Ophthalmic composition

Abstract

The present invention relates to an ophthalmic composition containing tramadol or a salt thereof. The ophthalmic composition is stored in a container in which some or all of a portion that contacts the ophthalmic composition is formed from a plastic, and the container, which is molded via a blow-fill-seal process, is filled with the ophthalmic composition.

Description

Ophthalmic composition

[0001] The present invention relates to ophthalmic compositions.

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

[0003] Tramal (registered trademark) Injection 100 package insert

[0004] On the other hand, when tramadol is used as a therapeutic agent for ophthalmic diseases, it is required that the amount of impurities derived from tramadol in the ophthalmic formulation is less than a certain amount, but no findings regarding impurities derived from tramadol in ophthalmic formulations containing tramadol have been reported so far. An object of the present invention is to provide a novel tramadol-containing ophthalmic composition in which the amount of impurities derived from tramadol is reduced.

[0005] The present inventors have found for the first time that when a tramadol-containing ophthalmic composition is filled into a plastic container simultaneously with molding by the blow-fill-seal method, the amount of tramadol-derived impurities is reduced regardless of the tramadol content in the ophthalmic composition. The present invention is based on this finding and provides the following inventions.

[0006] [1] An ophthalmic composition containing tramadol or a salt thereof, the ophthalmic composition being contained in a container in which a part or all of the portion that comes into contact with the ophthalmic composition is made of plastic, and the ophthalmic composition is filled in the container molded by the blow-fill-seal method. [2] The ophthalmic composition according to [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 [1] or [2], further comprising a buffer.

[0007] According to the present invention, it is possible to provide a novel tramadol-containing ophthalmic composition in which the amount of tramadol-derived impurities is reduced.

[0008] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0009] In this specification, unless otherwise specified, the unit of content "%" means "w / v %" and is synonymous with "g / 100 mL".

[0010] The ophthalmic composition according to this embodiment contains (A) tramadol or a salt thereof (also simply referred to as "component (A)").

[0011] [Component (A)] Tramadol is a compound represented by the following formula: It is a known compound represented by the formula: Although the above formula conveniently shows one of the enantiomers, other enantiomers are also included in the present invention.

[0012] The salt of tramadol is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical), 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 basic amino acids, etc.

[0013] 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, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt, 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, glutamic acid, 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 hydrochloride is more preferred.

[0014] The ophthalmic composition according to this embodiment contains tramadol or a salt thereof as an active ingredient, and can be used, for example, to suppress pain.

[0015] From the viewpoint of more significantly achieving the effects of the present invention, the content of component (A) may 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 this embodiment.

[0016] [Buffering Agent] The ophthalmic composition according to this embodiment may further contain a buffering agent. When the ophthalmic composition further contains a buffering agent, the effects of the present invention are more pronounced. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of the buffering agent include inorganic buffering agents derived from inorganic acids, and organic buffering agents derived from organic acids or organic bases.

[0017] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). Furthermore, hydrates of borate, phosphate, or carbonate may be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples of the borate buffer include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffer includes phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffer includes carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).

[0018] Examples of organic buffers include citrate buffers, acetate buffers, lactate buffers, succinate buffers, Tris buffers, and AMPD buffers. Examples of citrate buffers include citric acid or salts thereof (alkali metal citrates, alkaline earth metal citrates, etc.). Examples of acetate buffers include acetic acid or salts thereof (alkali metal acetates, alkaline earth metal acetates, etc.). Examples of lactate buffers include lactic acid or salts thereof (alkali metal lactates, alkaline earth metal lactates, etc.). Examples of succinate buffers include succinic acid or salts thereof (alkali metal succinates, etc.). Furthermore, hydrates of citrate, acetate, lactate, or succinate may be used as citrate buffers, acetate buffers, lactate buffers, or succinate buffers. More specific examples of the citrate buffer include citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid buffer includes acetic acid or a salt thereof (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); lactic acid buffer includes lactic acid or a salt thereof (sodium lactate, potassium lactate, calcium lactate, etc.); and succinic acid buffer includes succinic acid or a salt thereof (monosodium succinate, disodium succinate, etc.). An example of a Tris buffer is trometamol or a salt thereof (trometamol hydrochloride, etc.). An example of an AMPD buffer is 2-amino-2-methyl-1,3-propanediol or a salt thereof.

[0019] As the buffer, boric acid buffer, phosphate buffer and citrate buffer are preferred, boric acid buffer and phosphate buffer are more preferred, and boric acid or a salt thereof, and phosphoric acid or a salt thereof are even more preferred.

[0020] The buffering agent may be a commercially available product. One type of buffering agent may be used alone, or two or more types may be used in combination.

