labes) weighing approximately 2.5 kg was fixed with an Oshida-type fixator, then a pentobarbital anesthetic was administered from the ear vein, and Benoxeal 0.4% ophthalmic solution (Santen Pharmaceutical) under light anesthesia. The eye surface was anesthetized by eye drop. After anesthesia, the tear oil layer was removed by wiping the tear and eye drops in the ocular surface and conjunctival sac, and 50 μL of each of the eye drops of Examples 1 to 4 and Comparative Examples 1 to 3 was instilled. In addition, it was confirmed using the dry eye observation apparatus DR-1 (made by Kowa Co., Ltd.) that the tear oil layer was removed. Moisture transpiration from the surface of the eye immediately before instillation and 30 minutes after instillation was measured using a moisture transpiration measuring device (TEWAMETER TM300: COURAGE + KHAZAKA electronic GmbH). The rate of change in transpiration was calculated.

(Equation 1)
Moisture transpiration rate change rate (%) = (A / B) × 100
A: Moisture transpiration after instillation B: Moisture transpiration immediately before instillation

  From the above results, the ophthalmic solution of the example containing the emulsion obtained by emulsifying the oil component with the MPC polymer with respect to the increased water transpiration amount by removing the tear oil layer is the ophthalmic solution of the comparative example not containing the emulsion. Compared to the above, a tear oil layer was rapidly re-formed, and a clear water evaporation suppression effect was shown.

Manufacturing Example 8
Preparation of comparative emulsion 1:
95 g of purified water was heated to 70 ° C. and 0.55 g of hydrogenated soybean lecithin (Basis LP-20 (trade name) manufactured by Nisshin Oilio Co., Ltd.) was added and dispersed while stirring. While heating at 70 ° C., 5 g of castor oil (Japanese Pharmacopoeia compatible product) was added and stirred vigorously with a magnetic stirrer for about 10 minutes to obtain a preliminary emulsion. This emulsion was emulsified using a high-pressure homogenizer (PANDA 2K type: manufactured by Niro Soavi) to obtain a fine emulsion. The average particle size of this emulsion was 194 nm.

Manufacturing example 9
Preparation of comparative emulsion 2:
An emulsion was prepared in the same manner as in Production Example 8 except that the hydrogenated soybean lecithin was changed to 0.25 g. The average particle size of this emulsion was 277 nm.

Manufacturing example 10
Preparation of comparative emulsion 3:
An emulsion was prepared in the same manner as in Production Example 8 except that 5 g of hydrogenated soybean lecithin was used. The average particle size of this emulsion was 101 nm.

Comparative Example 4
Preparation of eye drops:
After 111 mg of Comparative Emulsion 1 prepared in Production Example 3 and 1,000 mg of taurine, 560 mg of sodium chloride and 113 mg of potassium chloride were dissolved in 85 mL of purified water and dissolved, the pH was adjusted to 7.4 with sodium hydroxide. The total volume was made up to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.

Comparative Example 5
Preparation of eye drops:
A sterile eye drop was prepared in the same manner as in Comparative Example 4 except that 111 mg of Comparative Emulsion 1 was changed to 105 mg of Comparative Emulsion 2 prepared in Production Example 9.

Comparative Example 6
Preparation of eye drops:
A sterile eye drop was prepared in the same manner as in Comparative Example 4 except that 111 mg of Comparative Emulsion 1 was changed to 200 mg of Comparative Emulsion 3 prepared in Production Example 10.

Test example 2
Formulation stability test:
The eye drops of Examples 1 to 7 and Comparative Examples 4 to 6 were stored in an atmosphere at 65 ° C. for 14 days. The appearance of the preparation before and after storage was visually observed and judged according to the following evaluation criteria.

<Stability evaluation criteria>
(Evaluation) (Content)
−: No separation ±: Slightly separated +: Clearly separated

  From the above results, the ophthalmic solution of the example containing an emulsion obtained by emulsifying oil with MPC polymer is a formulation that is clearly more stable than the ophthalmic solution of the comparative example containing an emulsion obtained by emulsifying oil with hydrogenated soybean lecithin. Met.

  The eye drop of the present invention can effectively prevent and treat dry eye while having a small amount of oil compared to conventional eye drops for dry eye. Moreover, since the preparation itself is stable, it is possible to produce various eye drops according to the purpose.

Therefore, the eye drops of the present invention can be widely used as eye drops for various purposes including those for dry eye.

that's all

Claims (6)

An oil component selected from the group consisting of castor oil, liquid paraffin, lanolin and petrolatum, and a water-soluble polymer which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate, in the form of an emulsion , An ophthalmic solution having an oil content of 0.001 to 10% by mass .   The eye drop according to claim 1, wherein the content of the water-soluble polymer which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and butyl (meth) acrylate is 0.0001 to 40% by mass with respect to the whole eye drop. The ophthalmic solution according to claim 1 or 2 , wherein a blending ratio of the oil and the water-soluble polymer is 0.01 to 5 parts by mass of the oil with respect to 1 part by mass of the water-soluble polymer. The eye drop according to any one of claims 1 to 3 , which is an agent for treating dry eye. The eye drop according to any one of claims 1 to 4 , which is a multi-dose type. The ophthalmic solution according to any one of claims 1 to 5 , further comprising taurine.