TW202408468A - Ophthalmic composition - Google Patents

Abstract

The present invention relates to an ophthalmic composition, which contains tramadol or a salt thereof and is contained in a container, wherein a part or all of the container in contact with the ophthalmic composition is formed of plastic, and the container is sterilized by means other than electron beam.

Description

Ophthalmic compositions

The present invention relates to an ophthalmic composition.

Tramadol is classified as a weak opioid non-narcotic analgesic and can be used as a systemic analgesic for cancer pain and other conditions (Non-Patent Document 1). [Prior technical literature] [Non-patent literature]

Non-Patent Document 1: Tramal (Registered Trademark) Note 100 Attached Documents

[The problem that the invention wants to solve]

On the other hand, when tramadol is used as a therapeutic drug for diseases in the field of ophthalmology, it is required that the amount of impurities derived from tramadol in the ophthalmic preparation does not reach a certain level, but to date, there has been no report on the existence of impurities derived from tramadol in ophthalmic preparations containing tramadol. The purpose of the present invention is to provide a novel ophthalmic composition containing tramadol in which impurities derived from tramadol are reduced. [Technical means for solving the problem]

The present inventors discovered for the first time that if an ophthalmic composition containing tramadol is contained in a plastic container that has been sterilized by means other than electron beams, regardless of the content of tramadol in the ophthalmic composition, the amount of tramadol derived from The impurities of tramadol are reduced; furthermore, by setting the tramadol content in the ophthalmic composition within a specific range, the impurities derived from tramadol are reduced when contained in a plastic container that has been sterilized by electron beam. Reduce. Based on this finding, the present invention provides the following inventions.

[1] An ophthalmic composition comprising tramadol or a salt thereof and contained in a container, wherein part or all of the portion of the container in contact with the ophthalmic composition is formed of plastic, and the container has been sterilized by means other than electron beam. [2] The ophthalmic composition as described in [1], wherein the sterilization by means other than electron beam is sterilization by hydrogen peroxide gas or sterilization by ethylene oxide gas. [3] An ophthalmic composition comprising 1.0 to 3.0 w/v% of tramadol or a salt thereof based on the total amount of the ophthalmic composition, and contained in a container, wherein part or all of the portion of the container in contact with the ophthalmic composition is formed of plastic, and the container has been sterilized by electron beam. [4] An ophthalmic composition as described in any one of [1] to [3], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymers. [Effects of the Invention]

According to the present invention, a novel tramadol-containing ophthalmic composition in which impurities derived from tramadol are reduced can be provided.

The following describes the embodiments of the present invention in detail. However, the present invention is not limited to the following embodiments.

In this manual, unless otherwise specified, the unit "%" of content means "w/v%", which is synonymous with "g/100 mL".

The ophthalmic composition of this embodiment contains (A) tramadol or its salt (also referred to as "(A) component").

[Component (A)] Tramadol is a known compound represented by the following formula. Furthermore, for the sake of convenience, the above formula shows one type of mirror image isomers, but the present invention also includes other mirror image isomers.

The salt of tramadol is not particularly limited as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with alkaline amino acids, and the like.

Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, mesylate, ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts with inorganic bases include alkaline metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts, etc. Examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamine, etc. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. As salts of tramadol, salts with inorganic acids are preferred, and hydrochlorides are more preferred.

The ophthalmic composition of the present embodiment contains tramadol or a salt thereof as an active ingredient and can be used, for example, to suppress pain.

When the ophthalmic composition of the present embodiment is contained in a container sterilized by means other than electron beam, the content of component (A) is not particularly limited and can be appropriately set according to the types and contents of other blending ingredients, the form of the preparation, etc. From the viewpoint of more significantly exerting the effect of the present invention, the content of component (A) can be 0.01 w/v% to 10 w/v%, 0.05 w/v% to 5 w/v%, 0.1 w/v% to 4 w/v%, or 3 w/v%, based on the total amount of the ophthalmic composition of the present embodiment.

When the ophthalmic composition of the present embodiment is housed in a container that has been sterilized by electron beam, the content of component (A) is 1.0 w/v% to 3.0 based on the total amount of the ophthalmic composition. w/v%.

[buffer] The ophthalmic composition of this embodiment may further contain a buffering agent. By further containing a buffering agent in the ophthalmic composition, the effects of the present invention can be exerted more significantly. The buffering agent is not particularly limited as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the buffer include an inorganic buffer, which is a buffer derived from an inorganic acid, and an organic buffer, which is a buffer derived from an organic acid or an organic base.

