Process for making ophthalmic lenses
Abstract
Problem to be solved.To provide a novel water-based manufacturing method for facilitating mold release of a silicone hydrogel / contact lens.
Solution.A reaction mixture containing at least one silicone-containing component and at least one shrinking agent is cured in a molding mold to form a cured article, and the cured article in the molding mold is brought into contact with a specific aqueous solution. Shrink the cured article. [Selection diagram] Fig. 1

Term
Projected expiry 22 June 2027.
- Priority
- Filed
- Published
- Today
- Projected expiry
50 claims: 2 independent, 48 dependent
- 1方法において、 (a)少なくとも一つのシリコーン含有成分と少なくとも一つの収縮剤とを含む反応混合物を成形型中で硬化して硬化物品を形成することと、 (b)前記成形型中の前記硬化物品を、前記硬化物品を収縮させる条件の下、水溶液と接触させることと、 (c)任意的に、前記成形型から前記硬化物品を取り出すことと、 を含む、方法。
- 2請求項1に記載の方法において、 前記収縮剤が、少なくとも一つの単官能低分子量の直鎖シリコーンを含む、方法。
- 3請求項2に記載の方法において、 前記直鎖シリコーンの分子量が、約1000未満である、方法。
- 4請求項2に記載の方法において、 前記直鎖シリコーンの分子量が、約800未満である、方法。
- 5請求項2に記載の方法において、 前記直鎖シリコーンの分子量が、約700未満である、方法。
- 6請求項2に記載の方法において、 前記直鎖シリコーンが、少なくとも一つのシロキサン基を含む、方法。
- 7請求項2に記載の方法において、 前記直鎖シリコーンが、少なくとも一つのポリジメチルシロキサンを含む、方法。
- 8請求項2に記載の方法において、 前記直鎖シリコーンが、モノメタクリロキシプロピル末端モノ-n-ブチル末端ポリジメチルシロキサン、2-メチル-,2-ヒドロキシ-3-[3-[1,3,3,3-テトラメチル-1-[(トリメチルシリル)オキシ]ジシロキサニル]プロポキシ]プロピルエステル、2-ヒドロキシ-3-メタクリロキシプロピロキシプロピル-トリス(トリメチルシロキシ)シラン、3-メタクリロキシプロピルトリス(トリメチルシロキシ)シラン、3-メタクリロキシプロピルビス(トリメチルシロキシ)メチルシランおよび3-メタクリロキシプロピルペンタメチルジシロキサン、モノ(3-メタクリロキシ-2-ヒドロキシプロピロキシ)プロピル末端,モノ-ブチル末端ポリジメチルシロキサン、シリコーン含有メタクリルアミド、ならびにそれらの組合せからなる群から選択される、方法。
- 9請求項2に記載の方法において、 前記少なくとも一つのシリコーン含有成分の少なくとも約10重量%が、前記少なくとも一つの単官能低分子量のシリコーンで置換される、方法。
- 10請求項2に記載の方法において、 前記少なくとも一つのシリコーン含有成分の約20~100重量%が、前記少なくとも一つの単官能低分子量のシリコーンで置換される、方法。
- 11請求項2に記載の方法において、 前記少なくとも一つのシリコーン含有成分の約40~100重量%が、前記少なくとも一つの単官能低分子量のシリコーンで置換される、方法。
- 12請求項1に記載の方法において、 前記収縮剤が、少なくとも一つの架橋性化合物を少なくとも約2モル%の量で含む、方法。
- 13請求項1に記載の方法において、 前記収縮剤が、少なくとも一つの架橋性化合物を少なくとも約2.5モル%の量で含む、方法。
- 14請求項12に記載の方法において、 前記架橋性化合物が、親水性架橋剤と疎水性架橋剤とからなる群から選択される、方法。
- 15請求項12に記載の方法において、 前記収縮剤が、テトラエチレングリコールジメタクリレート、トリエチレングリコールジメタクリレート、エチレングリコールジメタクリレート、エチレンジアミンジメタクリルアミド、グリセロールジメタクリレート、およびそれらの組合せからなる群から選択される親水性架橋性化合物を含む、方法。
- 16請求項12に記載の方法において、 前記収縮剤が、アクリロキシプロピル末端ポリジメチルシロキサン(n=10または20)、ヒドロキシルアクリレート官能シロキサンマクロマー、メタクリロキシプロピル末端PDMS、ブタンジオールジメタクリレート、ジビニルベンゼン、1,3-ビス(3-メタクリロキシプロピル)テトラキス(トリメチルシロキシ)ジシロキサン、およびそれらの混合物からなる群から選択される疎水性架橋性化合物を含む、方法。
- 17請求項12に記載の方法において、 前記収縮剤が、テトラエチレングリコールジメタクリレート、エチレングリコールジメタクリレート、アクリロキシプロピル末端ポリジメチルシロキサン(n=10または20)、およびそれらの組合せからなる群から選択される架橋性化合物を含む、方法。
- 18請求項1に記載の方法において、 前記反応混合物が、少なくとも一つの希釈剤をさらに含み、前記希釈剤は、前記反応混合物中の成分および前記希釈剤の重量に基づいて約40~約60重量%の量で存在する、方法。
- 19請求項18に記載の方法において、 前記希釈剤が、前記反応混合物中の成分および前記希釈剤の重量に基づいて、約50~約60重量%の量で存在する、方法。
- 20請求項1に記載の方法において、 前記接触条件が、少なくとも約80の°Cの温度を含む、方法。
- 21請求項1に記載の方法において、 前記接触条件が、少なくとも約90°Cの温度を含む、方法。
- 22請求項1に記載の方法において、 前記収縮剤が、少なくとも一つの水分減少用化合物を含む、方法。
- 23請求項1に記載の方法において、 前記反応混合物が、少なくとも一つの親水性モノマーをさらに含む、方法。
- 24請求項23に記載の方法において、 前記親水性モノマーが、約5~50重量%の量で存在する、方法。
- 25請求項23に記載の方法において、 前記親水性モノマーが、約20~50重量%の量で存在する、方法。
- 26請求項23に記載の方法において、 前記水溶液が、少なくとも約70重量%の水を含む、方法。
- 27請求項23に記載の方法において、 前記水溶液が、少なくとも約90重量%の水を含む、方法。
- 28請求項1に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約3%収縮する、方法。
- 29請求項1に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約5%収縮する、方法。
- 30請求項1に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約7%収縮する、方法。
- 31方法において、 (a)シリコーンヒドロゲル・コンタクトレンズを形成するための成形型中で、少なくとも一つの反応性シリコーン成分と希釈剤とを含む反応混合物を硬化することであって、前記希釈剤が、前記反応混合物の全成分に基づいて少なくとも約40重量%で存在する、反応混合物を硬化することと、 (b)前記成形型中で、前記コンタクトレンズを、前記コンタクトレンズを収縮させる条件の下、水溶液と接触させることと、 (c)任意的に、前記成形型から前記コンタクトレンズを取り出すことと、 を含む、方法。
- 32請求項31に記載の方法において、 前記反応混合物が、少なくとも一つの収縮剤をさらに含む、方法。
- 33請求項32に記載の方法において、 前記収縮剤が、少なくとも一つの単官能低分子量の直鎖シリコーンを含む、方法。
- 34請求項33に記載の方法において、 前記直鎖シリコーンの分子量が、約1000未満である、方法。
- 35請求項33に記載の方法において、 前記直鎖シリコーンが、少なくとも一つのシロキサン基を含む、方法。
- 36請求項33に記載の方法において、 前記直鎖シリコーンが、少なくとも一つのポリジメチルシロキサンを含む、方法。
- 37請求項33に記載の方法において、 前記直鎖シリコーンが、モノメタクリロキシプロピル末端モノ-n-ブチル末端ポリジメチルシロキサン、2-メチル-,2-ヒドロキシ-3-[3-[1,3,3,3-テトラメチル-1-[(トリメチルシリル)オキシ]ジシロキサニル]プロポキシ]プロピルエステル、2-ヒドロキシ-3-メタクリロキシプロピロキシプロピル-トリス(トリメチルシロキシ)シラン、3-メタクリロキシプロピルトリス(トリメチルシロキシ)シラン,3-メタクリロキシプロピルビス(トリメチルシロキシ)メチルシランおよび3-メタクリロキシプロピルペンタメチルジシロキサン、モノ-(3-メタクリロキシ-2-ヒドロキシプロピロキシ)プロピル末端,モノブチル末端ポリジメチルシロキサン、シリコーン含有メタクリルアミド、ならびにそれらの組合せからなる群から選択される、方法。
- 38請求項32に記載の方法において、 前記収縮剤が、少なくとも一つの架橋性化合物を、少なくとも約2モル%の量で含む、方法。
- 39請求項38に記載の方法において、 前記架橋性化合物が、親水性架橋剤と疎水性架橋剤とからなる群から選択される、方法。
- 40請求項38に記載の方法において、 前記架橋性化合物が、テトラエチレングリコールジメタクリレート、エチレングリコールジメタクリレート、アクリロキシプロピル末端ポリジメチルシロキサン(n=10または20)、およびそれらの組合せからなる群から選択される、方法。
- 41請求項31に記載の方法において、 前記希釈剤が、前記反応混合物中の成分および前記希釈剤の重量に基づいて、約40~約60重量%の量で存在する、方法。
- 42請求項31に記載の方法において、 前記希釈剤が、前記反応混合物中の成分および前記希釈剤の重量に基づいて、約45~約60重量%の量で存在する、方法。
- 43請求項31に記載の方法において、 前記希釈剤が、前記反応混合物中の成分および前記希釈剤の重量に基づいて、約50~約60重量%の量で存在する、方法。
- 44請求項31に記載の方法において、 前記接触条件が、少なくとも約80の°Cの温度を含む、方法。
- 45請求項32に記載の方法において、 前記収縮剤が、少なくとも一つの水分減少用化合物を含む、方法。
- 46請求項31に記載の方法において、 前記反応混合物が、少なくとも一つの親水性モノマーをさらに含む、方法。
- 47請求項31に記載の方法において、 前記水溶液が、少なくとも約70重量%の水を含む、方法。
- 48請求項31に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約3%収縮する、方法。
- 49請求項31に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約3%収縮する、方法。
- 50請求項31に記載の方法において、 前記コンタクトレンズが、接触ステップ(b)で少なくとも約7%収縮する、方法。
Independent claims50
108 paragraphs, as filed
Contents of disclosure
[Field of invention] The present invention relates to an aqueous method for producing a silicone hydrogel contact lens.
