Pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition that, despite containing rebamipide, exhibits excellent transparency and high stability. [Solution] A pharmaceutical composition containing rebamipide, amino sugar, a solubilizer, a buffer, and an organic acid.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing levamisole.

Background Art

[0002] Levamisole eye drops are used for the treatment of dry eye according to the dosage regimen of "usually 1 drop once and instill 4 times a day". Currently available eye drops in Japan are suspensions in which the drug (levamisole) is dispersed in water because levamisole is hardly soluble in water. Since it is a suspension in which the drug has precipitated, when administering, it is necessary to shake the eye drop container well and then disperse the drug before instilling it, which is very inconvenient. In addition, being a suspension causes fogging where the vision becomes white and cloudy immediately after instillation, which may continue for several minutes or more, making it difficult for patients to use.

[0003] Furthermore, there are also restrictions on the storage method. The orientation of the eye drop opening during storage is specified so that the drug does not become difficult to disperse, and it cannot be stored with the opening facing downwards. Therefore, despite the need to instill the eye drops 4 times a day, great care is required for the storage and transportation of the drug.

[0004] Since suspensions tend to be non-uniform, in multi-dose eye drop containers, even if sufficient redispersion is repeated, variations may occur in the amount of drug during instillation, and there is a possibility that the therapeutic effect cannot be effectively exerted. For patients with dry eye, the addition of preservatives that may be harmful to corneal injury is not desirable. Therefore, a single-use eye drop container is used to solve this problem, and products that do not require preservatives such as silver nitrate are available on the market.

[0005] However, rebamipide needs to be instilled four times a day, and coupled with the fact that the container must be stored in a specific orientation, the single-use container results in a large number of individual drops, making it inconvenient to use and carry. Furthermore, single-use eye drop containers are disposable formulations, and any remaining liquid must be discarded after instillation, increasing waste and not desirable from an SDG perspective. While there are commercially available products that allow for multiple doses, they not only contain preservatives but are also suspensions that require redispersion. Although the inconvenience of carrying them is resolved, the redispersion makes them difficult to use, and there is a risk of corneal damage from preservatives, which is not desirable for patients.

[0006] Various eye drops containing rebamipide have been proposed. Specifically, a pharmaceutical composition containing rebamipide, amino sugar (meglumine), and a buffer (boric acid), but without inorganic cations, is a pharmaceutical composition that meets the preservation efficacy test, exhibits good redispersibility, and has improved transparency (Patent Document 1). A pharmaceutical composition containing rebamipide, meglumine, boric acid, and a preservative (zinc compound) meets the preservation efficacy test and achieves excellent redispersibility and transparency (Patent Document 2). By using a cyclodextrin derivative and / or an amino acid and a buffer as a recrystallization inhibitor, a transparent eye drop composition containing rebamipide can be obtained (Patent Document 3). A water-soluble, multi-dose eye drop composition for the treatment of dry eye containing rebamipide with added paraben preservatives and chelating agents (stabilizers) does not form precipitates during storage (Patent Document 4). A multi-dose eye drop solution obtained by adding silver nitrate to an aqueous suspension containing rebamipide meets the preservation efficacy test (Patent Document 5). [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Special Publication No. 2011-524854 [Patent Document 2] Special Publication No. 2015-531338 [Patent Document 3] Special Publication No. 2018-531934 [Patent Document 4] Japanese Patent Publication No. 2020-002123 [Patent Document 5] Japanese Patent Publication No. 2022-087168 [Overview of the project] [Problems that the invention aims to solve]

[0008] However, these methods had questionable safety and effectiveness, as they required redispersion, lacked sufficient transparency, contained preservatives unsuitable for dry eye, or had low concentrations of rebamipide that could be dissolved, and did not always fully satisfy the desired effect. Therefore, there was a strong desire to develop eye drops that contained rebamipide at a therapeutically effective concentration in a clear solution, did not cause temporary blurring of vision after instillation, did not require redispersion, and could be administered multiple times without the need for preservatives.