Examples of inorganic buffers include boric acid buffers, phosphate buffers, and carbonate buffers. Examples of boric acid buffers include boric acid or its salts (metal borates, earth borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (metal phosphates, earth phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (metal carbonates, earth borates, etc.). Furthermore, as the boric acid buffer, phosphate buffer or carbonate buffer, a hydrate of borate, phosphate or carbonate may be used. As more specific examples, boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a boric acid buffer; phosphoric acid or its salts (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.) as a phosphate buffer; carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.) as a carbonate buffer, etc.

Examples of the organic buffer include citric acid buffer, acetic acid buffer, lactic acid buffer, succinic acid buffer, tris buffer, AMPD buffer, and the like. Examples of the citric acid buffer include citric acid or salts thereof (alkali metal citrate salts, alkaline earth metal salts of citrate, etc.). Examples of the acetic acid buffer include acetic acid or salts thereof (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of the lactic acid buffer include lactic acid or salts thereof (lactic acid alkali metal salts, lactic acid alkaline earth metal salts, etc.). Examples of the succinic acid buffer include succinic acid or a salt thereof (alkali metal succinate, etc.). Furthermore, hydrates of citrate, acetate, lactate or succinate may be used as the citrate buffer, acetate buffer, lactate buffer or succinate buffer. More specific examples include: citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as a citric acid buffer; an acetic acid buffer as Acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); lactic acid or its salts as lactate buffer (sodium lactate, potassium lactate, calcium lactate, etc.); succinic acid or its salts as succinic acid buffer Salt (monosodium succinate, disodium succinate, etc.), etc. Examples of the trishydroxymethylaminomethane buffer include trometamol or a salt thereof (trometamol hydrochloride, etc.). Examples of the AMPD buffer include 2-amino-2-methyl-1,3-propanediol or a salt thereof.

As the buffer, boric acid buffer, phosphoric acid buffer, and citric acid buffer are preferred, boric acid buffer and phosphoric acid buffer are more preferred, and boric acid or its salt, phosphoric acid or its salt are further preferred.

Commercially available buffers may be used. Buffers may be used alone or in combination of two or more.

The content of the buffer in the ophthalmic composition of this embodiment is not particularly limited and can be appropriately set depending on the type of buffer, the type and content of other blended ingredients, the use of the ophthalmic composition, the form of the preparation, etc. The content of the buffering agent is preferably 0.01 w/v% to 10 w/v%, and more preferably 0.05, based on the total amount of the ophthalmic composition, for example, in order to more effectively exert the effects of the present invention. w/v% to 5 w/v%, and more preferably 0.1 w/v% to 3 w/v%. When the buffer is a boric acid buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%, and even more preferably 0.1 w/v%. ~3 w/v%, especially 0.5 w/v% ~ 2 w/v%. When the buffer is a citrate buffer or a phosphate buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%, and even more preferably 0.1 w/v% to 3 w/v%, more preferably 0.1 w/v% to 1 w/v%, particularly preferably 0.1 w/v% to 0.3 w/v%.

The content ratio of the buffer to component (A) in the ophthalmic composition of this embodiment is not particularly limited, and can be determined according to the types of component (A) and buffer, the types and contents of other blended components, and the It can be set appropriately according to the purpose, preparation form, etc. Regarding the content ratio of the buffering agent relative to component (A), from the viewpoint of further improving the effect of the present invention, for example, the content ratio of the buffering agent relative to the total content of component (A) contained in the ophthalmic composition of the present embodiment 1 Parts by mass can be 0.001 to 1000 parts by mass, 0.01 to 100 parts by mass, or 0.025 to 30 parts by mass.

[Inorganic salts] The ophthalmic composition of this embodiment may further contain inorganic salts. By further containing inorganic salts in the ophthalmic composition, the effects of the present invention can be exerted more significantly. The inorganic salts are not particularly limited as long as they are medically, pharmacologically (pharmaceutically) or physiologically acceptable.

Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. As inorganic salts, sodium chloride and potassium chloride are preferred.

Commercially available inorganic salts may be used. The inorganic salts may be used alone or in combination of two or more.

The content of inorganic salts in the ophthalmic composition of the present embodiment is not particularly limited and can be appropriately set depending on the type of inorganic salts, the type and content of other blended ingredients, the use of the ophthalmic composition, the form of the preparation, etc. The content of the inorganic salt is preferably 0.00001 w/v% to 3 w/v% based on the total amount of the ophthalmic composition, and more preferably 0.0001 w/v% to 2 w/v%, and more preferably 0.001 w/v% to 1.5 w/v%.