[Background of invention] It is known that contact lenses can be used to improve vision, and for many years various contact lenses have been commercially produced. Hydrogel contact lenses are very popular today. These lenses are often more comfortable to wear than contact lenses made from hard materials. Highly adaptable soft contact lenses can be manufactured by forming the lens in a multipart molding mold. The combined parts form a shape that matches the desired final lens. Contact lenses made from silicone hydrogels have been disclosed so far.
Multipart molds used to make useful articles (eg eye lenses) from hydrogels include, for example, a first mold portion having a convex surface corresponding to the back curved surface of the eye lens and an eye. A second mold portion having a concave surface corresponding to the front curved surface of the lens may be included. In order to produce a lens using such a molding portion, an uncured hydrogel lens preparation is placed between the concave surface and the convex surface of the molding portion and then cured. Hydrogel lens formulations can be cured, for example, by exposure to heat and / or light. The cured hydrogel forms a lens according to the dimensions of the molded portion.
After curing, the mold portion is separated and the lens remains attached to one of the mold portions. The mold release process separates the lens from the molded portion where the lens remains. Release of the lens from the mold has been facilitated by exposing the lens to various solutions that act to swell the lens to reduce the adhesion of the lens to the mold.
New developments in the art have made it possible to manufacture contact lenses from silicone hydrogels. Known hydration processes that use aqueous solutions to cause mold release have not been efficient with silicone hydrogel lenses. As a result, attempts have been made to release the silicone lens using an organic solvent. In those processes, lenses can be immersed in alcohols, ketones, aldehydes, esters, amides or N-alkylpyrrolidones for 20-40 hours in the absence of water or in a mixture with water as a minor component. It was mentioned.
However, although some success has been achieved with these known processes, the use of high concentrations of organic solutions requires, for example, safety risks; increased production line downtime; release solutions. There may be drawbacks such as high cost; and the possibility of secondary damage from the explosion.
Therefore, silicone hydrogel contact lenses that require little or no use of organic solvents, avoid the use of flammable agents, and effectively release the lens from the mold in which it was formed. It is advantageous to find a manufacturing method.
[Outline of Invention] The present invention (a) To form a cured article by curing a reaction mixture containing at least one silicone-containing component and at least one shrinking agent in a molding die. (b) Hydration of the cured article in the mold under the condition of shrinking the cured article. (c) Optionally, remove the cured article from the mold and Including, methods, including processes. In another embodiment the invention (a) Curing a reaction mixture containing at least one reactive silicone component and a diluent in a mold for forming silicone hydrogel contact lenses, wherein the diluent is the entire component of the reaction mixture. With curing the reaction mixture, which is present in at least about 40% by weight based on (b) In the molding mold, the contact lens is brought into contact with the aqueous solution under the condition that the contact lens is contracted. (c) Optionally, remove the contact lens from the mold and Including, methods.
[Detailed description of the invention] It has been found that mold release of cast molded parts of silicone hydrogels using aqueous solutions can be facilitated by including at least one shrinkage agent in the reaction mixture used to form the silicone hydrogel parts. Surprisingly, a reaction mixture was found that contained a suitable amount of shrinkage agent to provide the desired release conditions and nevertheless provided the lens polymer with the desired modulus and water content.
When the "at least one shrinking agent" used here is contained in an amount effective for mold release, the molding mold in which the silicone portion is cast and the silicone portion thereof are exposed to at least one mold release process condition. Occasionally, it means at least one component that releases the silicone portion from at least a portion of the mold. Examples of process conditions that can cause shrinkage include temperature, pH, ionicity, hydrophilicity, combinations thereof and the like. In one embodiment, the mold release process conditions include contact with at least one aqueous solution. As used herein, "effective amount for mold release" means an amount sufficient to cause mold release in less than about 60 minutes. This time is less than about 10 minutes in some embodiments, less than about 6 minutes in other embodiments, and less than about 2 minutes in other embodiments.
"Release from mold" as used herein means that the lens is either completely separated from the mold or only loosely attached, resulting in light agitation or mild operation {eg vacuum. It means that it can be removed by assisted, manual or automated operations such as swabbing or any combination thereof).
Usually, when the molded part and the molding die are brought into contact with the aqueous solution, the shrinking agent shrinks the molded part. It was found that at least about 3% shrinkage was sufficient to cause mold release of the part from the mold. In some embodiments, this contraction is at least about 5%, in other embodiments it is at least about 7%. The percent shrinkage is the diameter of the mold obtained by forming the desired molded article from the reaction mixture with the shrinking agent (mold diameter) and the conditions used for mold release {lens diameter (w / agent). )} And can be measured by calculating as follows. % Shrinkage = [(mold diameter-lens diameter (w / agent) / mold diameter] x 100 These diameters can be measured using a "shadowgraph" equipped with VanKeuren, Varibeam, and Mitutoyo calipers.
Formulations that give higher shrinkage allow treatment under milder mold release conditions. Mold materials can also affect the amount of shrinkage desired to cause mold release.
As used herein, "reaction mixture" means a reactive component and diluent used to form a lens. Reactive components include silicone-containing components, hydrophilic monomers, lubricating polymers, photoinitiators and other components that form lenses when reacted.
In one embodiment, suitable shrinkage agents include components that, when included in the reaction mixture, increase the modulus of the resulting polymer, reduce water content, or both. Examples of these shrinking agents include, but are not limited to, cross-linking agents; low molecular weight monofunctional silicones, moisture-reducing ingredients, combinations thereof, and the like. The desired amount of shrinkage can also be achieved by increasing the amount of diluent used to form the reaction mixture. Each of these contractile agents will be described in detail below.
A cross-linking agent is a compound having two or more polymerizable groups. The "polymerizable group" used herein is a group that reacts under the polymerization conditions in which the reaction mixture is provided. In general, suitable reactive groups include free radicals such as acrylate, styryl, vinyl, vinyl ether, itaconate groups, acrylamide, N-vinyllactam, N-vinylamide or cationic reactive groups (eg vinyl ether or epoxide groups). Contains reactive groups. (Meta) acrylate groups are commonly used. The term "(meta)" used herein refers to an optional methyl substituent. Thus, terms such as "(meth) acrylate" mean both methacrylic and acrylic groups. The cross-linking agent may be hydrophilic or hydrophobic. In the present invention, the amount of cross-linking agent effective to provide the desired shrinkage is usually at least about 2 mol%, in some embodiments at least about 2.5 mol%, and in other embodiments at least about 3 mol%. It turned out to be. It is also known that the cross-linking agent affects the modulus of the resulting polymer. Usually about 200psi (about 14.1kg / cm)<sup>2</sup>) Is preferred. Approximately 150 psi (approximately 10.6 kg / cm) depending on the embodiment<sup>2</sup>Modulus less than) is preferred, and in other embodiments it is about 125 psi (about 8.8 kg / cm).<sup>2</sup>) Is preferred. Therefore, in order to produce a polymer with a modulus lower than the limits specified herein, the amount of cross-linking agent used should be selected. In some embodiments, it may be preferable to use a combination of multiple shrinkage agents in order to obtain the desired percentage shrinkage without raising the modulus beyond the desired range.
Examples of suitable hydrophilic cross-linking agents include compounds having two or more polymerizable groups and hydrophilic functional groups such as polyethers, amides or hydroxy groups. Specific examples of hydrophilic cross-linking agents include tetraethylene glycol dimethacrylate (TEGDMA), triethylene glycol dimethacrylate (TrEGDMA), ethylene glycol dimethacrylate (EGDMA), ethylene glycol dimethacrylate, glycerol dimethacrylate and their like. Combinations are included, but not limited to these.
Hydrophobic crosslinkers can also be used. Examples of suitable hydrophobic cross-linking agents include polyfunctional hydroxyl functional silicone-containing monomers, polyfunctional polyether polydimethylsiloxane block copolymers, combinations thereof and the like. Specific hydrophobic cross-linking agents include acryloxylpropyl-terminated polydimethylsiloxane (n = 10 or 20) (acPDMS), hydroxylacrylate functional siloxane macromer, methacryloxylpropyl-terminated PDMS, butanediol dimethicone, divinylbenzene, 1, Includes 3-bis (3-methacryloxypropyl) tetrakis (trimethylsiloxy) disiloxane and mixtures thereof.