[0021] The content of the buffering agent in the ophthalmic composition according to this embodiment is not particularly limited and is appropriately set depending on the type of buffering agent, the types and contents of other ingredients, the intended use and formulation of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the buffering agent is, for example, 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 % based on the total amount of the ophthalmic composition. When the buffering agent is a borate buffer, the content is preferably 0.01 w / v % to 10 w / v %, more preferably 0.05 w / v % to 5 w / v %, even more preferably 0.1 w / v % to 3 w / v %, and particularly preferably 0.5 w / v % to 2 w / v %. When the buffer is a citrate buffer or a phosphate buffer, the concentration is preferably 0.01 w / v% to 10 w / v%, more preferably 0.05 w / v% to 5 w / v%, even more preferably 0.1 w / v% to 3 w / v%, even more preferably 0.1 w / v% to 1 w / v%, and particularly preferably 0.1 w / v% to 0.3 w / v%.

[0022] The content ratio of the buffering agent relative to the component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the types of component (A) and buffering agent, the types and contents of other blended components, the intended use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent relative to the component (A) may 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 per 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to this embodiment.

[0023] [Inorganic Salts] The ophthalmic composition according to this embodiment may further contain an inorganic salt. When the ophthalmic composition further contains an inorganic salt, the effects of the present invention are more pronounced. The inorganic salt is not particularly limited as long as it is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.

[0024] Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc. Of the inorganic salts, sodium chloride and potassium chloride are preferred.

[0025] The inorganic salts may be commercially available. One type of inorganic salt may be used alone, or two or more types may be used in combination.

[0026] The content of inorganic salts in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of inorganic salt, the types and contents of other blended components, the intended use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of inorganic salts is, for example, preferably 0.00001 w / v % to 3 w / v %, more preferably 0.0001 w / v % to 2 w / v %, and even more preferably 0.001 w / v % to 1.5 w / v %, based on the total amount of the ophthalmic composition.

[0027] [Preservative] The ophthalmic composition according to this embodiment may not contain a preservative, but may further contain one.

[0028] Examples of preservatives include biguanide-based preservatives such as chlorhexidine, alexidine, polyhexanide, and salts thereof; quaternary ammonium salt-based preservatives such as benzalkonium chloride and benzethonium chloride; and paraben-based preservatives such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0029] As the preservative, from the viewpoint of exhibiting the effects of the present invention more significantly, a biguanide-based preservative is preferred, chlorhexidine or a salt thereof is more preferred, and chlorhexidine gluconate is even more preferred.

[0030] The preservatives may be commercially available ones. The preservatives may be used alone or in combination of two or more kinds.

[0031] The content of the preservative in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of preservative, the types and contents of other ingredients, the intended use and formulation of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the preservative is preferably 0.00001 w / v% to 2 w / v%, more preferably 0.00005 w / v% to 1 w / v%, and particularly preferably 0.00008 w / v% to 0.8 w / v% based on the total amount of the ophthalmic composition. In other embodiments, 0.00005 w / v% to 0.5 w / v%, or 0.0001 w / v% to 0.025 w / v% can also be presented as preferred contents.

[0032] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the aqueous composition according to this embodiment may be, for example, 4.5 to 7.5, preferably 5.0 to 7.0, and more preferably 5.5 to 6.5.

[0033] The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio can be appropriately determined depending on the intended use, formulation, and method of use of the ophthalmic composition, but can be, for example, 0.4 to 5.0. The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) according to the 18th Revised Japanese Pharmacopoeia. The osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the dried solution, and dissolving it in purified water to make exactly 100 mL. Alternatively, a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used.

[0034] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. For example, the viscosity of the ophthalmic composition according to this embodiment may be 1 to 10,000 mPa s at 20°C measured using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).

[0035] The ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing the component (A) and, if necessary, other components to a desired content. Specifically, the composition can be prepared, for example, by dissolving or suspending the components in purified water and sterilizing the mixture by filtration or the like.

[0036] The ophthalmic composition according to this embodiment can be in various dosage forms depending on the purpose, and examples thereof include liquids, gels, semi-solids (ointments, etc.), and the like.

[0037] When the ophthalmic composition according to this embodiment is a liquid formulation, it can be used, for example, as eye drops (also called eye drops or eye drops; eye drops include eye drops that can be applied while wearing contact lenses) or artificial tears. The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic contact lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0038] The ophthalmic composition according to this embodiment is preferably an eye drop (including an eye drop that can be applied while wearing contact lenses), as this allows the effects of the present invention to be more significantly exhibited. When the ophthalmic composition according to this embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and cause few side effects. For example, for adults (15 years of age or older) and children aged 7 years or older, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops are applied 1 to 4 times or 5 to 6 times a day.

