Ophthalmic composition

Abstract

The present invention pertains to an ophthalmic composition containing tramadol or a salt thereof, the ophthalmic composition having a pH of 4.0-6.8, and being housed in a container in which a portion of the ophthalmic composition, which is in contact with the ophthalmic composition, is partially or entirely made of plastic.

Description

Technical Field

[0001] The present invention relates to ophthalmic compositions. Background Art

[0002] Tramadol is a non-narcotic analgesic classified as a weak opioid, and is used as a systemic analgesic for cancer pain and the like (Non-Patent Document 1).

[0003] Prior art literature

[0004] Non-patent literature

[0005] Non-patent document 1: Tramal (registered trademark) Note 100 Attached documents Summary of the invention

[0006] Problems to be solved by the invention

[0007] On the other hand, when tramadol is used as a therapeutic drug for diseases in the field of ophthalmology, an ophthalmic preparation containing tramadol is required to have a certain stability, but no findings related to the stability of an ophthalmic preparation containing tramadol have been reported so far. An object of the present invention is to provide a novel ophthalmic composition containing tramadol having excellent stability.

[0008] Means for solving problems

[0009] The inventors of the present application have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that by setting the pH of an ophthalmic composition containing tramadol to a specific range, the stability of the ophthalmic composition is significantly improved even when contained in a container formed of plastic. The present invention is based on this finding and provides the following inventions. [1]

[0011] An ophthalmic composition comprising tramadol or a salt thereof, wherein the pH of the ophthalmic composition is 4.0 to 6.8 and the composition is contained in a container in which part or all of a portion in contact with the ophthalmic composition is made of plastic. [2]

[0013] The ophthalmic composition according to [1], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymers. [3]

[0015] The ophthalmic composition according to [1] or [2], further comprising a buffer. [4]

[0017] The ophthalmic composition according to any one of [1] to [3], wherein the content of the tramadol or a salt thereof is 0.01 w / v% to 10 w / v% based on the total amount of the ophthalmic composition. [5]

[0019] A method for improving the stability of tramadol or a salt thereof in an ophthalmic composition, the method comprising: adjusting the pH of the ophthalmic composition containing tramadol or a salt thereof contained in a container formed of plastic to 4.0 to 6.8. [6]

[0021] The method as described in [5], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymers. [7]

[0023] The method according to [5] or [6], wherein the ophthalmic composition further contains a buffer.

[0024] Effects of the Invention

[0025] According to the present invention, a novel tramadol-containing ophthalmic composition having excellent stability can be provided. DETAILED DESCRIPTION

[0026] Hereinafter, the mode for implementing the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0027] In this specification, unless otherwise specified, the unit "%" of content means "w / v%", which has the same meaning as "g / 100 mL".

[0028] [1. Ophthalmic composition]

[0029] The ophthalmic composition according to the present embodiment contains (A) tramadol or a salt thereof (also referred to simply as "component (A)").

[0030] [(A) Ingredient]

[0031] Tramadol is a known compound represented by the following formula:

[0032] [Chemical formula 1]

[0033]

[0034] It should be noted that, in the above formula, one of the enantiomers is shown for convenience, but the other enantiomers are also included in the present invention.

[0035] The salt of tramadol is not particularly limited as long as it is a substance that is medically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, such salts include salts formed with inorganic acids, salts formed with organic acids, salts formed with inorganic bases, salts formed with organic bases, salts formed with acidic amino acids, salts formed with basic amino acids, etc.

[0036] Examples of salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts formed with organic acids include salts formed with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (methanesulfonic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts formed with inorganic bases include alkali 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 formed with organic bases include salts formed with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc. Examples of salts formed with acidic amino acids include salts formed with aspartic acid, glutamic acid, etc. Examples of salts formed with basic amino acids include salts formed with arginine, lysine, ornithine, etc. As a salt of tramadol, a salt formed with an inorganic acid is preferred, and hydrochloride is more preferred.

[0037] The ophthalmic composition according to the present embodiment contains tramadol or a salt thereof as an active ingredient, and can be used, for example, for suppressing pain.

[0038] The content of the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited and can be appropriately set according to the types and contents of other ingredients, the formulation form, etc. The content of the 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 according to the present embodiment from the viewpoint of more significantly exerting the effect brought about by the present invention.

