技术领域technical field
本发明涉及一种基于交联共聚的抗菌角膜接触镜制备方法，属于角膜接触镜制备原料和制备方法的技术领域。The invention relates to a method for preparing an antibacterial contact lens based on cross-linking and copolymerization, and belongs to the technical field of raw materials and methods for preparing contact lenses.
背景技术Background technique
软镜(Contact Lens)，也叫隐形眼镜或角膜接触镜，是一种戴在眼球角膜上，用以矫正视力或保护眼睛的镜片。根据材料的软硬它包括硬性、半硬性、软性三种；从制备材料看，它可以进一步分为以聚甲基丙烯酸甲酯(PMMA)、聚甲基丙烯酸羟乙酯(PHEMA)、硅氧烷丙烯酸酯类或丙烯酸氟硅氧烷酯类等为主要成分的软镜。从使用寿命看，又分为日抛、月抛、季抛以及半年抛等类型。软镜不仅从外观上和方便性方面给近视、远视、散光等屈光不正患者带来很大的改善，而且视野宽阔、视物逼真。此外，由于佩戴软镜在防止青少年近视、散光发展，治疗特殊的眼病等方面也发挥了一定作用。因此，与普通的框架眼镜相比，软镜越来越受到学生、职场人士等群体的欢迎。尽管如此，软镜在使用过程中，由于涉及到手接触以及长时间暴露在空气里，容易造成细菌或其它微生物在其表面积聚现象，进而诱发眼部疾病。比如，急性卡他性结膜炎，俗称红眼病，就是一种由细菌感染引起的常见急性流行性眼病。常见的致病菌包括金黄色葡萄球菌及链球菌。因此，如何在佩戴软镜中避免上述问题将对软镜的进一步推广有着重要意义。Contact Lens, also called contact lens or contact lens, is a lens worn on the cornea of the eye to correct vision or protect the eyes. According to the softness and hardness of the material, it includes three types: rigid, semi-rigid, and soft; from the perspective of preparation materials, it can be further divided into polymethyl methacrylate (PMMA), polyhydroxyethyl methacrylate (PHEMA), silicon Soft lenses mainly composed of oxane acrylate or fluorosilicone acrylate. From the perspective of service life, it is divided into daily, monthly, quarterly and semi-annual throws. The soft mirror not only brings great improvement to patients with refractive errors such as myopia, hyperopia, and astigmatism in terms of appearance and convenience, but also has a wide field of vision and realistic vision. In addition, wearing soft lenses also plays a role in preventing the development of myopia and astigmatism in young people, and treating special eye diseases. Therefore, compared with ordinary frame glasses, soft lenses are more and more popular among students, professionals and other groups. However, during the use of soft mirrors, due to hand contact and long-term exposure to the air, it is easy to cause bacteria or other microorganisms to accumulate on the surface, thereby inducing eye diseases. For example, acute catarrhal conjunctivitis, commonly known as pink eye, is a common acute epidemic eye disease caused by bacterial infection. Common pathogens include Staphylococcus aureus and Streptococcus. Therefore, how to avoid the above-mentioned problems in wearing soft mirrors will be of great significance to the further promotion of soft mirrors.
为了解决上述现象，常见的护理手段就是佩戴结束后将软镜浸泡在镜片护理液中，利用后者中含有的少量抗菌剂如季铵盐类表面活性剂等，对镜片表面进行消毒、清洗。由此可以看出，如能制备出具有抗菌功能的镜片，直接抑制细菌在其表面生长，将可以从根本上克服软镜表面易繁殖细菌或其他微生物现象。为了制备出抗菌性软镜，目前有两大类合成路线：一种以银为主的抗菌制备方法，另一种以季铵盐为抗菌主体的制备路线。In order to solve the above phenomenon, the common care method is to soak the soft lens in the lens care solution after wearing, and use a small amount of antibacterial agent contained in the latter, such as quaternary ammonium salt surfactant, to disinfect and clean the lens surface. It can be seen from this that if a lens with antibacterial function can be prepared to directly inhibit the growth of bacteria on its surface, it will be possible to fundamentally overcome the phenomenon that bacteria or other microorganisms are prone to multiply on the surface of the soft lens. In order to prepare antibacterial soft mirrors, there are currently two major synthetic routes: one is an antibacterial preparation method based on silver, and the other is a preparation route using quaternary ammonium salts as the main antibacterial agent.
