JP2005266692A - Preservative solution for soft contact lens capable of releasing sustained drug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide preservative solution for an SCL capable of releasing a sustained drug obtained by using ion exchange reaction, especially the preservative solution that can suppresses elution of included drug, keep the shape of a lens itself being preserved in a stable state, and enables the SCL to be worn on the eye as it is from the preservative solution. <P>SOLUTION: The preservative solution for the SCL capable of releasing the sustained drug obtained by using ion exchange reaction is provided. The solution contains nonionic surfactant and a nonionic osmotic pressure conditioner, and no ionic compound. Further, the nonionic surfactant is a polyoxyethylene-polyoxpropylene nonionic surfactant (poloxamer type). Further, the nonionic osmotic pressure conditioner is propylene glycol or glycerol. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a preservative solution capable of suppressing elution of a drug included in a lens and stably maintaining the lens shape when storing a drug sustained-release soft contact lens by ion exchange reaction in a solution. It is.

  As a new administration method, a mechanism for sustained release of a drug at a constant rate, that is, a drug sustained release system is used in many clinical sites. As a conventional sustained drug release system, there are a reservoir type in which a drug encapsulated by a controlled release membrane is released to the outside through a membrane, and a monolithic type in which a drug is dispersed and dissolved in a polymer matrix.

  Various problems arise when these systems are applied to hydrous soft contact lenses (SCL). For example, the reservoir type is unsuitable for contact lenses where the drug must be present inside the device as a solid and require high transparency. Even in the monolithic type, when the drug is dispersed, the drug exists as a solid as in the case of the reservoir type, and the sustained release rate of the dissolved drug is fast, especially when 60% or more of the drug is eluted. The dissolution rate increases exponentially and the drug sustained release rate is not stable, and none of them is practical as a drug sustained release SCL.

  Thus, as a result of intensive studies, the present inventors have invented a sustained drug release SCL using an ion exchange reaction as a practical drug sustained release SCL. This has a site capable of trapping positive or negative drug ions, that is, a ligand, and the drug ions trapped in the site are exchanged with ions contained in tears to release the drug. Since the drug is included in the lens in an ionic state, the transparency of the lens is maintained, and the sustained release rate of the drug can be well controlled, which is practical. Moreover, since it can distribute | circulate in the state which included the medicine, the user can use it like normal disposable SCL.

  By the way, SCL is generally stored and used in a buffer solution, physiological saline, or a solution in which a surfactant, bactericidal agent, osmotic pressure adjusting agent or the like is added. When SCL is stored in such a solution, the wettability of the lens surface and the osmotic pressure inside the lens are kept constant, and a good wearing feeling can be obtained.

  Specifically, as a SCL cleaning storage solution, a combination of a surfactant, an osmotic pressure adjusting agent and a bactericidal agent and exhibiting a buffering capacity is disclosed (for example, see Patent Document 1). After washing SCL, it is said that it is possible to suppress the growth of microorganisms attached to SCL by storing it in this washing stock solution.

  Also, SCL preservation containing polyoxyethylene-polyoxypropylene substituted ethylenediamine nonionic surfactant (poloxamine type surfactant) and polyoxyethylene-polyoxypropylene nonionic surfactant (poloxamer type surfactant) A liquid is also disclosed (see, for example, Patent Document 2). It is said that by dipping in this preservation solution, wettability is imparted to the lens surface, and accumulation of lipids and other tear film substitutes can be suppressed.

Recently, an SCL preservation solution containing a surfactant and an osmotic pressure adjusting agent and having a buffering capacity has been disclosed (for example, see Patent Document 3). This preservation solution contains a nonionic surfactant and is intended to impart surface wetting properties to the SCL.
JP 59-129299 A JP-A-4-323721 Special Table 2002-504238

  However, in the case of the sustained drug release SCL using the above-described ion exchange reaction, if it is immersed in a conventional storage solution that has been conventionally used, the drug ions captured by the ligand and the ions in the storage solution are exchanged. The drug elutes quickly. That is, in the case of a drug sustained-release SCL stock solution using an ion exchange reaction, an ionic component cannot be used. For example, the preservation solutions of Patent Documents 1, 2, and 3 cannot be used as a preservation solution for the sustained drug release SCL of the present invention because they contain an ionic substance as a solution buffer and an osmotic pressure regulator.