Preferred cross-linking agents include TEGDMA, EGDMA, acPDMS and combinations thereof.
The shrinkage agent may also include at least one monofunctional low molecular weight silicone. Suitable monofunctional low molecular weight silicones include one polymerizable group, at least one siloxane, and a molecular weight of less than about 1000 (less than about 800 in some embodiments, less than about 700 in other embodiments). The siloxane group can be a terminal group {eg, mono, bis and tri (trialkylsiloxy) silane}, or it can be linear, as in polyalkylsiloxane (eg, polydimethylsiloxane). Specific examples of suitable monofunctional low molecular weight silicones include monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (mPDMS), 2-methyl-, 2-hydroxy-3- [3- [1, 3,3,3-Tetramethyl-1-[(trimethylsilyl) oxy] disiloxanyl] propoxy] propyl ester ("SiGMA"), 2-hydroxy-3-methacryloxypropyroxypropyl-tris (trimethylsiloxy) silane, 3- Methacryloxypropyltris (trimethylsiloxy) silane (TRIS), 3-methacryloxypropylbis (trimethylsiloxy) methylsilane and 3-methacryloxypropylpentamethyldisiloxane, mono- (3-methacryloxy-2-hydroxypropyroxy) Includes propyl-terminated, mono-butyl-terminated polydimethylsiloxanes, silicone-containing methacrylicamide monomers as disclosed in US2005-0176911 (the disclosure of which is incorporated herein by reference), combinations thereof, etc. , Not limited to these.
When silicones with molecular weights greater than about 1000 are replaced with monofunctional low molecular weight silicones, mold release is improved. In some embodiments, the amount of monofunctional low molecular weight silicone effective for mold release is such that at least about 10% by weight of the silicone having a molecular weight greater than about 1000 is replaced by at least one monofunctional low molecular weight silicone. This amount is from about 20 to about 100% by weight, depending on the embodiment. In other embodiments, about 40 to about 100% by weight of the silicone having a molecular weight greater than about 1000 is replaced with at least one monofunctional low molecular weight silicone.
Instead of or in addition to the above shrinking agents, the shrinking agent may include at least one water reducing compound (WCD compound). A suitable WCD compound reduces the water content of the polymer in which the compound is incorporated. In some embodiments, sufficient amounts of WCD compounds are incorporated to reduce water content by at least about 1% compared to configurations without WCD compounds, while in other embodiments at least about 2% water content is incorporated. A sufficient amount of WCD compound is incorporated to reduce it. Suitable WCD compounds are silicone-free compounds that are less hydrophilic than the components in the reaction mixture to be replaced. For example, comparing Example 1 and Example 5, in Example 5, 4.5% by weight of N, N-dimethylacrylamide (DMA) is replaced with 2-hydroxyethyl methacrylate (HEMA). As the ratio of HEMA used to the more hydrophilic components (eg N, N-dimethylacrylamide) increases, the mold release time decreases. This is especially true when other release agents are also included. The relative contribution of various contact lens-forming components to water is generally known in the art, and using the teachings herein, other suitable WCD compounds will be apparent to those skilled in the art. Let's do it.
The amount of diluent used in the reaction mixture also affects mold release, with larger amounts of diluent reducing mold release time. If the amount of other release agent is large (eg, the amount of shrinking agent that gives a shrinkage of 4% or more), the amount of diluent can be less than about 45% of the reaction mixture. Alternatively, it can be less than 40% by weight. However, if the amount of other shrinking agent is small (amount that gives less than 4% shrinkage), the amount of diluent can be between about 45 and about 60% by weight based on the weight of the reaction mixture.
As mentioned above, the effects of the various shrinkage agents can be additive, and by incorporating two or more shrinkage agents, a formulation with good releasability and polymer properties can be made. For example, if more than about 40% moisture is desired, a silicone-free crosslinker (such as TEDGMA) in an amount of about 2 mol% and a diluent at a level of about 55% by weight can be used. Based on the teachings here, other combinations of contractile agents will be apparent to those skilled in the art.
The shrinkage agent is incorporated into the reaction mixture along with the reactive components. Any reactive component suitable for making silicone hydrogels may be included. Suitable ingredients include hydrophilic ingredients, silicone-containing ingredients, reactive and non-reactive internal wetting agents, compatibilizing ingredients, reactive and non-reactive pigments {eg tints, dyes, pigments}, UV Absorbent compounds and other eye additives {photochromic compounds, therapeutic and nutriceutical eye additives (eg, eye medicines, antibacterial compounds, antifungal compounds, stabilizers, antioxidants) Agents, combinations thereof, etc.) are included, but not limited to}. One of the features of the present invention is that mold release in aqueous solution can be achieved without sacrificing desired lens properties. For example, in one embodiment, a silicone hydrogel contact lens with the following properties can be produced.
Oxygen permeability about 50 barrels (barrer), depending on the embodiment about 100 barrels Modulus 150psi (approx. 10.6kg / cm)<sup>2</sup>), 100psi (about 7.0kg / cm) depending on the embodiment<sup>2</sup>) Moisture> 30%, depending on the embodiment> 40%
In some embodiments, the manufactured article has two or more of the properties listed above.
The reaction mixture of the present invention contains at least one silicone-containing component.
The term "ingredient" includes monomers, macromers and prepolymers. "Monomer" means a low molecular weight compound that can be polymerized into a higher molecular weight compound, polymer, macromer or prepolymer. The term "macromer" as used herein means a high molecular weight polymerizable compound. The prepolymer is a partially polymerized monomer or a monomer that can be further polymerized.
A "silicone-containing component" is a component that contains at least one [-Si-O-] unit in a monomer, macromer or prepolymer. Preferably, the total Si and the O bound thereto are present in the silicone-containing component in an amount greater than about 20% by weight. More preferably, it is present in an amount larger than 30% by weight of the total molecular weight of the silicone-containing component. Preferably, useful silicone-containing components include polymerizable functional groups such as acrylates, methacrylates, acrylamides, methacrylamides, vinyls, N-vinyllactams, N-vinylamides and styryl functional groups. Examples of silicone-containing components useful in the present invention can be found in US Pat. Nos. 3,808,178; 4,120,570; 4,136,250; 4,153,641; 4,740,533; 5,034,461 and 5,070,215 and EP080539. These references disclose many examples of olefinic silicone-containing components.
Suitable silicone-containing components include compounds of formula 1.<chemistry num="1"><img file="JP2010501366A_D0001.tif" /></chemistry>
Where R<sup>1</sup>Is a monovalent reactive group, a monovalent alkyl group or a monovalent aryl group, any of these, and further, hydroxy, amino, oxa, carboxy, alkylcarboxy, alkoxy, amide, carbamate, carbonate, Those that may contain functional groups selected from halogens or combinations thereof; and monovalent siloxane chains containing 1-100 Si-O repeating units, further comprising alkyl, hydroxy, amino, oxa, carboxy, It is independently selected from those which may contain functional groups selected from alkylcarboxynes, alkoxys, amides, carbamates, halogens or combinations thereof.
Also, b = 0 to 500. Here, when b is non-zero, b is understood to be a distribution with a mode equal to the stated value.
Here, at least one R<sup>1</sup>Includes a monovalent reactive group. Also, depending on the embodiment, R between 1 and 3<sup>1</sup>Contains a monovalent reactive group.
The "monovalent reactive group" used herein is a group capable of performing free radical polymerization and / or cationic polymerization. Non-limiting examples of free radical reactive groups include (meth) acrylates, styryl, vinyl, vinyl ethers, C.<sub>1-6</sub>Alkyl (meth) acrylate, (meth) acrylamide, C<sub>1-6</sub>Alkyl (meth) acrylamide, N-vinyl lactam, N-vinylamide, C<sub>2-12</sub>Alkenyl, C<sub>2-12</sub>Alkenyl phenyl, C<sub>2-12</sub>Alkenyl naphthyl, C<sub>2-6</sub>Alkenyl Phenyl C<sub>1-6</sub>Includes alkyl, O-vinyl carbamate and O-vinyl carbonate. Non-limiting examples of cationically reactive groups include vinyl ether or epoxide groups and mixtures thereof. In one example, free radical reactive groups include (meth) acrylates, acryloxy, (meth) acrylamides and mixtures thereof.
Suitable monovalent alkyl and aryl groups include unsubstituted monovalent C<sub>1</sub>~ C<sub>16</sub>Alkyl group, C<sub>6</sub>-C<sub>14</sub>Aryl groups and the like (eg, substituted and unsubstituted methyl, ethyl, propyl, butyl, 2-hydroxypropyl, propoxypropyl, polyethyleneoxypropyl, combinations thereof) are included.
In one embodiment, b is zero and one R<sup>1</sup>Is a monovalent reactive group, with at least three Rs<sup>1</sup>Is selected from monovalent alkyl groups having 1 to 16 carbon atoms. In another embodiment, it is selected from monovalent alkyl groups having 1-6 carbon atoms. Non-limiting examples of the silicone component of this embodiment include 2-methyl-, 2-hydroxy-3- [3- [1,3,3,3-tetramethyl-1-[(trimethylsilyl) oxy] disyloxanyl. ] Propoxy] Propyl ester ("SiGMA"), 2-Hydroxy-3-methacryloxypropyroxypropyl-tris (trimethylsiloxy) silane, 3-methacryloxypropyltris (trimethylsiloxy) silane ("TRIS"), 3-methacry Includes loxypropylbis (trimethylsiloxy) methylsilane and 3-methacryloxypropylpentamethyldisiloxane.