[0009] Therefore, the object of the present invention is to provide a pharmaceutical composition that has excellent transparency despite containing rebamipide, while also having high stability. [Means for solving the problem]

[0010] As a result of diligent research by the inventors, we discovered that a pharmaceutical composition containing rebamipide, amino sugar, a solubilizer, a buffer, and an organic acid (excluding amino acids) exhibits excellent transparency and high stability, thus completing the present invention.

[0011] In other words, the present invention provides the following inventions [1] to

[14] . [1] A pharmaceutical composition containing rebamipide, amino sugars, a solubilizer, a buffer, and an organic acid (excluding amino acids). [2] The pharmaceutical composition according to [1], comprising 1-3 w / v% of rebamipide. [3] A pharmaceutical composition according to [1] or [2], comprising 3.5 to 12 w / v% amino sugars. [4] A pharmaceutical composition according to any one of [1] to [3], comprising 0.05 to 5 w / v% of a solubilizer. [5] A pharmaceutical composition according to any one of [1] to [4], comprising 0.1 to 2.5 w / v% of a buffering agent. [6] A pharmaceutical composition according to any one of [1] to [5], comprising 0.6 to 1.2 w / v% of an organic acid. [7] Furthermore, a pharmaceutical composition according to any one of [1] to [6], comprising an amino acid. [8] The pharmaceutical composition described in [7], comprising 0.05 to 0.4 w / v% of amino acids. [9] A pharmaceutical composition according to any one of [1] to [8], wherein the pH is 7 to 9.

[10] A pharmaceutical composition according to any one of [1] to [9], which is substantially free of preservatives.

[11] A pharmaceutical composition according to any one of [1] to

[10] , which is in liquid form.

[12] A pharmaceutical composition according to any one of [1] to

[11] for the treatment of dry eye by local administration to the eye. An eye drop containing one of the pharmaceutical compositions described in

[13] , [1], or

[12] , in a single-dose container. An eye drop containing a pharmaceutical composition described in any one of

[14] [1] to

[12] , filled into a multi-dose container. [Effects of the Invention]

[0012] The present invention provides a pharmaceutical composition that is transparent, free from the risk of fog, and possesses high stability.

[0013] Furthermore, depending on the composition, this pharmaceutical composition exhibits excellent safety and storage stability even without the addition of preservatives, making it suitable for use in multiple doses. [Modes for carrying out the invention]

[0014] The pharmaceutical composition of the present invention contains rebamipide, amino sugar, a solubilizer, a buffer, and an organic acid (excluding amino acids).

[0015] The levamiside used in the pharmaceutical composition of the present invention has the molecular formula: C

[0016] H 15 ClN2O4 and a molecular weight of 370.79, which is a quinolinone derivative. Since it promotes the production of mucin, which is a component of tears, and stabilizes the state of tears, thereby improving corneal epithelial disorders, it is used for the treatment of "dry eye" as an active ingredient of eye drops.

[0016] The concentration of levamiside in the pharmaceutical composition of the present invention varies depending on the dosage form and is not particularly limited. For example, in the case of a liquid dosage form such as eye drops, it is preferably 1 - 3 w / v%, more preferably 1.5 - 2.5 w / v%, and particularly preferably 2 w / v%. In this specification, 1 w / v% means containing 1 g of the component per 100 ml.

[0017] The amino sugar used in the pharmaceutical composition of the present invention is not particularly limited. For example, meglumine, D - glucosamine, D - galactosamine, D - mannosamine, mycaminose, canosamine, neosamine C, N - methyl - L - glucosamine, mycarose, muramic acid, streptamine, etc. can be mentioned. These amino sugars can be used alone or in combination of two or more. Among these, meglumine is preferred.

[0018] The concentration of amino sugar in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 3 - 12 w / v%, more preferably 3.5 - 10 w / v%, and particularly preferably 4 - 8 w / v%.