[0039] 〔Buffer〕

[0040] The ophthalmic composition involved in the present embodiment preferably further contains a buffer. By making the ophthalmic composition further contain a buffer, the effect brought about by the present invention is more significantly exerted. The buffer is not particularly limited as long as it is a substance permitted medically, pharmacologically (pharmaceutically) or physiologically. As the buffer, for example, a buffer derived from an inorganic acid, i.e., an inorganic buffer, and a buffer derived from an organic acid or an organic base, i.e., an organic buffer, can be cited.

[0041] As inorganic buffers, for example, boric acid buffers, phosphate buffers, carbonate buffers, etc. can be cited. As boric acid buffers, boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.) can be cited. As phosphate buffers, phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.) can be cited. As carbonate buffers, carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.) can be cited. In addition, as boric acid buffers, phosphate buffers or carbonate buffers, hydrates of borates, phosphates or carbonates can be used. As for more specific examples, as the boric acid buffer, boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) can be exemplified; as the phosphate buffer, phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.) can be exemplified; as the carbonate buffer, carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.) can be exemplified.

[0042] As the organic buffer, for example, citric acid buffer, acetic acid buffer, lactic acid buffer, succinic acid buffer, Tris buffer, AMPD buffer, etc. can be mentioned. As the citric acid buffer, citric acid or its salts (citric acid alkali metal salts, citric acid alkaline earth metal salts, etc.) can be mentioned. As the acetic acid buffer, acetic acid or its salts (acetic acid alkali metal salts, acetic acid alkaline earth metal salts, etc.) can be mentioned. As the lactic acid buffer, lactic acid or its salts (lactic acid alkali metal salts, lactic acid alkaline earth metal salts, etc.) can be mentioned. As the succinic acid buffer, succinic acid or its salts (succinic acid alkali metal salts, etc.) can be mentioned. In addition, as the citric acid buffer, acetic acid buffer, lactic acid buffer or succinic acid buffer, a hydrate of citrate, acetate, lactate or succinate can be used. As for more specific examples, as a citric acid buffer, citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) can be exemplified; as an acetic acid buffer, acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.) can be exemplified; as a lactic acid buffer, lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.) can be exemplified; as a succinic acid buffer, succinic acid or its salts (monosodium succinate, disodium succinate, etc.) can be exemplified. As a Tris buffer, for example, trometamol or its salts (trometamol hydrochloride, etc.) can be exemplified. As an AMPD buffer, for example, 2-amino-2-methyl-1,3-propanediol or its salts can be exemplified.

[0043] As the buffer, a boric acid buffer, a phosphate buffer, and a citric acid buffer are preferred, a boric acid buffer and a phosphate buffer are more preferred, and boric acid or a salt thereof, and phosphoric acid or a salt thereof are further preferred.

[0044] As the buffer, a commercially available one may be used. The buffer may be used alone or in combination of two or more.

[0045] The content of the buffer in the ophthalmic composition according to the present embodiment is not particularly limited, and can be appropriately set according to the type of buffer, the type and content of other ingredients, the use of the ophthalmic composition, and the formulation form. As the content of the buffer, from the viewpoint of more significantly exerting the effect brought about by the present invention, for example, based on the total amount of the ophthalmic composition, it is preferably 0.01 w / v% to 10 w / v%, more preferably 0.05 w / v% to 5 w / v%, and further 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%, further preferably 0.1 w / v% to 3 w / v%, and particularly preferably 0.5 w / v% to 2.0 w / v%. When the buffer is a citric acid 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%, further preferably 0.1 w / v% to 3 w / v%, further more preferably 0.1 w / v% to 1 w / v%, and particularly preferably 0.1 w / v% to 0.3 w / v%.

[0046] The content ratio of the buffer relative to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and can be appropriately set according to the types of the component (A) and the buffer, the types and contents of other ingredients, the use of the ophthalmic composition, the formulation form, etc. The content ratio of the buffer relative to the component (A) can be, for example, 0.001 to 1000 parts by mass, 0.01 to 100 parts by mass, or 0.025 to 30 parts by mass relative to 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of further improving the effect of the present invention.

[0047] 〔Inorganic salts〕

[0048] The ophthalmic composition of the present embodiment may further contain inorganic salts. By making the ophthalmic composition further contain inorganic salts, the effect brought by the present invention can be more significantly exerted. The inorganic salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically permitted substances.

[0049] Examples of the inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. As the inorganic salts, sodium chloride and potassium chloride are preferred.

[0050] As the inorganic salt, commercially available ones can be used. The inorganic salt can be used alone or in combination of two or more.