In another embodiment, b is 2 to 20, 3 to 15, or 3 to 10 in some embodiments; at least one terminal R.<sup>1</sup>Contains a monovalent reactive group, with a residual R<sup>1</sup>Is selected from monovalent alkyl groups having 1 to 16 carbon atoms. Then, in another embodiment, it is selected from monovalent alkyl groups having 1 to 6 carbon atoms. In yet another embodiment, b is 3 to 15 and one terminal R.<sup>1</sup>Contains a monovalent reactive group and the other terminal R<sup>1</sup>Contains a monovalent alkyl group having 1 to 6 carbon atoms, with a residual R<sup>1</sup>Contains a monovalent alkyl group having 1-3 carbon atoms. A non-limiting example of the silicone component of this embodiment is (mono- (2-hydroxy-3-methacryloxypropyl) -propyl ether-terminated polydimethylsiloxane (400-1000 molecular weight)) ("OH-mPDMS"). , Monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (800-1000 molecular weight) (mPDMS).
In another embodiment, b is 5 to 400 or 10 to 300 and both ends R<sup>1</sup>Contains a monovalent reactive group, with a residual R<sup>1</sup>Is independently selected from monovalent alkyl groups that have 1 to 18 carbon atoms, can have ether bonds between the carbon atoms, and can also contain halogens.
In another embodiment, one to four Rs<sup>1</sup>Includes the following vinyl carbonate or vinyl carbamate. Equation II<chemistry num="2"><img file="JP2010501366A_D0002.tif" /></chemistry>
Here, Y means O-, S- or NH-. R means hydrogen or methyl. d is 1,2,3 or 4. And q is 0 or 1.
Specific examples of the silicone-containing vinyl carbonate monomer or vinyl carbamate monomer include 1,3-bis [4- (vinyloxycarbonyloxy) but-1-yl] tetramethyl-disiloxane; 3- (vinyloxycarbonylthio). ) Propyl- [Tris (trimethylsiloxy) silane]; 3- [Tris (trimethylsiloxy) silyl] propylallyl carbamate; 3- [Tris (trimethylsiloxy) silyl] propylvinylcarbamate; trimethylsilylethyl vinyl carbonate; and,<chemistry num="3"><img file="JP2010501366A_D0003.tif" /></chemistry>Is included.
One R if a biomedical device with a modulus of less than about 200 is desired<sup>1</sup>Only have a monovalent reactive group, the residual R<sup>1</sup>Two or less of the groups have a monovalent siloxane group.
In one embodiment, if a silicone hydrogel lens is desired, the lenses of the invention are at least about 20% by weight, and preferably about 20-70, based on the total weight of the reactive monomer components for making the polymer. Manufactured from a reaction mixture containing% by weight of silicone-containing components.
Another group of silicone-containing ingredients includes polyurethane macromers of the formula: Equation IV ~ VI (* D * A * D * G)<sub>a</sub>* D * D * E<sup>1</sup>; E (* D * G * D * A)<sub>a</sub>* D * G * D * E<sup>1</sup>, Or; E (* D * A * D * G)<sub>a</sub>* D * A * D * E<sup>1</sup>here,
D means an alkyl diradical, an alkylcycloalkyldiradical, a cycloalkyldiradical, an aryldiradical or an alkylaryldiradical having 6 to 30 carbon atoms.
G means an alkyl diradical, a cycloalkyl diradical, an alkylcycloalkyldiradical, an aryldiradical or an alkylaryldiradical having 1 to 40 carbon atoms, which may contain an ether, thio or amine bond in the main chain.
* Means urethane or ureido bond.<sub>a</sub>Is at least 1. A represents the divalent polymerizable group of the following formula. Equation VII<chemistry num="4"><img file="JP2010501366A_D0004.tif" /></chemistry>
R<sup>11</sup>Means an alkyl or fluorine-substituted alkyl group having 1 to 10 carbon atoms, which may independently contain an ether bond between the carbon atoms. y is at least 1. And p gives a partial weight of 400-10,000. E and E<sup>1</sup>Means each independently a polymerizable unsaturated organic group represented by the following formula. Equation VIII<chemistry num="5"><img file="JP2010501366A_D0005.tif" /></chemistry>Where R<sup>12</sup>Is hydrogen or methyl; R<sup>13</sup>Is hydrogen, an alkyl group with 1-6 carbon atoms or -CO-YR<sup>15</sup>Group (where Y is -O-, YS- or -NH-) and R<sup>14</sup>Is a divalent group with 1-12 carbon atoms; X is -CO- or -OCO-; Z is -O- or -NH-; Ar is 6-30 carbons It is an aromatic group with atoms; w is 0-6; x is 0 or 1; y is 0 or 1; and z is 0 or 1.
A preferred silicone-containing component is a polyurethane macromer represented by the following formula. Expression IX<chemistry num="6"><img file="JP2010501366A_D0006.tif" /></chemistry>Where R<sup>16</sup>Is a diradical after removing the isocyanate group of the diisocyanate (for example, the diradical of isophorone diisocyanate). Another suitable monosilicone-containing macromer is a compound of formula X formed by the reaction of fluoroether, hydroxy-terminated polydimethylsiloxane, isophorone diisocyanate and isocyanatoethyl methacrylate (where x + y is in the range 10-30). Is the number of). Expression X<chemistry num="7"><img file="JP2010501366A_D0007.tif" /></chemistry>
Other silicone-containing components suitable for use in the present invention include those described in WO 96/31792 (eg, macromers including polysiloxanes, polyalkylene ethers, diisocyanates, polyfluorinated hydrocarbons, polyfluorinated ethers and polysaccharide groups). ) Is included. US Pat. Nos. 5,321,108; 5,387,662 and 5,539,016 describe polysiloxanes with polar fluorinated graft groups or side groups that have hydrogen atoms attached to terminal difluorosubstituted carbon atoms. US2002 / 0016383 describes hydrophilic siloxanyl methacrylate having an ether bond and a siloxanyl bond, and a crosslinkable monomer having a polyether group and a polysiloxanyl group. Any of the above-mentioned polysiloxanes can also be used as the silicone-containing component of the present invention.
The reaction mixture may also contain at least one hydrophilic component. The hydrophilic monomer can be any hydrophilic monomer known to be useful for making hydrogels.
One group of suitable hydrophilic monomers includes acrylic or vinyl containing monomers. Such hydrophilic monomers can themselves be used as cross-linking agents, but when hydrophilic monomers with two or more polymerizable functional groups are used, in order to provide contact lenses with the desired modulus, Their concentration must be limited as described above. The term "vinyl type" or "vinyl-containing" monomer is a vinyl group (-CH = CH).<sub>2</sub>), Which is usually very reactive. Such hydrophilic vinyl-containing monomers are known to polymerize relatively easily.
An "acrylic type" or "acrylic-containing" monomer is a monomer containing an acrylic group (CH).<sub>2</sub>= CRCOX) (where R is H or CH<sub>3</sub>And X is O or N. This monomer is also known to be easily polymerized. For example, N, N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), glycerol methacrylate, 2-hydroxyethylmethacrylamide, polyethylene glycol monomethacrylate, methacrylic acid and acrylic acid.
Hydrophilic vinyl-containing monomers that can be incorporated into the silicone hydrogels of the present invention include N-vinylamide, N-vinyllactam (eg, N-vinylpyrrolidone or NVP), N-vinyl-N-methylacetamide, N-vinyl-N. -Contains monomers such as ethylacetamide, N-vinyl-N-ethylformamide, N-vinylformamide. NVP is preferred.
Other hydrophilic monomers that can be used in the present invention include polyoxyethylene polyols in which one or more terminal hydroxyl groups are replaced with functional groups containing polymerizable double bonds. Examples of this example are polyethylene glycol, an ethoxylated alkyl glucoside, and a polyethylene polyol having one or more terminally polymerizable olefin groups bonded to the polyethylene polyol via a bonding moiety such as a carbamate or an ester group. , And ethoxylated bisphenol A reacted with at least one molar equivalent of a terminal-capping group {eg, isocyanatoethyl methacrylate (IEM), methacrylic anhydride, methacryl chloride, vinyl benzoyl, etc.} included.
Further examples include the hydrophilic vinyl carbonate monomer or vinyl carbamate monomer disclosed in US Pat. No. 5,070,215 and the hydrophilic oxazolone monomer disclosed in US Pat. No. 4,910,277. Other suitable hydrophilic monomers will be apparent to those skilled in the art.
In one embodiment, hydrophilic monomers include DMA, HEMA, glycerol methacrylate, 2-hydroxyethylmethacrylate, NVP, N-vinyl-N-methylacrylamide, N-methyl-N-vinylacetamide, polyethylene glycol monomethacrylate, methacrylic. Includes at least one of acid and acrylic acid. In one embodiment, the hydrophilic monomer comprises DMA.