[0019] The solubilizer used in the pharmaceutical composition of the present invention is not particularly limited, but examples include polysorbate 80, polyvinylpyrrolidone (povidone), polyethylene glycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, and polyoxyl stearate 40. One or more of these solubilizers can be used. Among these, polyvinylpyrrolidone is preferred. Furthermore, among polyvinylpyrrolidones, those with a K value (viscosity characteristic value) of K12, K17, K25, or K30 are preferred. The viscosity characteristic value can be measured by conventional methods.

[0020] The concentration of the solubilizer in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.5 to 2 w / v%.

[0021] The buffering agents used in the pharmaceutical composition of the present invention are not particularly limited, but examples include sodium citrate hydrate, sodium acetate hydrate, sodium bicarbonate, trometamol, boric acid, borax, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate. One or more of these buffering agents can be used. Among these, it is preferable to use at least boric acid, and it is preferable to use boric acid and trometamol.

[0022] The concentration of the buffer in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.1 to 2.5 w / v%, and more preferably 0.5 to 1.5 w / v%. When boric acid is used as the buffer, its concentration is preferably 0.1 to 2 w / v%, more preferably 0.5 to 2 w / v%, and particularly preferably 0.5 to 1.5 w / v%. When boric acid and trometamol are used simultaneously as buffers, the concentration of trometamol, in addition to the boric acid, is preferably 0.05 to 1 w / v%, and more preferably 0.1 to 0.5 w / v%. When boric acid and trometamol are used simultaneously, it is preferable to use the same amount of boric acid as trometamol, or in greater quantities. Therefore, when using boric acid and trometamol, their mass ratio is preferably 1 to 15, more preferably 3 to 13, and particularly preferably 4 to 11. Furthermore, when using trometamol, the mass ratio of amino sugar to trometamol is preferably 21 to 120, more preferably 22.8 to 120, and particularly preferably 25 to 100.

[0023] The organic acids used in the pharmaceutical composition of the present invention are not particularly limited, but examples include monocarboxylic acid salts (e.g., acetic acid, trifluoroacetic acid, butyric acid, palmitic acid, stearic acid, etc.), polycarboxylic acids (e.g., fumaric acid, maleic acid, succinic acid, malonic acid, etc.), oxycarboxylic acids (lactic acid, tartaric acid, citric acid, etc.), and organic sulfonic acids (methanesulfonic acid, toluenesulfonic acid, tosylic acid, etc.). One or more of these organic acids can be used. Among these, it is preferable to use polycarboxylic acids such as fumaric acid, maleic acid, succinic acid, and malonic acid, and succinic acid is particularly optimal for improving the preservative effect of the pharmaceutical composition containing rebamipide. Note that the organic acids used in the present invention do not contain amino acids.

[0024] The concentration of the organic acid in the pharmaceutical composition of the present invention is not particularly limited, but for example, 0.1 to 3 w / v is preferred, 0.6 to 1.2 w / v% is more preferred, 0.7 to 1.2 w / v% is even more preferred from the viewpoint of preservation efficacy, and 1.0 to 1.2 w / v% is particularly preferred.

[0025] In addition to the above-mentioned rebamipide, amino sugar, solubilizer, buffer, and organic acid, the pharmaceutical composition of the present invention may further contain amino acids. The amino acids are not particularly limited, but examples include alanine, aspartic acid, glutamic acid, and arginine. One or more of these amino acids can be used. Among these amino acids, glutamic acid is preferred.

[0026] The concentration of amino acids in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.01 to 0.5 w / v%, and more preferably 0.05 to 0.4 w / v%. When the pharmaceutical composition of the present invention contains amino acids and boric acid and trometamol are used simultaneously as buffers, the concentrations and mass ratios of boric acid and trometamol are preferably within the same range as described above. Furthermore, the mass ratio of amino sugars to trometamol is also preferably within the above range.