[Preservative] The ophthalmic composition of this embodiment may further contain a preservative. By further containing a preservative, the effect of the present invention can be more significantly exerted.

Examples of the preservative include biguanide preservatives such as chlorhexidine, alexidine, polyhexanide or salts thereof; quaternary ammonium salt preservatives such as benzyl ammonium chloride and benzathonine chloride; and para-hydroxybenzoate preservatives such as methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate and butyl para-hydroxybenzoate.

As the preservative, from the viewpoint of more significantly exerting the effect of the present invention, a biguanide preservative is preferred, lohexidine or a salt thereof is more preferred, and lohexidine gluconate is further preferred.

A commercially available preservative may be used. A single preservative may be used alone, or two or more preservatives may be used in combination.

The content of the preservative in the ophthalmic composition of this embodiment is not particularly limited and can be appropriately set according to the type of preservative, the type and content of other blended ingredients, the use of the ophthalmic composition, the form of the preparation, etc. The content of the preservative is preferably 0.00001 w/v% to 2 w/v%, and more preferably 0.00005 w, based on the total amount of the ophthalmic composition, in order to more effectively exert the effects of the present invention. /v%～1 w/v%, preferably 0.00008 w/v%～0.8 w/v%. As another aspect, 0.00005 w/v% to 0.5 w/v% and 0.0001 w/v% to 0.025 w/v% can also be presented as preferred contents.

The pH of the ophthalmic composition of this embodiment is not particularly limited as long as it is within a medically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the aqueous composition of this embodiment can be, for example, 4.5 to 7.5, preferably 5.0 to 7.0, more preferably 5.5 to 6.5.

The ophthalmic composition of this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the organism, if necessary. The appropriate osmotic pressure ratio can be appropriately set according to the purpose of the ophthalmic composition, preparation form, usage method, etc., and can be set to 0.4 to 5.0, for example. The osmotic pressure ratio is based on the 18th revised edition of the Japanese Pharmacopoeia. It is set as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of 0.9 w/v% sodium chloride aqueous solution). The osmotic pressure is based on the osmotic pressure recorded in the Japanese Pharmacopoeia. It is measured using manometry (freezing point depression method). Furthermore, the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) can be obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, and then placing it in a desiccator (silica gel) Place it in a medium to cool, accurately weigh 0.900 g, dissolve it in purified water, and prepare it accurately to 100 mL; or use a commercially available standard solution for osmotic pressure ratio determination (0.9 w/v% sodium chloride aqueous solution).

The viscosity of the ophthalmic composition of the present embodiment is not particularly limited as long as it is within the range permitted in medicine, pharmacology (pharmaceuticals) or physiology. The viscosity of the ophthalmic composition of the present embodiment, for example, can be 1 to 10000 mPa･s at 20°C measured using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24).

The ophthalmic composition of the present embodiment can be prepared, for example, by adding and mixing component (A) and other components as required in a desired amount. Specifically, it can be prepared, for example, by dissolving or suspending the above components in purified water and sterilizing them by filtration sterilization.

The ophthalmic composition of this embodiment can be in various dosage forms depending on the purpose, for example, liquid, gel, semisolid (ointment, etc.), etc.

When the ophthalmic composition of the present embodiment is a liquid, it can be used, for example, as eye drops (also called eye drops or eye drops). In addition, eye drops include those that can be dropped into the eyes when wearing contact lenses. Eye drops), artificial tears, eyewash (also called eyewash or eyewash. Also, eyewash includes eyewash that can be used to wash the eyes when wearing contact lenses). Furthermore, "contact lenses" include hard contact lenses, soft contact lenses (including both ionic and non-ionic), and include both polysilicone hydrogel contact lenses and non-polysilicone hydrogel contact lenses. ).

In order to more significantly exert the effects of the present invention, the ophthalmic composition of the present embodiment is preferably an eye drop (including eye drops that can be applied to the eye when wearing contact lenses). When the ophthalmic composition of the present embodiment is an eye drop, its usage and dosage are not particularly limited as long as they can exert the effects and have fewer side effects. For example, in the case of adults (over 15 years old) and children over 7 years old, the following method of use can be exemplified: 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops per time, 1 to 4 times, or 5 to 6 times a day.

[container] The ophthalmic composition of this embodiment is provided in a container (also referred to as a "plastic container" for short) in which a part or all of the portion in contact with the ophthalmic composition is made of plastic.