Hydrophilic monomers can be present in a wide range of amounts, depending on the specific balance of desired properties. An amount of hydrophilic monomer up to about 50% by weight, preferably between about 5 and about 50% by weight, is acceptable based on all components in the reactive component. For example, in one embodiment, the lens of the present invention contains at least about 30% water content, and in another embodiment it contains water content between about 30 and about 70%. For these embodiments, the hydrophilic monomer may be included in an amount between about 20% and about 50% by weight.
Other ingredients such as reactive and non-reactive wetting agents disclosed in US2003 / 016862, US05 / 06640, US2006 / 0072069, WO2006 / 039276 may also be included. When a wetting agent is used, it is also preferable that a compatibilizing component is contained. Suitable compatible components include those that meet the compatibility test disclosed in US2003 / 016862. Any of the above silicone components can be converted into a compatible component by incorporating a compatible group such as a hydroxyl group into the structure. In some embodiments, the Si to OH ratio is less than about 15: 1, and in other embodiments it is between about 1: 1 and about 10: 1. Non-limiting examples of compatibilizing components include (mono- (2-hydroxy-3-methacryloxypropyl) -propyl ether-terminated polydimethylsiloxane (400-1000 molecular weight)), "OH-mPDMS", 2-methyl. -, 2-Hydroxy-3- [3- [1,3,3,3-Tetramethyl-1-[(trimethylsilyl) oxy] disiloxanyl] Propyl] Propyl ester "SiGMA", 2-Hydroxy-3-methacryloxypropi Includes loxypropyl-tris (trimethylsiloxy) silanes, combinations thereof and the like.
The reaction mixture may contain a polymerization catalyst. The polymerization initiator includes, for example, compounds such as lauryl peroxide, benzoyl peroxide, isopropyl percarbonate, and azobisisobutyronitrile that generate free radicals at a slightly high temperature, and aromatic α-hydroxyketone and alkoxyoxy. Photoinitiator systems such as benzoins, acetophenones, acylphosphine oxides, bisacylphosphine oxides and tertiary amines + diketones, mixtures thereof, etc. are included. Typical examples of photoinitiators are 1-hydroxycyclohexylphenyl ketone, 2-hydroxy-2-methyl-1-phenyl-propan-1-one, bis (2,6-dimethoxybenzoyl) -2,4- 4-trimethylpentylphosphine oxide (DMBAPO), bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide (Irgacure) 819), 2,4,6-trimethylbenzyldiphenylphosphine oxide and 2,4,6-trimethylbenzoyldiphenylphosphine oxide, benzoin methyl ester and a combination of camphoquinone and ethyl 4- (N, N-dimethylamino) benzoate is there. Commercially available visible light initiator systems include Irgacure 819, Irgacure 1700, Irgacure 1800, Irgacure 819, Irgacure 1850 (all available from Ciba Specialty Chemicals) and Lucirin TPO initiators (available from BASF). Commercially available UV photoinitiators include Darocur 1173 and Darocur 2959 (Ciba Specialty Chemicals). These and other photoinitiators that can be used are Photoinitiators for Free Radical Cationic & Anionic Photopolymerization by JV Crivello & K. Dietliker, Volume 3, 2nd Edition, G.M. Published in Bradley, edited by John Wiley and Sons, New York, 1998. The initiator is used in the reaction mixture in an amount effective to initiate photopolymerization of the reaction mixture, eg, about 0.1 to about 2 parts by weight per 100 parts by weight of the reactive monomer. Polymerization of the reaction mixture can be initiated by appropriate selection of heat or visible light or ultraviolet light or other means, depending on the polymerization initiator used. Alternatively, no photoinitiator is used and the initiation can be performed using, for example, an electron beam. However, if a photoinitiator is used, bisacylphosphine oxide {eg, bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide (Irgacure) 819®) or a combination of 1-hydroxycyclohexylphenyl ketone and bis (2,6-dimethoxybenzoyl) -2,4-4-trimethylpentylphosphine oxide (DMBAPO)} is the preferred initiator. In another embodiment, excitation with visible light is the method of initiating polymerization. A preferred initiator is bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide (Irgacure 819®).
Under reaction conditions, a diluent having a low polarity sufficient to solubilize the non-polar components in the reaction mixture is a suitable diluent. One method that characterizes the polarity of the diluent of the present invention is the method based on the Hansen solubility parameter, δp. In some embodiments, δp is less than about 10, preferably less than about 6. Suitable diluents are further disclosed in US Serial Numbers 60/452898 and US 6,020,445. Suitable groups of diluents include alcohols with 2 to 20 carbons, amides with 10 to 20 carbon atoms and derived from primary amines, ethers with 3 to 10 carbon atoms, polyethers, Includes, but is not limited to, ketones and carboxylic acids with 8 to 20 carbon atoms. For all solvents, as the number of carbons increases, so does the number of polar moieties, so that the desired level of miscibility with water can be obtained. In some embodiments, primary and tertiary alcohols are preferred. Preferred groups include alcohols having 4 to 20 carbons and carboxylic acids having 10 to 20 carbon atoms.
In some embodiments, the diluent has some solubility in water. In some embodiments, at least 5% diluent can be miscible with water. Examples of water-soluble diluents include 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, 2-pentanol, t- Amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol, 3,3-dimethyl-2-butanol, decanoic acid, octanoic acid, Dodecanoic acid, 1-ethoxy-2-propanol, 1-tert-butoxy-2-propanol, EH-5 (commercially available from Ethox Chemicals), 2,3,6,7-tetrahydroxy-2,3 , 6,7-Tetramethyloctane, 9- (1-methylethyl) -2,5,8,10,13,16-hexaoxaheptadecane, 3,5,7,9,11,13-hexamethoxy- 1-Tetradecanol, tripropylene glycol methyl ether, mixtures thereof, etc. are included.
The reaction mixture of the present invention can be cured by any known method for molding the reaction mixture in the manufacture of contact lenses, such as spin casting and static casting. The spincast method is disclosed in US Pat. Nos. 3,408,429 and 3,660,545, and the static cast method is disclosed in US Pat. Nos. 4,113,224 and 4,197,266. In one embodiment, the contact lenses of the invention are made by direct molding of silicone hydrogel, but this method is economical and allows precise control of the final shape of the hydrated lens. is there. In this method, the reaction mixture is placed in a mold with the shape of the final desired silicone hydrogel (ie, a water-swelled polymer) and the reaction mixture is subjected to conditions under which the monomers polymerize, thereby finalizing. A polymer having a shape close to that of a desired product is produced.
With reference to FIG. 1, an ocular lens 100 (eg, a contact lens) and a molded portion 101-102 used to form the ophthalmic lens 100 are illustrated. In some embodiments, the mold portion includes a back mold portion 101 and a front mold portion 102. As used herein, the term "front molded portion" means a molded portion whose concave surface 104 is a lens forming surface used to form the anterior surface of an ophthalmic lens. Similarly, the term "back molding mold portion" means a molding mold portion 101 whose convex surface 105 forms a lens forming surface that forms the back surface of the ophthalmic lens 100. In some embodiments, the mold portions 101 and 102 have a concavo-convex shape and preferably include a planar annular flange that surrounds the top edge of the concavo-convex region of the mold portions 101-102.
Typically, mold portions 101-102 are arranged as a "sandwich". The front mold portion 102 is at the bottom, and the concave surface 104 of the mold portion faces upward. The back molding portion 101 may be symmetrically arranged on the front molding portion 102 with the convex surface 105 of the back molding portion 101 partially protruding into the concave area of the front molding portion 102. The back mold portion 101 has a convex surface 105 that engages with the outer edge of the concave surface 104 of the front mold portion 102 over the entire circumference, thereby forming a sealed mold for forming the ophthalmic lens 100. The dimensions are preferably such that they cooperate to form a cavity.
In some embodiments, molding portions 101-102 are formed from a thermoplastic and are permeable to polymerization initiation chemicals. Permeable to this polymerization initiation chemical line means at least some, preferably all, of radiation having an intensity and wavelength effective to initiate the polymerization of the reaction mixture in the cavity of the mold. Means that can pass through mold portions 101-102.
For example, suitable thermoplastics for making mold parts include polystyrene; polyvinyl chloride; polyolefins (eg polyethylene and polypropylene); copolymers of styrene and acrylonitrile or butadiene or mixtures thereof, polyacrylonitrile, polyamides, polyesters, etc. Cyclic olefin copolymers or other known materials may be included.
After polymerization of the reaction mixture to form the lens 100, the lens surface 103 usually adheres to the molded partial surface 104. The steps of the present invention facilitate the release of the surface 103 from the surface of the molding part.
The first mold portion 101 can be separated from the second mold portion 102 in the mold removal process. In some embodiments, the lens 100 adheres to the second mold portion 102 (ie, the front curved mold portion) during the curing process, and after separation, the lens 100 is removed from the front curved mold portion 102. It is left in the second mold portion 102 until it is made. In other embodiments, the lens 100 may adhere to the first mold portion 101.
The lens 100 and the molded portion to which the lens is attached after demolding are brought into contact with the aqueous solution. The aqueous solution can be heated to any temperature below the boiling point of the aqueous solution. For example, in one embodiment, the temperature of the aqueous solution can be raised to about 40 to about 80 ° C, in another embodiment it can be raised to about 30 to 70 ° C, and in yet another embodiment, it can be raised to about 30 to 70 ° C. It can be raised to about 46 to about 65 ° C. Heating can be achieved using a heat exchanger that minimizes the possibility of explosion, or by using any other available means or device for heating the liquid.