[0027] The pH of the pharmaceutical composition of the present invention is not particularly limited, but in order to maintain the solubility of rebamipide and not irritate the cornea of ​​patients with dry eye, a pH of 7 to 9 is preferred, 7 to 8 is more preferred, and 7.5 to 7.9 is particularly preferred.

[0028] The pharmaceutical composition of the present invention may also contain, in addition to the above-mentioned rebamipide, amino sugars, solubilizers, buffering agents, organic acids, amino acids, etc., one or more pharmaceutical additives that can be commonly used in pharmaceutical preparations, such as solubilizers, stabilizers, isotonic agents, buffering agents, pH adjusters, viscosity modifiers, etc., as long as they do not impair the effects of the present invention. Specific examples of these additives are listed in the Pharmaceutical Additives Dictionary 2021 (edited by the Japan Pharmaceutical Additives Association, Yakuji Nippo Co., Ltd.), Yakushokuhatsu No. 1204-1 (Pharmaceutical Administration Laws and Regulations), and the website of the Japan Pharmaceutical Additives Association (http: / / www.jpec.gr.jp / ).

[0029] The pharmaceutical composition of the present invention is not particularly limited in dosage form, but it is preferably an aqueous liquid that can be produced by adding the pharmaceutical composition and, if necessary, the above-mentioned additives to purified water, stirring and dissolving them, and specifically, an eye drop. The eye drop is preferably used for the treatment of dry eye by topical administration to the eye. In the above production, heating or cooling may be performed as necessary, and known methods and apparatus can be used for heating or cooling.

[0030] The pharmaceutical composition of the present invention meets the requirements for preservative efficacy testing based on its composition, and therefore does not require preservatives; it is preferable that it does not contain preservatives. Examples of preservatives used in eye drops include benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, sorbic acid, zinc compounds, and silver nitrate. However, since the present invention does not contain these, the possibility of corneal damage in patients with dry eye can be significantly reduced.

[0031] The pharmaceutical composition of the present invention is provided as eye drops, filled into an eye drop container. The eye drop container is not particularly limited, but examples include single-use, disposable containers and multi-dose containers. Among these containers, multi-dose containers are preferred, as they improve convenience and cost-effectiveness, such as ease of carrying.

[0032] The eye drops containing the pharmaceutical composition of the present invention obtained in this way can be used to treat dry eye by instilling them once or multiple times a day. Furthermore, despite containing rebamipide, these eye drops have excellent transparency and high stability. Here, transparency means that when the prepared eye drops are kept at room temperature, they can be visually confirmed to be colorless to slightly yellowish and clear at the time of preparation (initial stage), and no visual change can be confirmed even after standing at room temperature for 24 hours after preparation. Stability means that when the prepared eye drops are stored at a high temperature such as 60°C, they can be visually confirmed to be colorless to slightly yellowish and clear at the time of preparation (initial stage), no visual change can be confirmed even after 1 month of storage, and the pH change is ±0.5.

[0033] One aspect of the present invention is an eye drop solution obtained by dissolving the following pharmaceutical composition in purified water and filling it into a multi-dose container. This eye drop solution has excellent transparency and high stability. Rebamipide: 1-3 w / v% Amino sugars: 2-12 w / v% Solubilizer: 0.1~3 w / v% Buffering agent: 0.1~2.5 w / v% Organic acid: 0.1~3w / v

[0034] One aspect of the present invention is an eye drop solution obtained by dissolving the following pharmaceutical composition in purified water and filling it into a multi-dose container. This eye drop solution has excellent transparency and high stability. Rebamipide: 1-3 w / v% Amino sugars: 2-12 w / v% Solubilizer: 0.1~3 w / v% Buffering agent: 0.1~2.5 w / v% Organic acid: 0.1~3w / v Amino acids: 0.01~0.5 w / v%