Examples of polymers constituting plastics include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate, polyarylate, polycarbonate, polyethylene (PE; high-density polyethylene (HDPE), low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE)), polypropylene (PP), polystyrene (PS), acrylonitrile-butadiene-styrene (ABS), polymethylpentene (PMP), polyimide (PI), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), copolymers of monomers constituting the same, and mixtures of two or more of the above. Polymers constituting plastics are preferably polyethylene (PE), polypropylene (PP), and cyclic olefin copolymer (COC). In addition, plastics may also include elastomers.

Plastics can also contain additives such as stabilizers. In addition, the plastic may contain reinforcing agents such as glass fiber and be reinforced.

As the plastic, commercially available ones can be used without particular limitation.

The plastic container for containing the ophthalmic composition may be a container generally used in the field of ophthalmology, specifically, an eye drop container or an eye wash container. The type of container is preferably an eye drop container.

Part or all of the part of the plastic container in contact with the ophthalmic composition of this embodiment is made of plastic. For example, when the plastic container is a container with a perforated inner plug (nozzle), only the perforated inner plug part may be made of plastic, or the receiving part other than the perforated inner plug may be made of plastic, or it may be The entire container is made of plastic.

The plastic container of this embodiment only needs to be partially formed of plastic in contact with the ophthalmic composition, but from the perspective of more significantly exerting the effect of the present invention, it is preferred that the entire portion in contact with the ophthalmic composition is formed of plastic. In addition, the plastic container may be formed of one type of plastic alone or of two or more types of plastic.

The shape and capacity of the container are not particularly limited and may be appropriately set according to the intended use. In addition, the container may be a container that accommodates multiple-use amounts of the ophthalmic composition (multi-dose container), or may be a container that accommodates a single-use amount of the ophthalmic composition (single-dose container).

When the container is a multi-dose container, for example, the capacity may be 1.5 to 7.5 mL, 2 to 6 mL, or 2.5 to 5.0 mL. Also, when the container is a single-dose container, for example, the capacity may be 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.

[Sterilization treatment] The plastic container containing the ophthalmic composition of this embodiment has been sterilized.

Examples of sterilization methods include sterilization by electron beam, sterilization by gamma rays, sterilization by hydrogen peroxide gas (VHP), and sterilization by ethylene oxide gas (EOG). Examples of sterilization methods other than electron beam include sterilization by gamma rays, sterilization by hydrogen peroxide gas (VHP), and sterilization by ethylene oxide gas (EOG). Among these methods, sterilization by hydrogen peroxide gas (VHP) and sterilization by ethylene oxide gas (EOG) are preferred. Sterilization by electron beam, sterilization by gamma ray, sterilization by hydrogen peroxide gas (VHP), and sterilization by ethylene oxide gas (EOG) can be performed by methods known to those skilled in the art.

If the plastic container containing the ophthalmic composition of the present embodiment is sterilized by electron beam, the effect of "reducing impurities derived from tramadol" can be exerted by making the content of tramadol in the ophthalmic composition within a specific range (for example, 1.0 to 3.0 w/v% based on the total amount of the ophthalmic composition). In addition, if the plastic container containing the ophthalmic composition of the present embodiment is sterilized by means other than electron beam, the effect of "reducing impurities derived from tramadol" can be exerted regardless of the content of tramadol in the ophthalmic composition.

The ophthalmic composition of this embodiment can also be provided in the form of an ophthalmic composition enclosed in a container. In addition, the present invention can also be understood as an ophthalmic product (eye drops, etc.) containing the ophthalmic composition of the present invention in a container. [Example]

Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited to these. In addition, unless otherwise stated, the unit of each component in the table is w/v%.

[Test Example 1: Thermal Severity Test] With the composition shown in Table 1 and Table 2, an ophthalmic composition was prepared according to a conventional method. Each prepared ophthalmic composition was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition is filled into an eyedropper bottle (material: polyethylene or COC; capacity: 5 mL) that has been previously treated with each sterilization method, and is stored under the conditions described in the upper left column of the table while shielding from light. . The content of impurities (tramadol analogues) contained in the aqueous composition after storage was measured by HPLC, and the production rate (%) of the tramadol analogues relative to the blended amount of tramadol hydrochloride was calculated. Furthermore, based on the calculated production rate of tramadol-like substances, the reduction rate of tramadol-like substances was determined according to the following equation. The results are shown in Table 1 and Table 2. The reduction rate of tramadol-like substances in Test Examples 2 and 3 (%) = {100×(the production rate of Test Example 1 - the production rate of each test example)}/the production rate of Test Example 1 The reduction rate (%) of tramadol-like substances in Test Examples 5 and 6 = {100×(the production rate of Test Example 4 - the production rate of each test example)}/the production rate of Test Example 4