The aqueous solution is mainly water. In some embodiments, the aqueous solution contains at least about 70% by weight of water, and in other embodiments contains at least about 90% water. The aqueous solution can also be a packaging solution for contact lenses. This aqueous solution may contain additives. This additive includes, for example, Tween 80 (polyethylene sorbitan monooleate), tyroxapol, octylphenoxy (oxyethylene) ethanol, amphoteric 10 (amphoteric 10), preservatives (eg EDTA), sorbic acid, DYMED, chlor. There are hexadin gluconate, hydrogen peroxide, thimerosal, polyquad, polyhexamethylene biguanide, antibacterial agents, lubricants, salts and buffers. In some embodiments, the additive may be added to the hydrated solution in an amount between 0.01 and 10% by weight (although the cumulative value is less than about 10% by weight).
Exposure of the ophthalmic lens 100 to an aqueous solution can be performed by any method, such as washing, spraying, dipping, submerging, or any combination thereof. For example, in some embodiments, the lens 100 may be washed in an aqueous solution containing deionized water in a hydration tower.
In embodiments that use a hydration tower, the front curved mold portion 102 that houses the lens 100 can be placed in a pallet or tray and stacked vertically. The aqueous solution can be supplied from the top of the stack of lenses 100 so that the solution flows down over the lenses 100. The solution can also be supplied from various locations on the tower. In some embodiments, the tray can be moved upwards to allow the lens 100 to better expose the fresher solution.
In another embodiment, the ophthalmic lens 100 is immersed or submerged in an aqueous solution.
The contact step may continue for about 2 to about 400 minutes, for some embodiments about 10 to about 180 minutes, and for other embodiments about 15 to about 30 minutes. However, the length of the contact step depends on the lens material containing any additives, the material used in the solution or solvent, and the temperature of the solution. Generally, after a sufficient treatment time, the contact lens contracts and is released from the molding part.
Depending on the preferred method, when the contact lens demolds from the front surface after separation or demolding, the lens on the front surface, which can be part of the frame, is individually grooved to receive the contact lens. Combined with a cup. These cups can be part of the tray. Examples include trays, each with 32 lenses, and 20 trays that can be stacked in a magazine.
According to another embodiment of the present invention, the lens is immersed in an aqueous solution. In one embodiment, the magazines can be stacked and then dropped into a tank containing the aqueous solution. The aqueous solution may also contain other additives as described above.
Modulus is measured using a crosshead lowered to the initial gauge height of a constant speed moving type tension tester equipped with a load cell. Suitable test machines include the Instron model 1122. Grip a bone-shaped sample for dogs with a length of 0.522 inches, an "ear" width of 0.276 inches, and a "neck" width of 0.213 inches. And pull at a constant speed of 2 inches / minute (about 5.1 cm / minute) until it breaks. Measure the initial gauge length (Lo) of the sample and the sample length (Lf) at break. For each composition, 12 samples are measured and the mean is reported. Measure the tensile modulus at the initial linear part of the stress / strain curve.
Moisture was measured as follows. Place the lens under test in the packaging solution for 24 hours. Using a cotton swab with a sponge tip, each of the three test lenses is removed from the packaging solution and placed on a suction wipe moistened with the packaging solution. Bring both sides of the lens into contact with the wipe. Using tweezers, place the test lens on the weighing balance plate and weigh it. Prepare a set of two more samples and weigh as above. The balance plate is weighed three times, and the average value is taken as the wet weight.
Dry weight is measured by placing the balance dish containing the sample in a vacuum oven preheated to 60 ° C for 30 minutes. Evacuation is carried out until at least 0.4 inch Hg (about 1 mmHg, ie 133 Pa) is achieved. Turn off the vacuum valve and pump and let the lens dry for 4 hours. Open the purge valve and return the oven to atmospheric pressure. Take out the balance plate and weigh it. Moisture is calculated as follows.
Wet Weight = Wet Weight Combining Balance Plate and Lens-Weight Weight of Weighing Balance Plate Dry weight = Dry weight of the combination of the balance plate and the lens-Weight of the balance plate for weighing
% Moisture content = {(wet weight-dry weight) / wet weight} x 100
The reported samples are for the mean and standard deviation of water.
Oxygen permeability (Dk) can be measured by the polarographic method generally described in ISO9913-1: 1996 (E), including the following modifications. Measurements are performed in an environment containing 2.1% oxygen. This environment is achieved by adjusting the ratio of nitrogen input to air input in the test room to an appropriate ratio (eg, 1800 mL / min of nitrogen and 200 mL / min of air). t / Dk is adjustment po<sub>2</sub>Is calculated using. Borate-buffered saline was used. Dark current was measured using a pure wet nitrogen environment instead of using an MMA lens. Prior to the measurement, the lens was not wiped of moisture. Instead of using lenses of various thicknesses, four lenses were stacked. A curve sensor was used instead of a flat sensor. The obtained Dk value is reported in barrers units.
The dynamic contact angle or DCA is generally measured at 23 ° C using a borate-buffered saline solution and a Wilhelmy balance. A sample piece cut from the central part of the lens at a speed of 100 μm / sec is immersed in the above-mentioned saline solution, and while the sample piece is taken out from the sample piece, the wetting force between the lens surface and the borate-buffered saline solution is measured by using a Wilhelmy microbalance. Use to measure. Use the following formula.
F = 2γpcos θ or θ = cos<sup>-1</sup>(F / 2γp) Here, F is the wetting force, γ is the surface tension of the test liquid, p is the peripheral length of the sample in the meniscus, and θ is the contact angle. Generally, a dynamic wetting test determines two contact angles-a forward contact angle and a backward contact angle. The forward contact angle is determined from the wet test part when the sample is immersed in the test liquid. These are the values reported here. Measure at least 4 lenses for each composition and report the mean.
It goes without saying that all the tests specified here have a certain amount of unique test error. Therefore, the results reported here are not absolute numbers and are expressed in a numerical range based on the accuracy of a particular test.
The following examples are included to illustrate the invention. These examples do not limit the invention. These are only intended to propose one way of carrying out the present invention. Anyone with expertise in a specialized field such as contact lenses will be able to find other ways to carry out the present invention. However, those methods are considered to be within the scope of the present invention.
[Example] The following abbreviations are used in the following examples. Macromer US-2003-0052424-A1 Macromer made according to the procedure disclosed in the section "Macromer Preparation" of Example 1. DMA N, N-dimethylacrylamide HEMA 2-Hydroxyethyl methacrylate Monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane produced by mPDMS Gelest (molecular weight specified in Examples) Norbloc 2- (2'-Hydroxy-5-methacryloxyethyl phenyl) -2H-benzotriazole PVP Poly (N-Vinylpyrrolidone) (Note K Value) Blue HEMA Reaction product of Reactive Blue 4 and HEMA described in Example 4 of US Pat. No. 5,944,853. mPDMS-OH Mono- (3-methacryloxy-2-hydroxypropyroxy) propyl-terminated, monobutyl-terminated polydimethylsiloxane prepared according to Example 29, molecular weight 612 TEGDMA Tetraethylene glycol dimethacrylate EGDMA ethylene glycol dimethacrylate acPDMS bis-3-acryloxy-2-hydroxypropyroxypropyl polydimethylsiloxane (molecular weight 1000 and 2000, acrylated polydimethylsiloxane) (from Gelest and Degussa, respectively) MaPDMS Gelest methacryloxypropyl-terminated polydimethylsiloxane (molecular weight 550-700) CGI 819 bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide
Throughout the examples, the intensity is measured using an IL1400A radiometer with an XRL140A sensor.
[Examples 1 to 10-Manufacturing of contact lenses] The monomer components listed in Table 1 (denoted by weight% based on all components except diluent) were mixed with t-amyl alcohol (% by weight based on all components including diluent) and 20 (% by weight based on all components including diluent). Degassed at vacuum {650 (± 100) mmHg (approximately 865 (± 133) hPa)} and 25 (± 5) ° C for ± 5) minutes. Each reaction mixture was charged into a thermoplastic contact lens molding die (a front curved surface made from Zeonor® obtained from Zeon Co., Ltd. and a back curved surface made from polypropylene) at 55 (± 5) ° C. TL20W 03T lamp (approx. 1.5 ~ 3.0mW / cm) under nitrogen atmosphere for 25 (± 5) minutes.<sup>2</sup>) Was used for irradiation. The resulting lens is manually demolded and released by immersing the lens in the front curved surface (FC) mold in DI (deionized) water at 90 (± 5) ° C for approximately 2 minutes. did. If the lens did not release from the FC mold in 2 minutes, the lens was maintained in DI water at 90 (± 5) ° C and sprayed with this DI water using a disposable pipette. If the lens still did not release from the FC, then I swabbed the lens from the FC by hand. Lens release speed is 1 = complete lens release, 2 = simple operation required to release the lens (eg watering with a pipette), and 3 = lens does not release from FC Swabbing is required, evaluated on a scale of 1-3. The lens was then transferred to a jar and subjected to two "change-out" steps: Step 1) 90 (± 5) ° C DI for a minimum of 30 minutes with water, Step 2) 25 (± 5) ° C DI Water for a minimum of 30 minutes. The lens was then equilibrated in the packaging solution and tested in the packaging solution. The lens was placed in a vial containing 5-7 mL of borate-buffered saline, covered, and disinfected at 120 ° C for 30 minutes. Tables 1 and 2 show the formulation, lens properties and mold release properties, respectively. The listed lens diameters were measured at room temperature in the packaging solution.