[0035] Another aspect of the present invention is an eye drop solution obtained by dissolving the following pharmaceutical composition in purified water and filling it into a multi-dose container. This eye drop solution has excellent transparency, high stability, and passes the preservation efficacy test. Furthermore, the pH of this eye drop solution is 7.5 to 7.9 and it does not contain preservatives. Here, the preservation efficacy test is the test described in the 18th edition of the Japanese Pharmacopoeia (JP18), and passing the preservation efficacy test means that a judgment of conformity is obtained. Rebamipide: 2w / v% Meglumine: 4.2~7 w / v% Povidone K17: 0.5~2 w / v% Boric acid: 0.5~1.5 w / v% Trometamol: 0.1-0.5 w / v% (as needed) Succinic acid: 0.7~1.2 w / v% Glutamic acid; 0.05~0.4 w / v% [Examples]

[0036] The present invention will now be described in more detail with reference to examples, but the present invention is not limited thereto.

[0037] Examples 1-4 and Comparative Example 1 (Manufacturing and stability testing of pharmaceutical compositions) The pharmaceutical compositions shown in Table 1 were manufactured by conventional methods, filled into multi-dose containers, and obtained eye drops for Examples 1-4 and Comparative Example 1. These were stored at 60°C for one month, and changes in pH and properties (visual observation) were observed. The results are also shown in Table 1.

[0038] [Table 1]

[0039] Examples 1 to 4, which correspond to the pharmaceutical compositions of the present invention, contained rebamipide, the amino sugar meglumine, the solubilizer povidone, the buffer boric acid, and the organic acid succinic acid. As a result, they did not show a significant decrease in pH, maintained a colorless to slightly yellowish clear state, and exhibited excellent stability. On the other hand, Comparative Example 1, which did not contain the buffer boric acid, showed a significant decrease in pH, making it impossible to maintain a dissolved state and resulting in crystal precipitation.

[0040] Examples 5-8 (Manufacturing and stability testing of pharmaceutical compositions) The pharmaceutical compositions shown in Table 2 were manufactured by conventional methods, filled into multi-dose containers, and obtained the eye drops of Examples 5-8. These were stored at 60°C for one month, and changes in pH and properties (visual observation) were observed. The results are also shown in Table 2.

[0041] [Table 2]

[0042] Examples 5-8, which represent the pharmaceutical compositions of the present invention, contained rebamipide, the amino sugar meglumine, the solubilizer povidone, the buffering agents boric acid and trometamol, and the organic acid succinic acid. As a result, they did not show a significant decrease in pH, maintained a colorless to slightly yellowish clear state, and exhibited excellent stability. Furthermore, combining the buffering agents boric acid and trometamol generally improved pH stability.

[0043] Examples 9-13 and Comparative Examples 2-3 (Manufacturing of transparent pharmaceutical compositions) The pharmaceutical compositions shown in Table 3 were manufactured by conventional methods, filled into multi-dose containers, and eye drops for Examples 9-13 and Comparative Examples 2-3 were obtained. These were stored at room temperature, and their properties were observed (visually) after 24 hours. The results are shown in Table 3.

[0044] [Table 3]

[0045] Examples 9 to 13, which correspond to the pharmaceutical compositions of the present invention, maintained a colorless to slightly yellowish clear state by containing rebamipide, the amino sugar meglumine, the solubilizer povidone, the buffering agents boric acid and trometamol, the organic acid succinic acid, and the amino acid glutamic acid. On the other hand, it was found that crystals precipitated in Comparative Examples 2 and 3 because the amount of the amino sugar meglumine was low.

[0046] Examples 14-18 (Manufacturing of transparent pharmaceutical compositions) The eye drops of Examples 14-18 were obtained by preparing the compositions shown in Table 4 using conventional methods and filling them into multi-dose containers. Their properties were observed (visually). The results are shown in Table 4.