  In particular, in the solutions described in Patent Documents 1 and 2, since the contained poloxamine-type surfactant and bactericidal agent are cationic, the dissolution rate when the drug sustained-release SCL in this case is included in the solution is cationic. Will be significantly faster. In addition, when the drug sustained-release SCL of the present invention has a cationic property, it cannot be used because the storage solution component forms an insoluble complex on the lens surface and decreases the drug elution rate.

  The object of the present invention is to provide a drug sustained-release SCL preservation solution using an ion exchange reaction, and in particular, it is possible to suppress the dissolution of a comprehensive drug, keeping the shape of the lens itself during storage in a stable state, And it is providing the preservation | save liquid which can be used for eyes as it is from a preservation | save liquid.

  The present invention is a preservative solution for sustained drug release soft contact lenses by an ion exchange reaction, which contains a nonionic surfactant and a nonionic osmotic pressure regulator, and does not contain an ionic compound Is a preservation solution characterized by

  The present invention also provides the above preservation solution, wherein the nonionic surfactant is a polyoxyethylene-polyoxypropylene nonionic surfactant (poloxamer type).

  Furthermore, the present invention provides the above preservation solution, wherein the nonionic osmotic pressure adjusting agent is propylene glycol or glycerin.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to preserve | save in the state which suppressed the change of the dimension of a lens, without eluting the drug included by the drug sustained release SCL using ion exchange reaction. In addition, the SCL stored in the storage solution of the present invention does not need to be rinsed with pure water or the like at the time of use, and can be worn on the eye as it is.

  The present invention is obtained by adding a nonionic surfactant and a nonionic osmotic pressure regulator to pure water. The nonionic surfactant referred to in the present invention is effective in forming a layer of a surfactant on the SCL surface and suppressing the dissolution of the incorporated drug. Moreover, since hydrophilicity is imparted to the SCL surface, the wettability of the lens after immersion can be improved and the wearing feeling can be improved. For example, a polyoxyethylene ether type, a polyoxypropylene ether type, a polyoxyethylene-polyoxypropylene block copolymer system, etc. can be mentioned, and among them, a polyoxyethylene-polyoxypropylene block copolymer system is preferable.

  The nonionic surfactant preferably used in the present invention is a block polymer in which ethylene oxide is added to both ends of polypropylene glycol (poloxamer type), the ethylene oxide content in the molecule is 60 to 80 wt%, and the molecular weight is 4000 or more are preferable. When the ethylene oxide content is lower than 60 wt%, the aqueous solution tends to become cloudy and is not practical. On the other hand, if the molecular weight is less than 4000, it tends to penetrate into the network structure of the SCL material, which is a hydrogel, and the elution of the drug tends to be promoted, and the safety of the lens itself is reduced and the dimension is changed.

  Generally, an HLB value (hydrophile-lipophile balance) is used as an index representing the relative balance between hydrophilicity and lipophilicity of a surfactant. This is an ethylene oxide addition-type nonionic surfactant, considering a hypothetical compound in which the hydrophilic group added to the hydrophobic group is infinitely long and has the greatest hydrophilicity, and the HLB value of this compound is set to 20. The HLB value of a hydrophobic compound having no group at all is determined as 0, and the HLB value of the compound is calculated as a relative value to the HLB value, and is defined by the following formula.

HLB = 20 (M _H / M)
Where _MH is the molecular weight of the hydrophilic group, M = the molecular weight of the activator

  In the case of the present invention, a polyoxyethylene-polyoxypropylene nonionic surfactant having an HLB value of 12 to 16 is used. When the HLB value is smaller than 12, sufficient hydrophilicity cannot be obtained, the affinity with the SCL surface is lowered, and a sufficient effect for reducing wettability and drug elution cannot be obtained. On the other hand, when the ratio is larger than 16, the water molecules around the SCL interact with the surfactant, the water molecules enter the gel, and a lens having a stable dimension cannot be obtained.

  The nonionic surfactant (poloxamer type) used in the present invention is not limited as long as it satisfies the above conditions. As a specific example, among the Pluronic (registered trademark) of Asahi Denka Co., Ltd. Examples include Lutrol F108, F98, F88, F68, and F38 having an ethylene oxide content of 80%, and F127 and F77 having an ethylene oxide content of 70%.