<tables num="1"><img file="JP2010501366A_D0008.tif" /></tables>
<tables num="2"><img file="JP2010501366A_D0009.tif" /></tables>
Examples 1 and 2 have the same composition and diluent except that the concentration of the cross-linking agent in Example 2 is twice that of Example 1 (4% by weight instead of 2% by weight). In Examples 3-8, the cross-linking agent concentration varies from 0.75 to 6% by weight, but the diluent concentration is constant at 50% by weight. Examples 9 and 10 are comparisons between a 2% by weight crosslinker concentration and a 4% by weight crosslinker concentration at a 55% by weight diluent concentration. In each set of examples, mold release improves as the crosslinker concentration increases.
[Examples 11 to 13] The steps of Examples 1-10 were repeated using the monomeric components listed in Table 3 (expressed in% by weight based on all components except diluent). The lens characteristics and mold release results are listed in Table 4. The lens diameter was measured at room temperature in the packaging solution.
<tables num="3"><img file="JP2010501366A_D0010.tif" /></tables>
<tables num="4"><img file="JP2010501366A_D0011.tif" /></tables>
[Examples 14 to 25] Using the cross-linking agent and cross-linking agent concentration as shown in Table 5 below, the following formulations: 46% by weight HO-mPDMS, 7% by weight Macromer, 15% by weight DMA, 12.53% by weight HEMA, 17% by weight PVP, 0.25 wt% CGI 819, 2.2 wt% Norbloc and 0.02 wt% Blue HEMA and 45 wt% t-amyl alcohol / PVP k-12 7: 1 mixture and the process described in Example 1. So, I made a contact lens. The lens was released as described in Example 1. The release results are shown in the last column of Table 5.
<tables num="5"><img file="JP2010501366A_D0012.tif" /></tables>
[Examples 26 to 28] The reaction mixture of Example 26 shown in Table 6 was degassed and cured according to the procedures of Examples 1-10. The reaction mixture of Examples 27 and 28 was evacuated for 15 (± 3) minutes in a vacuum [20 (± 2) mmHg {about 2700 (± 270) Pa}], 25 (± 3) ° C, 127 (± 3) rpm. } Below, degassed. The reaction mixture was placed in a molding die for thermoplastic contact lenses, a weight was placed on the molding die for 10 seconds, and then the molding die was placed in a nitrogen atmosphere for 8 minutes {1.5 mW / cm.<sup>2</sup>Irradiation (2 minutes) followed by 6.0 mW / cm<sup>2</sup>Irradiation (6 minutes) (Philips, High Intensity Bulbs: M2-B1-10)}, cured at 80 ° C. The resulting lens was demolded, immersed in DI water for 10 (± 2) minutes at 90 (± 5) ° C, and then manually swabbed from the front curved surface to release the lens. The lens was then transferred to a hydration tray and placed in a staging tank of 45 (± 10) ° C DI water for a minimum of 30 minutes. The lenses were equilibrated in the packaging solution and tested in the packaging solution. Lenses were placed in vials containing 7 mL borate buffered saline and disinfected at 120 ° C for approximately 20 minutes. The lens characteristics are shown in Table 7.
<tables num="6"><img file="JP2010501366A_D0013.tif" /></tables>
<tables num="7"><img file="JP2010501366A_D0014.tif" /></tables>
[Example 29] A mixed solution of 45.5 kg of 3-allyloxy-2-hydroxypropane methacrylate (AHM) and 3.4 g of butylated hydroxytoluene (BHT) in a xylene solution of Pt (0) divinyltetramethyldisiloxane (2.25% Pt concentration). 10 mL was added, followed by 44.9 kg of n-butylpolydimethylsilane. The reaction temperature was maintained at about 20 ° C by adjusting the heat generated by the reaction. After the n-butylpolydimethylsilane was completely consumed, 6.9 g of diethylethylenediamine was added to inactivate the Pt catalyst. The crude reaction mixture was extracted several times with 181 kg of ethylene glycol to give the raffinate residual AHM concentration <0.1%. To the obtained raffinate, 10 g of BHT was added, and the mixture was stirred until dissolved, and then the residual ethylene glycol was removed to obtain 64.5 kg of OH-mPDMS. 6.45 g of 4-methoxyphenol (MeHQ) was added to the resulting liquid, stirred and filtered to give 64.39 kg of final OH-mPDMS as a colorless oil.
A desired embodiment of the present invention is as follows. [Implementation mode] (1) In the method (a) To form a cured article by curing a reaction mixture containing at least one silicone-containing component and at least one shrinking agent in a molding die. (b) Bringing the cured article in the mold into contact with an aqueous solution under the condition of shrinking the cured article. (c) Optionally, removing the cured article from the mold and Including methods. (2) In the method described in embodiment (1), A method in which the shrinking agent comprises at least one monofunctional low molecular weight linear silicone. (3) In the method described in embodiment (2), A method in which the molecular weight of the linear silicone is less than about 1000. (4) In the method described in embodiment (2), A method in which the molecular weight of the linear silicone is less than about 800. (5) In the method described in embodiment (2), A method in which the molecular weight of the linear silicone is less than about 700. (6) In the method described in embodiment (2), A method in which the linear silicone comprises at least one siloxane group. (7) In the method described in embodiment (2), A method in which the linear silicone comprises at least one polydimethylsiloxane. (8) In the method described in embodiment (2), The linear silicone is monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane, 2-methyl-, 2-hydroxy-3- [3- [1,3,3,3-tetramethyl-1- [3- [1,3,3,3-tetramethyl-1- [3]. (Trimethylsilyl) Oxy] Disiloxanyl] Propyl] Propyl Ester, 2-Hydroxy-3-methacryloxyPropyloxypropyl-Tris (trimethylsiloxy) Silane, 3-Methyloxypropyltris (trimethylsiloxy) Silane, 3-Methyloxypropylbis A group consisting of trimethylsiloxy) methylsilane and 3-methacryloxypropylpentamethyldisiloxane, mono (3-methacryloxy-2-hydroxypropyloxy) propyl-terminated, mono-butyl-terminated polydimethylsiloxane, silicone-containing methacrylicamide, and combinations thereof. The method to choose from. (9) In the method described in embodiment (2), A method in which at least about 10% by weight of the at least one silicone-containing component is replaced with the at least one monofunctional low molecular weight silicone. (10) In the method described in embodiment (2), A method in which about 20-100% by weight of the at least one silicone-containing component is replaced with the at least one monofunctional low molecular weight silicone. (11) In the method described in embodiment (2), A method in which about 40-100% by weight of the at least one silicone-containing component is replaced with the at least one monofunctional low molecular weight silicone. (12) In the method described in embodiment (1), A method in which the contractile agent comprises at least one crosslinkable compound in an amount of at least about 2 mol%. (13) In the method described in embodiment (1), A method in which the contractile agent comprises at least one crosslinkable compound in an amount of at least about 2.5 mol%. (14) In the method described in embodiment (12), A method in which the crosslinkable compound is selected from the group consisting of a hydrophilic crosslinker and a hydrophobic crosslinker. (15) In the method described in embodiment (12), The shrinking agent comprises a hydrophilic crosslinkable compound selected from the group consisting of tetraethylene glycol dimethacrylate, triethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylenediamine dimethacrylate, glycerol dimethacrylate, and combinations thereof. Method. (16) In the method described in embodiment (12), The contractile agents are acryloxipropyl-terminated polydimethylsiloxane (n = 10 or 20), hydroxyl acrylate functional siloxane macromer, methacryloxypropyl-terminated PDMS, butanediol dimethacrylate, divinylbenzene, 1,3-bis (3-methacryloxy). A method comprising a hydrophobic crosslinkable compound selected from the group consisting of propyl) tetrakis (trimethylsiloxy) disiloxane and mixtures thereof. (17) In the method described in embodiment (12), A method, wherein the shrinking agent comprises a crosslinkable compound selected from the group consisting of tetraethylene glycol dimethacrylate, ethylene glycol dimethacrylate, acryloxipropyl-terminated polydimethylsiloxane (n = 10 or 20), and combinations thereof. (18) In the method described in embodiment (1), The method, wherein the reaction mixture further comprises at least one diluent, the diluent being present in an amount of about 40 to about 60% by weight based on the components in the reaction mixture and the weight of the diluent. (19) In the method described in embodiment (18), A method in which the diluent is present in an amount of about 50 to about 60% by weight, based on the components in the reaction mixture and the weight of the diluent. (20) In the method described in embodiment (1), The method, wherein the contact condition comprises a temperature of at least about 80 ° C. (21) In the method described in embodiment (1), The method, wherein the contact conditions include a temperature of at least about 90 ° C. (22) In the method described in embodiment (1), A method in which the shrinking agent comprises at least one water-reducing compound. (twenty three) In the method described in embodiment (1), A method in which the reaction mixture further comprises at least one hydrophilic monomer. (24) In the method described in embodiment (23), A method in which the hydrophilic monomer is present in an amount of about 5-50% by weight. (25) In the method described in embodiment (23), A method in which the hydrophilic monomer is present in an amount of about 20-50% by weight. (26) In the method described in embodiment (23), A method in which the aqueous solution comprises at least about 70% by weight of water. (27) In the method described in embodiment (23), A method in which the aqueous solution comprises at least about 90% by weight of water. (28) In the method described in embodiment (1), A method in which the contact lens shrinks at least about 3% in contact step (b). (29) In the method described in embodiment (1), A method in which the contact lens shrinks at least about 5% in contact step (b). (30) In the method described in embodiment (1), A method in which the contact lens shrinks at least about 7% in contact step (b).