其中，对于第一种路线，美国专利5,213,801(CN1541119A)中公开了一种将具有抗菌性的金属陶瓷物质引入隐形眼镜中技术路线。该方法首先需要制备出银陶瓷材料，且其粒径足以细小到到添加于软镜中，然后再将上述粉末陶瓷形成透镜。可以看出，上述过程涉及步骤较多，不适于在现行工艺，且也不利于产品的多样化开发。另外，可以发现利用该工艺制成的透镜经常缺乏隐形眼镜用户要求的清晰度。为此，CN01822766提出将纳米尺寸的活化银添加到软镜单体混合物中进行聚合，待单体固化后，再用氧化剂氧化，最终得到抑制微生物生长的隐形眼镜。专利CN101573146亦提出一种制备抗菌隐形眼镜的酸性方法，利用金属盐进行抗菌，该专利希望找到生产一致产品的隐形眼镜制备技术，在制备过程中，他们利用包括盐前体和有效量的酸性物质处理固化镜片。专利CN1281282C也提出另一种制备路线，其所制备的抗菌透镜中包含银与含I、II、III或IV单体的聚合物，其结构分别如下：Among them, for the first route, US Patent No. 5,213,801 (CN1541119A) discloses a technical route of introducing antibacterial cermet substances into contact lenses. The method first needs to prepare silver ceramic material, and its particle size is fine enough to be added to the soft mirror, and then the above-mentioned powder ceramic is formed into a lens. It can be seen that the above-mentioned process involves many steps, which is not suitable for the current process, and is not conducive to the diversified development of products. Additionally, it has been found that lenses made using this process often lack the clarity desired by contact lens users. For this reason, CN01822766 proposes to add nanometer-sized activated silver to the soft lens monomer mixture for polymerization, and after the monomer is cured, it is oxidized with an oxidant to finally obtain a contact lens that inhibits microbial growth. Patent CN101573146 also proposes an acidic method for preparing antibacterial contact lenses, which uses metal salts for antibacterial. This patent hopes to find a contact lens preparation technology that produces consistent products. In the preparation process, they use salt precursors and effective amounts of acidic substances Handle cured lenses. Patent CN1281282C also proposes another preparation route, which contains silver and polymers containing I, II, III or IV monomers in the prepared antibacterial lens, and its structures are as follows:
以其中单体I为例，R1是氢或C1-6烷基，R2是-OR3、-NH-R3、-S-(CH2)d-R3或-(CH2)d-R3,其中d是0-8；而R3为取代的C1-6烷基，其取代基来自以下基团中的一个或多个：羧酸、磺酸、胺、眯、乙酰胺、腈、硫醇、C1-6烷基硫脲、苯基硫脲的C1-6烷基化二硫、取代的二硫二苯、取代的C1-6烷基硫脲，以及取代的苯基硫脲，其中C1-6烷基化二硫二苯、C1-6烷基脲、C1-6烷基硫脲、苯脲，以及苯基硫脲取代C1-6烷基、卤代C1-6烷基、卤素、羟基、羧酸、羧基、磺酸、磷酸、胺乙酰胺和腈等。其余单体Ⅱ、Ⅲ、Ⅳ中也含有类似其余单体I中例举的官能团。在该路线中，银仍是抗菌的主要成分，其它单体聚合物的引入主要是通过物理吸附或化学配位作用，来稳定或分散银。尽管上述过程，可以简化抗菌软镜的制备路线，但吸附在软镜中银粒子或离子易在使用过程中发生流失现象，造成镜片的抗菌性能下降。同时，银的流失还可能影响到软镜的佩戴，对眼睛造成伤害。Take monomer I as an example, R1 is hydrogen or C1-6 alkyl, R2 is -OR3 , -NH-R3 , -S-(CH2 )d -R3 or -(CH2 )d -R3 , wherein d is 0-8; and R3 is a substituted C1-6 alkyl group whose substituents are from one or more of the following groups: carboxylic acid, sulfonic acid, amine, squid, ethyl Amides, nitriles, thiols, C1-6 alkylthioureas, C1-6 alkylated disulfides of phenylthioureas, substituted dithiodiphenyls, substituted C1-6 alkylthioureas, and Substituted