[0039] [Container] The ophthalmic composition according to this embodiment is provided in a container (also simply referred to as a "plastic container") in which part or all of the parts that come into contact with the ophthalmic composition are made of plastic.

[0040] 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 of these. Preferred polymers constituting plastics are polyethylene (PE), polypropylene (PP), and cyclic olefin copolymer (COC). Plastics may also contain elastomers.

[0041] The plastic may contain additives such as stabilizers, etc. The plastic may also be reinforced by including reinforcing agents such as glass fibers.

[0042] Any commercially available plastic can be used without any particular restrictions.

[0043] The plastic container for containing the ophthalmic composition may be a container commonly used in the ophthalmic field, and is preferably an eye drop container.

[0044] In the plastic container according to the present embodiment, it is sufficient that only a portion of the portion that comes into contact with the ophthalmic composition is made of plastic, but from the viewpoint of more significantly achieving the effects of the present invention, it is preferable that the entire portion that comes into contact with the ophthalmic composition is made of plastic. Furthermore, the plastic container may be made of a single type of plastic or two or more types of plastic.

[0045] The shape and capacity of the container are not particularly limited and may be appropriately determined depending on the intended use. The container may be a container that contains an amount of the ophthalmic composition for multiple uses (multi-dose container) or a container that contains an amount of the ophthalmic composition for a single use (unit dose container).

[0046] 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 unit-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.

[0047] The plastic container containing the ophthalmic composition according to this embodiment can be manufactured by the blow-fill-seal (BFS) method (see, for example, International Publication No. 2004 / 093775). First, a parison is produced by extrusion molding a plastic. Next, the resulting parison is sandwiched between split molds, and each part of the container body is molded by either forcing air into the interior or by suctioning the parison through vacuum holes installed on the mold surface (blowing process), and the ophthalmic composition is filled into the storage part (filling process). Finally, the container is sandwiched between split molds to form a lid, and the opening of the spout is sealed (sealing process), thereby completing the manufacturing process. The blowing process and filling process may be performed sequentially or simultaneously.

[0048] The ophthalmic composition according to this embodiment may also be provided as a container-packaged ophthalmic composition. The present invention can also be understood as an ophthalmic product (e.g., eye drops) in which the ophthalmic composition of the present invention is contained in a container.

[0049] The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. Unless otherwise specified, the unit of each component in the tables is w / v %.

[0050] Test Example: Severe Heat Test Ophthalmic compositions were prepared according to a conventional method using the compositions shown in Table 1. Each prepared ophthalmic composition was sterilized by filtration through a 0.2 μm membrane filter. Comparative Examples 1 and 2 were prepared by filling eye dropper bottles (material: polyethylene, capacity: 5 mL) that had been previously sterilized by electron beam sterilization in a conventional manner with the ophthalmic compositions. Examples 1 to 4 were prepared by filling eye dropper bottles (material: polyethylene or a mixed resin of polyethylene / cyclic olefin copolymer (COC) and capacity: 0.5 mL) manufactured by the blow-fill-seal (BFS) method with the ophthalmic compositions. The eye dropper bottles containing the ophthalmic compositions of the Comparative Examples and Examples were stored under light-protected conditions at 50°C for one month. The content of impurities (tramadol analogues) in the ophthalmic compositions after storage was measured by HPLC, and the production rate (%) of tramadol analogues relative to the amount of tramadol hydrochloride was calculated. The reduction rate of tramadol analogues was calculated from the calculated production rates of tramadol analogues according to the following formula. The results are shown in Table 1. Reduction rate of tramadol analogues (%) in Examples 1 and 2 = {100 x (production rate of Comparative Example 1 - production rate of each Example)} / production rate of Comparative Example 1 Reduction rate of tramadol analogues (%) in Examples 3 and 4 = {100 x (production rate of Comparative Example 2 - production rate of each Example)} / production rate of Comparative Example 2

[0051]

[0052] When an ophthalmic composition containing tramadol hydrochloride was filled into a plastic container by a conventional method, it was confirmed that tramadol analogues were produced as shown in the comparative examples. On the other hand, when the composition was filled into a plastic container by the blow-fill-seal method, it was confirmed that the amount of tramadol analogues was significantly reduced and tramadol hydrochloride was stably present as shown in the examples.

Claims

1. An ophthalmic composition containing tramadol or a salt thereof, which is housed in a container in which part or all of the portion in contact with the ophthalmic composition is formed of plastic, and the ophthalmic composition is filled in the container formed by the blow-fill-seal method.

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 containing a buffering agent.

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