  In addition, since drug sustained-release SCL contains a drug in the lens, it is not preferable to wash with pure water or the like when worn on the eye. For this reason, the nonionic surfactant and the osmotic pressure regulator in the preservation solution are required to be added in amounts that do not irritate the eye and do not elute the drug in the lens.

  For example, the addition amount of the nonionic surfactant is generally preferably 0.005 to 1.0 wt% with respect to pure water. Particularly preferred is 0.01 to 0.5 wt%. If it is less than 0.005 wt%, the effect of the added nonionic surfactant cannot be sufficiently exhibited, the wettability of the SCL surface is lowered, and a good wearing feeling cannot be obtained. In addition, since a nonionic surfactant layer is not formed on the SCL surface, it is not possible to expect an effect of suppressing dissolution of the included drug. An amount exceeding 1.0 wt% is not preferable because it is irritating to the eyes.

  By the way, when SCL made of hydrogel is immersed in pure water or a preservation solution with significantly different osmotic pressure, the dimensions change due to the difference in osmotic pressure inside and outside the gel, so the osmotic pressure of the preservation solution must be adjusted to the same level as tear fluid. In general, an ionic osmotic pressure regulator such as potassium chloride or sodium chloride is used.

  However, in the case of the sustained drug release SCL utilizing an ion exchange reaction, which is an object of the present invention, there is a problem that a comprehensive drug is eluted in a preservation solution using an ionic osmotic pressure regulator.

  Therefore, in the case of the preservation solution of the present invention, the ionic compound cannot be used, and the osmotic pressure is adjusted to 200 to 400 mmol / kg, which is a nonionic compound and is substantially equal to the physiological osmotic pressure. Preferably it is in the range of 220-380 mmol / kg. When the osmotic pressure is less than 200 mmol / kg, the osmotic pressure of the immersed SCL is lower than that of tears. For this reason, tear fluid flows into the SCL, and the lens dimension increases and is absorbed by the eyeball. On the other hand, if it is higher than 400 mmol / kg, the osmotic pressure regulator inside the lens is suddenly released, resulting in a smaller dimension and causing pain during wearing.

  As the nonionic osmotic pressure adjusting agent in the present invention, glycerin, ethylene glycol, propylene glycol, polyethylene glycol, glucose, fructose, mannitol, sorbitol, xylitol, cyclodextrin, trehalose, etc. are blended alone or in appropriate combination. You can also.

  Moreover, in this invention, arbitrary components, such as various thickeners which show nonionicity in a solution, for example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, can be added. In addition, even a cationic polymer such as polyhexamethylene biguanide (PHMB) that exhibits ionicity in a solution such as a preservative, a bactericidal agent, an antibacterial agent, or a buffering agent is used in the present invention. If the amount does not affect the function of the releasable SCL, for example, about 2 ppm, it can be added as an optional component.

  The method for preparing a preservation solution of the present invention can be easily obtained by dissolving a certain amount of a nonionic surfactant and a nonionic osmotic pressure regulator in pure water at room temperature and stirring. The obtained preservation solution may be sterilized by a method such as filtration, heating / pressurization, and electron beam irradiation. When this preservation solution is used, SCL containing the drug can be distributed in a sanitary state if it is immersed in this solution and sterilized in a sealed state.

Hereinafter, the present invention will be described in detail, but the present invention is not limited to these examples.
(Method of synthesizing drug sustained-release SCL)
The drug sustained-release soft contact lens by ion exchange reaction in the present invention may be synthesized according to the examples of Japanese Patent Application No. 2003-100236 and Japanese Patent Application No. 2003-100238. Specifically, a polymerization initiator is dissolved in a monomer mixture comprising constituent components, and the temperature is raised in a range of 25 to 120 ° C. in a plastic ophthalmic lens mold, and polymerization is carried out for 5 to 120 hours. Thereafter, the polymer obtained by cooling to room temperature is taken out of the mold and hydrated and swollen in pure water at 60 to 100 ° C. Next, in the aqueous solution (0.5 wt%) in which the drug having an anionic or cationic substituent is dissolved, the obtained SCL is immersed in accordance with the ionicity of the lens to include the desired drug, and then The free drug was eluted with pure water to obtain a sample of the present invention. In this example, naphazoline nitrate was used as a drug having a cationic substituent, and water-soluble azulene was used as a drug having an anionic substituent. In addition, the lenses as samples were (I), (II), (III), and (IV), and the ionicity, specific constituent components, and blending amounts thereof are shown in Table 1.
(Evaluation method of preservation solution)
The above-obtained drug sustained-release SCL having a cationic or anionic ligand is immersed in a preservation solution, and the amount of the drug eluted from the lens immediately after sterilization and after storage for 30 days into the preservation solution is analyzed by high performance liquid chromatography. Quantify using HPLC (manufactured by JASCO Corporation).