[0051] The content of inorganic salts in the ophthalmic composition according to the present embodiment is not particularly limited, and can be appropriately set according to the type of inorganic salts, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. As the content of inorganic salts, from the viewpoint of more significantly exerting the effect brought about by the present invention, for example, based on the total amount of the ophthalmic composition, it is preferably 0.00001 w / v% to 3 w / v%, more preferably 0.0001 w / v% to 2 w / v%, and further preferably 0.001 w / v% to 1.5 w / v%.

[0052] 〔preservative〕

[0053] The ophthalmic composition according to the present embodiment may further contain a preservative. By further containing a preservative, the effect of the present invention can be more significantly exerted.

[0054] Examples of the preservative include biguanide preservatives such as chlorhexidine, alexidine, polyhexanide or salts thereof; quaternary ammonium salt preservatives such as benzalkonium chloride and benzethonium chloride; and paraben preservatives such as methylparaben, ethylparaben, propylparaben and butylparaben.

[0055] As the preservative, from the viewpoint of more significantly exerting the effect of the present invention, a biguanide-based preservative is preferred, chlorhexidine or a salt thereof is more preferred, and chlorhexidine gluconate is further preferred.

[0056] As the preservative, a commercially available one may be used. The preservative may be used alone or in combination of two or more.

[0057] The content of the preservative in the ophthalmic composition of the present embodiment is not particularly limited, and can be appropriately set according to the type of preservative, the type and content of other ingredients, the use of the ophthalmic composition, and the formulation form. As the content of the preservative, from the viewpoint of more significantly exerting the effect brought by the present invention, the total amount of the ophthalmic composition is used as a reference, preferably 0.00001w / v% to 2w / v%, more preferably 0.00005w / v% to 1w / v%, and particularly preferably 0.00008w / v% to 0.8w / v%. As another embodiment, 0.00005w / v% to 0.5w / v%, 0.0001w / v% to 0.025w / v% can also be provided as a preferred content.

[0058] The pH of the ophthalmic composition involved in the present embodiment is 4.0 to 6.8. By making the pH of the ophthalmic composition within this range, the stability of the ophthalmic composition containing tramadol or its salt as an active ingredient is significantly improved. From the viewpoint of further significantly improving the stability of the ophthalmic composition, the pH of the ophthalmic composition is preferably 4.3 to 6.7, more preferably 4.5 to 6.6, further preferably 5.0 to 6.6, further more preferably 5.0 to 6.5, particularly preferably 5.5 to 6.5, and most preferably 5.8 to 6.2. In addition, the pH of the ophthalmic composition involved in the present embodiment may be 4.0 or more, 4.5 or more, 5.0 or more, 5.5 or more, 5.7 or more, 5.8 or more, and may be 6.8 or less, 6.5 or less, 6.3 or less, 6.2 or less, or 6.0 or less.

[0059] The ophthalmic composition involved in the present embodiment can be adjusted to an osmotic pressure ratio within the range allowed by the organism as needed. The appropriate osmotic pressure ratio can be appropriately set according to the purpose, formulation form, and method of use of the ophthalmic composition, for example, it can be set to 0.4 to 5.0. The osmotic pressure ratio is based on the 18th revised edition of the Japanese Pharmacopoeia, and is set to the ratio of the osmotic pressure of the sample to 286mOsm (the osmotic pressure of 0.9w / v% sodium chloride aqueous solution). The osmotic pressure is measured with reference to the osmotic pressure determination method (freezing point depression method) recorded in the Japanese Pharmacopoeia. It should be noted that, with respect to the standard solution for osmotic pressure ratio determination (0.9w / v% sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) can be dried at 500 to 650°C for 40 to 50 minutes, placed in a desiccator (silica gel) for cooling, accurately weighing 0.900g of the sodium chloride, and dissolving it in purified water to accurately prepare 100mL, or a commercially available standard solution for osmotic pressure ratio determination (0.9w / v% sodium chloride aqueous solution) can be used.

[0060] The viscosity of the ophthalmic composition involved in this embodiment is not particularly limited as long as it is within the range permitted medically, pharmacologically (pharmaceutically) or physiologically. The viscosity of the ophthalmic composition involved in this embodiment, for example, can be 1 to 10000 mPa·s at 20°C measured by a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34'×R24).

[0061] The ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing component (A) and other components as needed in a desired content. Specifically, for example, the ophthalmic composition can be prepared by dissolving or suspending the above components in purified water and sterilizing them by filtration sterilization or the like.

[0062] The ophthalmic composition according to the present embodiment can adopt various dosage forms depending on the purpose, and examples thereof include liquid preparations, gel preparations, and semisolid preparations (ointments, etc.).

[0063] When the ophthalmic composition involved in the present embodiment is a liquid, for example, it can be used as eye drops (also called eye drops or eye drops; in addition, eye drops include eye drops that can be used when wearing contact lenses), artificial tears, eye washes (also called eye washes or eye washes; in addition, eye washes include eye washes that can be used when wearing contact lenses). It should be noted that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and non-ionic, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0064] From the perspective of being able to more significantly exert the effects brought about by the present invention, the ophthalmic composition involved in this embodiment is preferably an eye drop (including eye drops that can be instilled while wearing contact lenses). When the ophthalmic composition involved in this embodiment is an eye drop, its usage and dosage are not particularly limited as long as it is an usage and dosage that exerts the effect and has few side effects. For example, in the case of adults (over 15 years old) and children over 7 years old, the following method can be exemplified: 1 to 4 times, or 5 to 6 times a day, and 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops are used at a time.

[0065] 〔container〕

[0066] The ophthalmic composition according to the present embodiment is provided by being contained in a container (also simply referred to as a "plastic container") in which part or all of the portion in contact with the ophthalmic composition is formed of plastic.

[0067] 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 these, and mixtures of two or more thereof. Polyethylene (PE), polypropylene (PP), and cyclic olefin copolymer (COC) are preferred polymers constituting plastics. In addition, the plastic may contain an elastomer.

[0068] The plastic may contain additives such as stabilizers, etc. In addition, the plastic may be reinforced plastic containing reinforcing agents such as glass fibers.

[0069] As the plastic, commercially available ones can be used without particular limitation.

[0070] The plastic container for housing the ophthalmic composition may be a container commonly used in the ophthalmic field, and specifically, for example, may be an eye drop container or an eye wash container. The type of the container is preferably an eye drop container.

[0071] In the plastic container according to the present embodiment, part or all of the portion in contact with the ophthalmic composition is formed of plastic. For example, when the plastic container is a container having an open-hole plug (nozzle), only the open-hole plug portion may be formed of plastic, or the housing portion other than the open-hole plug may be formed of plastic, or the entire container may be formed of plastic.

[0072] The plastic container according to the present embodiment only needs to be partially formed of plastic in the portion in contact with the ophthalmic composition, but from the viewpoint of further significantly exerting the effect brought about by 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 a single type of plastic or may be formed of two or more types of plastic.

[0073] The shape and capacity of the container are not particularly limited and can be appropriately set according to the purpose. In addition, the container can be a container containing multiple doses of the ophthalmic composition (multiple dose container) or a container containing a single dose of the ophthalmic composition (single dose container).

[0074] When the container is a multi-dose container, the capacity may be, for example, 1.5 to 7.5 mL, 2 to 6 mL, or 2.5 to 5.0 mL. When the container is a single-dose container, the capacity may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.

[0075] The ophthalmic composition according to the present embodiment may be provided in the form of an ophthalmic composition in a container. In addition, the present invention may also be understood as an ophthalmic product (eye drops, etc.) containing the ophthalmic composition of the present invention in a container.

[0076] [2. Method for improving stability of tramadol or its salt in ophthalmic composition]

[0077] In one embodiment, when the ophthalmic composition containing (A) tramadol or a salt thereof is contained in a container formed of plastic, the stability of tramadol or a salt thereof in the ophthalmic composition is improved by adjusting the pH of the ophthalmic composition to 4.0 to 6.8. Therefore, as one embodiment of the present invention, there is provided a method for improving the stability of (A) tramadol or a salt thereof in the ophthalmic composition, the method comprising adjusting the pH of the ophthalmic composition containing (A) tramadol or a salt thereof contained in a container formed of plastic to 4.0 to 6.8.

[0078] The type and content of the component (A), the types and contents of other components, the formulation form and use of the ophthalmic composition in this method are as described in [1. Ophthalmic composition].

[0079] Example

[0080] Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited thereto. In addition, the unit of each component in the table is w / v% unless otherwise specified.