(31) In the method (a) Curing a reaction mixture containing at least one reactive silicone component and a diluent in a mold for forming silicone hydrogel contact lenses, wherein the diluent is the reaction mixture. Curing the reaction mixture, which is present in at least about 40% by weight based on all components, (b) In the molding mold, the contact lens is brought into contact with an aqueous solution under the condition of contracting the contact lens. (c) Optionally, remove the contact lens from the mold and Including methods. (32) In the method described in embodiment (31), A method in which the reaction mixture further comprises at least one shrinking agent. (33) In the method according to embodiment (32), A method in which the shrinking agent comprises at least one monofunctional low molecular weight linear silicone. (34) In the method according to embodiment (33), A method in which the molecular weight of the linear silicone is less than about 1000. (35) In the method described in embodiment (33), A method in which the linear silicone comprises at least one siloxane group. (36) In the method according to embodiment (33), A method in which the linear silicone comprises at least one polydimethylsiloxane. (37) In the method according to embodiment (33), The linear silicone is monomethacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane, 2-methyl-, 2-hydroxy-3- [3- [1,3,3,3-tetramethyl-1- [3- [1,3,3,3-tetramethyl-1- [3]. (Trimethylsilyl) oxy] disyloxanyl] propoxy] propyl ester, 2-hydroxy-3-methacryloxypropyroxypropyl-tris (trimethylsiloxy) silane, 3-methacryloxypropyltris (trimethylsiloxy) silane, 3-methacryloxypropylbis ( From the group consisting of trimethylsiloxy) methylsilane and 3-methacryloxypropylpentamethyldisiloxane, mono- (3-methacryloxy-2-hydroxypropyloxy) propyl-terminated, monobutyl-terminated polydimethylsiloxane, silicone-containing methacrylicamide, and combinations thereof. The method of choice. (38) In the method described in embodiment (32), A method in which the contractile agent comprises at least one crosslinkable compound in an amount of at least about 2 mol%. (39) In the method according to embodiment (38). A method in which the crosslinkable compound is selected from the group consisting of a hydrophilic crosslinker and a hydrophobic crosslinker. (40) In the method according to embodiment (38), A method, wherein the crosslinkable compound is selected from the group consisting of tetraethylene glycol dimethacrylate, ethylene glycol dimethacrylate, acryloxypropyl-terminated polydimethylsiloxane (n = 10 or 20), and combinations thereof. (41) In the method described in embodiment (31), A method in which the diluent is present in an amount of about 40 to about 60% by weight, based on the components in the reaction mixture and the weight of the diluent. (42) In the method described in embodiment (31), A method in which the diluent is present in an amount of about 45 to about 60% by weight, based on the components in the reaction mixture and the weight of the diluent. (43) In the method described in embodiment (31), A method in which the diluent is present in an amount of about 50 to about 60% by weight, based on the components in the reaction mixture and the weight of the diluent. (44) In the method according to embodiment (31), The method, wherein the contact condition comprises a temperature of at least about 80 ° C. (45) In the method according to embodiment (32), A method in which the shrinking agent comprises at least one water-reducing compound. (46) In the method according to embodiment (31), A method in which the reaction mixture further comprises at least one hydrophilic monomer. (47) In the method described in embodiment (31), A method in which the aqueous solution comprises at least about 70% by weight of water. (48) In the method according to embodiment (31), A method in which the contact lens shrinks at least about 3% in contact step (b). (49) In the method described in embodiment (31), A method in which the contact lens shrinks at least about 3% in contact step (b). (50) In the method described in embodiment (31), A method in which the contact lens shrinks at least about 7% in contact step (b).
<figref num="1">It is a figure of an ophthalmic lens and a molded part used for forming an ophthalmic lens.</figref>
14 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6 Sheet 7 Sheet 8 Sheet 9 Sheet 10 Sheet 11 Sheet 12 Sheet 13 Sheet 14
Every citation, both ways
| Document | Relation | Office | Cited during |
|---|---|---|---|
| JP2015524090A | Cited by | Japan | Search report |
| KR20190026826A | Cited by | Republic of Korea | Search report |
| JP2014510953A | Cited by | Japan | Search report |
| WO0144861A1 | Cites | World Intellectual Property Organization (WIPO) | Search report |
| WO2005005517A2 | Cites | World Intellectual Property Organization (WIPO) | Examiner |
| US2005054546A1 | Cites | United States of America | Search report |
| WO2005113028A1 | Cites | World Intellectual Property Organization (WIPO) | Search report |
| US2005179862A1 | Cites | United States of America | Search report |
| US2006202368A1 | Cites | United States of America | Search report |
| JP2006251792A | Cites | Japan | Search report |
| JP2009530690A | Cites | Japan | Examiner |
| US4546123A | Cites | United States of America | Search report |
| JPS57189116A | Cites | Japan | Search report |
38 members in 12 offices
Priority claims9
| Document | Office | Kind | Date |
|---|---|---|---|
| 11427582 | United States of America | – | |
| 42758206 | United States of America | A | |
| 42758206 | United States of America | A | |
| 2007014771 | United States of America | W | |
| 2007014771 | United States of America | W | |
| 2006427582 | – | – | – |
| 2007014771 | – | – | – |
| US20060427582 | – | – | – |
| WO2007US14771 | – | – | – |
Members38
| Document | Office | Kind | |
|---|---|---|---|
| US2007222094A1 | United States of America | A1 | |
| US2007222095A1 | United States of America | A1 | |
| AU2007229482A1 | Australia | A1 | |
| CA2647177A1 | Canada | A1 | |
| WO2007111973A2 | World Intellectual Property Organization (WIPO) | A2 | |
| AU2007269885A1 | Australia | A1 | |
| CA2655878A1 | Canada | A1 | |
| WO2008005229A2 | World Intellectual Property Organization (WIPO) | A2 | |
| TW200804888A | Taiwan Province of China | A | |
| WO2007111973A3 | World Intellectual Property Organization (WIPO) | A3 | |
| TW200819818A | Taiwan Province of China | A | |
| AR060091A1 | Argentina | A1 | |
| AR061755A1 | Argentina | A1 | |
| KR20080113253A | Republic of Korea | A | |
| EP2038683A2 | European Patent Office (EPO) | A2 | |
| KR20090045914A | Republic of Korea | A | |
| CN101454144A | China | A | |
| JP2009530690A | Japan | A | |
| JP2010501366AThis record | Japan | A | |
| RU2008141891A | Russian Federation | A | |
| EP2180992A2 | European Patent Office (EPO) | A2 | |
| WO2008005229A3 | World Intellectual Property Organization (WIPO) | A3 | |
| RU2009102828A | Russian Federation | A | |
| CN102105819A | China | A | |
| RU2422278C2 | Russian Federation | C2 | |
| BRPI0709116A2 | Brazil | A2 | |
| BRPI0713545A2 | Brazil | A2 | |
| AU2007229482B2 | Australia | B2 | |
| US8414804B2 | United States of America | B2 | |
| US2013175722A1 | United States of America | A1 | |
| TWI404991B | Taiwan Province of China | B | |
| CN101454144B | China | B | |
| KR101342878B1 | Republic of Korea | B1 | |
| CA2647177C | Canada | C | |
| US8714738B2 | United States of America | B2 | |
| JP5686967B2 | Japan | B2 | |
| BRPI0709116B1 | Brazil | B1 | |
| EP2180992B1 | European Patent Office (EPO) | B1 |
4 legal events, as the office reported them to INPADOC
Over the term
Point at a mark for the eventEvents
| Event | Code | |
|---|---|---|
| Decision of refusalJAPANESE INTERMEDIATE CODE: A02A02 | A02 | |
| Notification of reasons for refusalJAPANESE INTERMEDIATE CODE: A131A131 | A131 | |
| Notification of resignation of power of attorneyJAPANESE INTERMEDIATE CODE: A7424RD04 | RD04 | |
| Written request for application examinationJAPANESE INTERMEDIATE CODE: A621A621 | A621 |
Numbers
- Publication
- 2010501366
- Publication, DOCDB
- 2010501366
- Publication, EPODOC
- JP2010501366
- Application
- 2009518211
- Application, DOCDB
- 2009518211
- Application, EPODOC
- JP20090518211
Titles2
- Japanese
- 眼用レンズの製造方法
- English
- Manufacturing method of ocular lens
Classification
- CPC, 4
- B29D11/0025
- G02B1/043
- B29D11/00067
- C08L83/04
- IPC, 5
- B29D11 00
- G02C7 04
- B29C33 64
- B29C33 60
- B29L11 00
Designated states4
- Regional, 4
- Zimbabwe
- Turkmenistan
- Türkiye
- Togo