  A drug having an elution amount of 0 to less than 1 ppm was marked as ◯. A drug dissolution amount of 1 ppm or more was marked as x because it was not practical for use in a drug sustained-release lens.

(Example 1)
Propylene glycol (4.0 g) and nonionic surfactant Lutrol F127 (0.1 g) were added to pure water, stirred and dissolved at room temperature, then made up to a volume of 100 mL with pure water, pH 5.0 to 7.5, osmotic pressure 220 to 380 Prepared to be mmol / kg. Pour 5.0 mL of the obtained solution into a glass vial, enclose each of the above-mentioned drug sustained-release SCLs (I) to (IV), sterilize at 121 ° C. for 20 minutes, and determine the drug elution amount according to the above evaluation method. Quantified.

  Both the elution amount immediately after sterilization and the elution amount after 30 days were hardly observed. The evaluation results after 30 days are shown in Table 2.

(Examples 2 to 4)
Lutrol F127 0.5 g, 0.05 g, and 0.01 g were dissolved in 100 mL of pure water with respect to 4.0 g of propylene glycol, and the drug elution amount was measured in the same manner as in Example 1. Both the elution amount immediately after sterilization and the elution amount after 30 days were hardly observed. The evaluation results after 30 days are shown in Table 2.

(Examples 5-7)
Lutrol F108, F68, F38 0.1 g was dissolved in 100 mL of pure water with respect to 4.0 g of propylene glycol, and the drug elution amount was measured in the same manner as in Example 1. Both the elution amount immediately after sterilization and the elution amount after 30 days were hardly observed. The evaluation results after 30 days are shown in Table 2.

(Examples 8 to 10)
Propylene glycol 4.5 g, 3.5 g, and 2.5 g were dissolved in 100 mL of pure water with respect to 0.1 g of the nonionic surfactant Lutrol F127, and the drug elution amount was measured in the same manner as in Example 1. In either case, the osmotic pressure was kept within the range of 220 to 380 mmol / kg, and no change in the lens dimension during storage was observed. Both the elution amount immediately after sterilization and the elution amount after 30 days were hardly observed. The evaluation results after 30 days are shown in Table 2.
(Example 11)
0.1 g of nonionic surfactant Lutrol F127 and 4.0 g of glycerin as an osmotic pressure regulator were dissolved in 100 mL of pure water, and the drug elution amount was measured in the same manner as in Example 1. Even in the system using glycerin as the osmotic pressure adjusting agent, the elution amount immediately after sterilization and the elution amount after 30 days were hardly seen. The evaluation results after 30 days are shown in Table 2.

(Comparative Example 1)
In the same operation as in Example 1, instead of the nonionic osmotic pressure adjusting agent, the osmotic pressure was adjusted to about 220 to 380 mmol / kg with sodium chloride and potassium chloride as the ionic osmotic pressure adjusting agent. evaluated. The elution amount immediately after sterilization and the elution amount after 30 days were not suitable for practical use because any of the lenses (I) to (IV) showed elution of 1000 ppm or more. The evaluation results after 30 days are shown in Table 2.

・ Unit of monomer amount is wt%
・ HEMA; 2-hydroxyethyl methacrylate ・ MOEP; methacryloxyethyl phosphate ・ MAPTAC; methacrylamide propyltrimethylammonium chloride ・ MAm; methacrylamide ・ ED; ethylene glycol dimethacrylate

Claims (3)

  Preservative solution for drug sustained release soft contact lens by ion exchange reaction, characterized in that it contains a nonionic surfactant and a nonionic osmotic pressure regulator, and does not contain an ionic compound Stock solution.   The preservation solution according to claim 1, wherein the nonionic surfactant is a polyoxyethylene-polyoxypropylene nonionic surfactant (poloxamer type). The preservation solution according to claim 1 or 2, wherein the nonionic osmotic pressure adjusting agent is propylene glycol or glycerin.