[Table 1] 50℃, 1 month Test Example 1 Test Example 2 Test Example 3 Tramadol hydrochloride 0.3 0.3 0.3 Sodium dihydrogen phosphate hydrate 0.3 0.3 0.3 Sodium Hydrogen Phosphate Hydrate 0.14 0.14 0.14 Sodium chloride 0.65 0.65 0.65 Potassium chloride 0.1 0.1 0.1 Lohexidine gluconate 0.01 0.01 0.01 Purified water Remaining amount Remaining amount Remaining amount Total 100 mL 100 mL 100 mL pH 6 6 6 container PE PE COC Sterilization method Electron beam VHP VHP Reduction rate of similar substances (%) - 100 100

[Table 2] 50℃, 2 months Test example 4 Test example 5 Test example 6 tramadol hydrochloride 0.3 1 3 Sodium dihydrogen phosphate hydrate 0.3 0.3 0.3 Sodium hydrogen phosphate hydrate 0.14 0.13 0.12 sodium chloride 0.65 0.5 0.1 potassium chloride 0.1 0.1 0.1 Lohesidine gluconate 0.01 0.01 0.01 purified water margin margin margin total amount 100mL 100mL 100mL pH 6 6 6 container PE PE PE Sterilization method electron beam electron beam electron beam Reduction rate of similar substances (%) - 47.4 75.2

Regarding the ophthalmic composition containing tramadol hydrochloride, it was confirmed that when it is filled into a plastic container that has been sterilized by an electron beam and a thermal severity test is performed, as shown in Test Example 1, a tramadol-like substance is produced. On the other hand, it was confirmed that , it was confirmed that when filled in a plastic container sterilized by means other than electron beam such as VHP sterilization, as shown in Test Examples 2 and 3, tramadol-like substances were not generated, and tramadol hydrochloride was stable. exist. Furthermore, it was confirmed that even if the ophthalmic composition containing tramadol hydrochloride is filled in a plastic container that has been sterilized by electron beam, when the blending amount of tramadol hydrochloride is 1% as shown in Test Examples 5 and 6 In the above case, tramadol hydrochloride also exists more stably than in the case of low concentration like Test Example 4.

[Test Example 2: Heat Severity Test] An ophthalmic composition was prepared according to a conventional method using the composition shown in Table 3. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into an eye drop bottle (material: polyethylene or polypropylene; volume: 5 mL) that had been previously treated using various sterilization methods, and stored under light-shielding conditions as described in the left column of the table. The content of impurities (tramadol analogs) contained in the aqueous composition after storage was determined by HPLC, and the generation rate (%) of tramadol analogs relative to the blending amount of tramadol hydrochloride was calculated. In addition, the reduction rate of tramadol analogs was calculated according to the following formula based on the calculated generation rate of tramadol analogs. The results are shown in Table 3. The reduction rate of tramadol-like substances in Test Examples 8 to 10 (%) = {100 × (the generation rate of Test Example 7 - the generation rate of each test example)} / the generation rate of Test Example 7

[table 3] 50℃, 2 months Test Example 7 Test Example 8 Test Example 9 Tramadol hydrochloride 0.1 0.1 0.1 Boric acid 1 1 1 Borax 0.008 0.008 0.008 Sodium chloride 0.3 0.3 0.3 Purified water Remaining amount Remaining amount Remaining amount Total 100 mL 100 mL 100 mL pH 6.1 6.1 6.1 container PE PE PP Sterilization method Electron beam EOG VHP Reduction rate of similar substances (%) - 91.8 95.2

It was confirmed that, as shown in Test Examples 8 and 9, tramadol-like substances and tramadol hydrochloride were not generated when filled in plastic containers that had been sterilized by means other than electron beams, such as EOG sterilization and VHP sterilization. Salt is present stably.

without

without

Claims (4)

An ophthalmic composition contains tramadol or a salt thereof and is contained in a container, wherein a part or the whole of the container in contact with the ophthalmic composition is formed of plastic, and the container is sterilized by means other than electron beam. The ophthalmic composition of claim 1, wherein the sterilization treatment by means other than electron beam is sterilization by hydrogen peroxide gas or sterilization by ethylene oxide gas. An ophthalmic composition containing 1.0 to 3.0 w/v% of tramadol or its salt based on the total amount of the ophthalmic composition, and contained in a container, the part of the container in contact with the ophthalmic composition Partly or entirely made of plastic, the container is sterilized by electron beam. The ophthalmic composition according to any one of claims 1 to 3, wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymers.