Ophthalmic composition

Abstract

The present invention relates to ophthalmic compositions containing tramadol or a salt thereof and substantially free of preservatives.

Description

Technical Field

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

[0002] Generally, multiple doses (multiple doses) of eye drops contain preservatives, which prevent the eye drops from being contaminated by microorganisms such as bacteria and fungi, and have the effect of inhibiting the proliferation of microorganisms. On the other hand, the following situation has been reported: preservatives also contain cytotoxic components, and frequent or long-term use of eye drops containing preservatives can cause corneal epithelial damage. Therefore, there is a need for a prescription design of eye drops that inhibits the proliferation of microorganisms and reduces the risk of corneal epithelial damage without using preservatives.

[0003] As a formulation design of such preservative-free eye drops, a technique of blending a zinc salt such as zinc chloride into an ophthalmic composition has been reported (for example, Patent Document 1).

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent Application No. 2010-504358 Summary of the invention

[0007] Problems to be solved by the invention

[0008] An object of the present invention is to provide a novel ophthalmic composition having excellent preservative efficacy without using a preservative and / or a novel ophthalmic composition having further improved preservative efficacy while containing a preservative.

[0009] Means for solving problems

[0010] The inventors of the present application have conducted intensive studies to solve the above-mentioned problems and have found that the preservation efficacy of an ophthalmic composition is unexpectedly significantly enhanced by adding tramadol, a non-narcotic analgesic classified as a weak opioid and used as a systemic analgesic for cancer pain and the like, to the ophthalmic composition. The present invention is based on this finding and provides the following inventions. [1]

[0012] An ophthalmic composition comprising tramadol or a salt thereof and containing substantially no preservative. [2]

[0014] An ophthalmic composition characterized in that it is an ophthalmic composition contained in a multi-dose container and contains tramadol or a salt thereof, tramadol or a salt thereof has a preservative effect, and an ophthalmic composition containing the same amount of the same components as the ophthalmic composition except that tramadol or a salt thereof is not contained does not have a preservative effect (however, an ophthalmic composition containing a preservative is not included). [3]

[0016] An ophthalmic composition characterized in that it is contained in a multi-dose container and contains tramadol or a salt thereof, wherein tramadol or a salt thereof exhibits an antiseptic effect, and an antiseptic effect higher than that of an ophthalmic composition containing the same amount of the same components as the ophthalmic composition except that tramadol or a salt thereof is not contained. [4]

[0018] 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]

[0020] The ophthalmic composition according to any one of [1] to [4], further comprising a buffer. [6]

[0022] A method for enhancing the preservation efficacy of an ophthalmic composition, the method comprising formulating tramadol or a salt thereof in the ophthalmic composition which does not contain a preservative.

[0023] Effects of the Invention

[0024] According to the present invention, it is possible to provide a novel ophthalmic composition having excellent preservative efficacy without using a preservative and / or a novel ophthalmic composition having further improved preservative efficacy while containing a preservative. DETAILED DESCRIPTION

[0025] Hereinafter, the mode for implementing the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0026] In the present specification, unless otherwise specified, the unit "%" of content means "w / v%", which has the same meaning as "g / 100 mL".

[0027] [1. Ophthalmic composition]

[0028] The ophthalmic composition according to the present embodiment contains (A) tramadol or a salt thereof (abbreviated as “component (A)”).

[0029] [(A) Ingredient]

[0030] Tramadol is a known compound represented by the following formula:

[0031] [Chemical formula 1]

[0032]

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] The content of the component (A) in the ophthalmic composition of the present embodiment is not particularly limited and can be appropriately set according to the types and contents of other ingredients, the form of the preparation, etc. The content of the component (A) can be 0.5 w / v% or more, 1 w / v% or more, 2 w / v% or more, 3 w / v% or more, or 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 1 w / v% to 3 w / v%, based on the total amount of the ophthalmic composition of the present embodiment.

[0038] The ophthalmic composition involved in the present embodiment may be substantially free of preservatives. In this specification, "preservative" refers to an ingredient that exerts a preservative effect. In this specification, "substantially free of preservatives" means that no preservatives are contained at all, or that the amount of preservatives contained is less than that required to exert a preservative effect. In this specification, "exhibiting a preservative effect" means that the ophthalmic composition containing the substance meets the standards in the preservation effectiveness test method specified in the 18th revised edition of the Japanese Pharmacopoeia. In this specification, "high preservation effectiveness" means that the preservation effectiveness based on the preservation effectiveness test method specified in the 18th revised edition of the Japanese Pharmacopoeia is improved.

[0039] As preservatives, for example, alkyl polyaminoethyl glycines, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), polychloridium chloride, sodium benzoate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, hydroxyquinoline sulfate, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide hydrochloride), chlorhexidine gluconate, alexidine, etc.), etc. can be cited. 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 completely free of preservatives. It should be noted that metal salts such as zinc salts (zinc chloride, etc.) and silver salts (silver nitrate, etc.) are not included in the "preservatives" of this specification.

[0040] 〔Buffer〕

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] As the buffer, a commercially available one may be used. The buffer may be used alone or in combination of two or more.

[0046] 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%.

[0047] 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.

[0048] 〔Inorganic salts〕

[0049] 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.

[0050] 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.

[0051] As the inorganic salt, commercially available ones can be used. The inorganic salt can be used alone or in combination of two or more.

[0052] The content of inorganic salts in the aqueous composition of 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 aqueous 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%.

[0053] The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within the range permitted medically, pharmacologically (pharmaceutically) or physiologically. The pH of the ophthalmic composition according to the present embodiment may be, for example, 4.5 to 7.5, preferably 5.0 to 7.0, and more preferably 5.5 to 6.5.

[0054] 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.

[0055] 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).

[0056] 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.

[0057] 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.).

[0058] 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).

[0059] 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.

[0060] The ophthalmic composition involved in the present embodiment is provided in an arbitrary container. There is no particular limitation on the container for accommodating the ophthalmic composition involved in the present embodiment, for example, it can be made of glass, or it can be made of plastic. It is preferably made of plastic. As plastic, for example, 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), and copolymers of monomers constituting them, and materials obtained by mixing two or more of them.

[0061] The 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.

[0062] 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).

[0063] 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.

[0064] 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.

[0065] [2. Method for enhancing the preservation efficacy of ophthalmic compositions]

[0066] The ophthalmic composition according to the present embodiment contains (A) tramadol or a salt thereof, thereby enhancing the preservation efficacy without a preservative. Therefore, as one embodiment of the present invention, a method for enhancing the preservation efficacy of an ophthalmic composition is provided, the method comprising adding (A) tramadol or a salt thereof to an ophthalmic composition that does not contain a preservative.

[0067] 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].

[0068] Example

[0069] 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.

[0070] [Test Example 1: Preservation Effectiveness Test]

[0071] An ophthalmic composition was prepared according to a conventional method with the composition shown in Table 1. Each prepared ophthalmic composition was filtered and sterilized using a 0.2 μm membrane filter. The preservation efficacy of each ophthalmic composition was evaluated in accordance with the preservation efficacy test method specified in the 18th revised edition of the Japanese Pharmacopoeia. Specifically, Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Pseudomonas aeruginosa (Pseudomonas aeruginosa) were inoculated on the surface of soybean casein digest agar medium and cultured at 30-35°C for 24 hours. The cultured bacteria were aseptically collected using a platinum inoculation loop and suspended in an appropriate amount of sterile saline to prepare a 1×107 CFU / mL of viable bacteria. 5 After adding to each preparation in the form of CFU / mL, it was left to stand at 20-25°C for 7 days. Then, the bacteria were recovered according to the agar pouring method, and after standing at 30-35°C for 2-3 days, the number of viable bacteria per 1mL of each ophthalmic composition was measured. Based on the measured value, the log reduction value was calculated, and the preservation efficacy was determined according to the preservation efficacy test method (preparation category IA). The results are shown in Table 1.

[0072] [Table 1]

[0073]

[0074] In Comparative Examples 1 to 4 in which tramadol hydrochloride was not added, the preservation efficacy was extremely weak. On the other hand, it was confirmed that in Examples 1 to 4 in which tramadol hydrochloride was added, the preservation efficacy was significantly enhanced compared with Comparative Examples 1 to 4.

Claims

1. An ophthalmic composition comprising tramadol or a salt thereof and containing substantially no preservative.

2. An ophthalmic composition, characterized in that An ophthalmic composition contained in a multi-dose container and containing tramadol or a salt thereof, wherein tramadol or a salt thereof has a preservative effect, and an ophthalmic composition containing the same amount of the same components as the ophthalmic composition except that tramadol or a salt thereof is not contained has no preservative effect, Wherein, the ophthalmic composition does not include an ophthalmic composition containing a preservative.

3. An ophthalmic composition, characterized in that An ophthalmic composition contained in a multi-dose container and containing tramadol or a salt thereof has a preservative effect of tramadol or a salt thereof, and has a higher preservative effect than an ophthalmic composition containing the same amount of the same components as the ophthalmic composition except that tramadol or a salt thereof is not contained.

4. The ophthalmic composition according to any one of claims 1 to 3, 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 . The ophthalmic composition according to claim 1 , further comprising a buffer.

6. A method for enhancing the preservation efficacy of an ophthalmic composition, the method comprising formulating tramadol or a salt thereof in the ophthalmic composition.

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