[0081] [Test Example 1: Influencing Factor (High Temperature) Test (Japanese: Thermal Overheating Test)]

[0082] With the composition shown in Tables 1 to 3, an ophthalmic composition was prepared according to a conventional method. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Then, the ophthalmic composition was filled in a glass ampoule and an eye dropper (material: polyethylene, polypropylene or COC, capacity: 5 mL), and stored under the conditions described in the upper column of the table. The content of tramadol hydrochloride contained in the ophthalmic composition just prepared and the ophthalmic composition after storage was quantified by HPLC, and the tramadol hydrochloride residual rate was calculated according to the following formula. In addition, for Test Examples 4 to 10, the residual improvement (%) was calculated based on the tramadol hydrochloride residual rate according to the following formula. The results are shown in Tables 1 to 3.

[0083] Tramadol hydrochloride residual rate (%) = (tramadol hydrochloride content of stored product / tramadol hydrochloride content immediately after preparation × 100)

[0084] Residual improvement of test examples 5 and 6 (%) = residual rate of each test example - residual rate of test example 4

[0085] Residual improvement of Test Example 8 (%) = Residual rate of Test Example 8 - Residual rate of Test Example 7

[0086] Residual improvement of Test Example 10 (%) = Residual rate of Test Example 10 - Residual rate of Test Example 9

[0087] [Table 1]

[0088]

[0089] [Table 2]

[0090]

[0091] [Table 3]

[0092]

[0093] When the ophthalmic composition containing tramadol hydrochloride is contained in a glass container, the residual rate of tramadol hydrochloride is highly stable at any pH. On the other hand, when the ophthalmic composition containing tramadol hydrochloride is contained in a polyethylene container or a COC container, a decrease in the residual rate of tramadol hydrochloride is observed at pH 6.9 to 7.0, but the stability of tramadol can be improved by setting the pH to 6.8 or less.

[0094] [Test Example 2: Influencing Factors (High Temperature) Test 2]

[0095] With the composition shown in Tables 4 to 6, an ophthalmic composition was prepared according to a conventional method. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Then, the ophthalmic composition was filled in an eye dropper (material: polyethylene, polypropylene, or polyethylene terephthalate, capacity: 5 mL) and stored under the conditions described in the upper column of the table. The content of tramadol hydrochloride contained in the ophthalmic composition just prepared and the ophthalmic composition after storage was quantified by HPLC, and the tramadol hydrochloride residual rate was calculated according to the following formula. In addition, for Test Examples 15 to 17 and 20 to 24, the residual improvement (%) was calculated based on the tramadol hydrochloride residual rate according to the following formula. The results are shown in Tables 4 to 6.

[0096] Tramadol hydrochloride residual rate (%) = (tramadol hydrochloride content of stored product / tramadol hydrochloride content immediately after preparation × 100)

[0097] Residual improvement of test examples 16 and 17 (%) = residual rate of test examples 16 and 17 - residual rate of test example 15

[0098] Residual improvement of test examples 21 to 23 (%) = residual rate of test examples 21 to 23 - residual rate of test example 20

[0099] [Table 4]

[0100]

[0101] [Table 5]

[0102]

[0103] [Table 6]

[0104]

[0105] When an ophthalmic composition containing tramadol hydrochloride is contained in a polyethylene container or a polypropylene container, a decrease in the residual rate of tramadol hydrochloride is observed at pH 8.0 or 1.0, but the stability of tramadol can be improved by setting the pH to 4.0 to 6.8. In addition, tramadol analogs (structure undetermined) were detected at pH 1.0, but no tramadol analogs were detected at pH 4.0 and 6.1.

Claims

1. An ophthalmic composition comprising tramadol or a salt thereof, wherein the pH of the ophthalmic composition is 4.0 to 6.8 and the composition is contained in a container in which part or all of a portion in contact with the ophthalmic composition is made of plastic.

2. The ophthalmic composition according to claim 1, wherein The plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymer.

3. The ophthalmic composition according to claim 1 or 2, further comprising a buffer.

4. The ophthalmic composition according to claim 1 or 2, wherein The content of tramadol or its salt is 0.01 w / v% to 10 w / v% based on the total amount of the ophthalmic composition.

5. A method for improving the stability of tramadol or a salt thereof in an ophthalmic composition, the method comprising: The pH of the ophthalmic composition containing tramadol or a salt thereof contained in a plastic container is adjusted to 4.0 to 6.

8.

6. The method of claim 5, wherein: The plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymer.

7. The method according to claim 5 or 6, wherein: The ophthalmic composition also contains a buffer.

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