[0047] [Table 4]

[0048] Examples 14 to 18, which correspond to the pharmaceutical compositions of the present invention, contained rebamipide, meglumine (an amino sugar), povidone (regardless of K value) as a solubilizer, boric acid and trometamol as buffers, succinic acid as an organic acid, and glutamic acid as an amino acid, thereby maintaining a colorless to slightly yellowish clear state.

[0049] From the above results, it was found that the following composition of the pharmaceutical composition of the present invention is preferable because it has excellent transparency and high stability. Rebamipide: 1-3 w / v% Amino sugars: 2-12 w / v% Solubilizer: 0.1~3 w / v% Buffering agent: 0.1~2.5 w / v% Organic acid: 0.1~3w / v%

[0050] Furthermore, it was found that the pharmaceutical composition of the present invention preferably contains an additional 0.01-0.5 w / v% of amino acids in addition to the above composition.

[0051] Examples 19-21 (Manufacturing and preservation efficacy testing of pharmaceutical compositions) The compositions shown in Table 5 were prepared by conventional methods, filled into multi-dose containers, and obtained the eye drops of Examples 19-21. These were tested according to the preservative efficacy test method of the 18th edition of the Japanese Pharmacopoeia (JP18).

[0052] [Table 5]

[0053] Of the examples corresponding to the pharmaceutical compositions of the present invention, Examples 19-20 contained rebamipide, the amino sugar meglumine, the solubilizer povidone, the buffering agent boric acid (trometamol if necessary), the organic acid succinic acid, and the amino acid glutamic acid. Because the succinic acid concentration was 0.7-1.2 w / v%, the mixture maintained a colorless to slightly yellowish clear state, exhibited excellent stability, and passed the preservation efficacy test, indicating that multiple doses were possible. On the other hand, Example 21, with a succinic acid concentration of 0.4 w / v%, maintained a colorless to slightly yellowish clear state and exhibited excellent stability, but failed the preservation efficacy test. However, it was found that a single dose was possible.

[0054] From the above results, it was found that the following composition of the pharmaceutical composition of the present invention is preferable because it exhibits excellent transparency, high stability, and is suitable for preservation efficacy testing. Rebamipide: 2w / v% Meglumine: 4.2~7 w / v% Povidone K17: 0.5~2 w / v% Boric acid: 0.5~1.5 w / v% Trometamol: 0.1-0.5 w / v% (as needed) Succinic acid: 0.7~1.2 w / v% Glutamic acid; 0.05~0.4 w / v% [Industrial applicability]

[0055] The pharmaceutical composition of the present invention can be used in eye drops.

Claims

1. A pharmaceutical composition containing rebamipide, amino sugars, a solubilizer, a buffer, and an organic acid (excluding amino acids).

2. The pharmaceutical composition according to claim 1, comprising 1 to 3 w / v% of rebamipide.

3. The pharmaceutical composition according to claim 1, comprising 3 to 12 w / v% amino sugars.

4. The pharmaceutical composition according to claim 1, comprising 0.05 to 5 w / v% of a solubilizing agent.

5. The pharmaceutical composition according to claim 1, comprising 0.1 to 2.5 w / v% of a buffering agent.

6. The pharmaceutical composition according to claim 1, comprising 0.1 to 3 w / v% of an organic acid.

7. Furthermore, the pharmaceutical composition according to claim 1, further comprising an amino acid.

8. The pharmaceutical composition according to claim 7, comprising 0.01 to 0.5 w / v% of an amino acid.

9. The pharmaceutical composition according to claim 1, wherein the pH is 7 to 9.

10. The pharmaceutical composition according to claim 1, which is substantially free of preservatives.

11. The pharmaceutical composition according to claim 1, which is in liquid form.

12. The pharmaceutical composition according to claim 1, for the treatment of dry eye by local administration to the eye.

13. An eye drop containing the pharmaceutical composition according to any one of claims 1 to 12, filled into a single-dose container.

14. An eye drop containing the pharmaceutical composition according to any one of claims 1 to 12, filled into a multi-dose container.

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