phenylthiourea, wherein C1-6 alkylated dithiodiphenyl, C1-6 alkylurea, C 1-6alkylthiourea , phenylurea, and phenylthiourea substituted for C1-6 Alkyl, halogenated C1-6 alkyl, halogen, hydroxyl, carboxylic acid, carboxyl, sulfonic acid, phosphoric acid, amine acetamide and nitrile, etc. The remaining monomers II, III, and IV also contain functional groups similar to those exemplified in the remaining monomer I. In this route, silver is still the main antibacterial component, and the introduction of other monomer polymers is mainly through physical adsorption or chemical coordination to stabilize or disperse silver. Although the above process can simplify the preparation route of antibacterial soft mirrors, the silver particles or ions adsorbed in the soft mirrors are prone to loss during use, resulting in a decrease in the antibacterial performance of the lenses. At the same time, the loss of silver may also affect the wearing of soft lenses and cause damage to the eyes.
而以季铵盐为主体的技术路线主要涉及以下专利：EP2067797A1、JP11502949、JP06337378与JP6330820。其中，前两个专利报道的路线均以硅氧烷类角膜接触镜为背景，通过将将季胺盐类单体添加到硅氧烷类单体混合物中聚合得到。而后两种专利则集中在非硅氧烷类单体混合物为主体的角膜接触镜上。但不管上述哪一种路线，其季胺盐类单体中都包含一个不饱和键与一个季铵盐基团，具体结构如下：The technical route based on quaternary ammonium salts mainly involves the following patents: EP2067797A1, JP11502949, JP06337378 and JP6330820. Among them, the routes reported in the first two patents are all based on silicone contact lenses, which are obtained by adding quaternary ammonium salt monomers to silicone monomer mixtures for polymerization. The latter two patents focus on contact lenses based on non-silicone monomer mixtures. But no matter which of the above routes, the quaternary ammonium salt monomer contains an unsaturated bond and a quaternary ammonium salt group, the specific structure is as follows:
其中R8、R9与R10指C1-18烷基或其取代烷基，X代表F、Cl、Br或I，R11为甲基或氢，Z为O或NHWhere R8 , R9 and R10 refer to C1-18 alkyl or substituted alkyl, X represents F, Cl, Br or I, R11 is methyl or hydrogen, Z is O or NH
然而，在我们的实验中发现，利用上述EP2067797A1、JP11502949、JP06337378与JP6330820中的抗菌单体进行聚合时，无论后期如何水化处理，其角膜接触镜抽提液都会导致细胞发生凋亡，使得所制备的角膜接触镜很难通过生物相容性评价。However, in our experiments, it was found that when the antibacterial monomers in EP2067797A1, JP11502949, JP06337378 and JP6330820 were used for polymerization, no matter how the hydration treatment was performed in the later stage, the corneal contact lens extract would lead to cell apoptosis, making all The prepared contact lenses are difficult to pass the biocompatibility evaluation.
发明内容Contents of the invention
发明目的：本发明的目的在于提供一种易于进行后期水化处理的制造抗菌角膜接触镜的制备方法。Purpose of the invention: The purpose of the present invention is to provide a preparation method for making antibacterial contact lenses that is easy to carry out post-hydration treatment.
技术方案：本发明包括一种基于交联共聚的抗菌角膜接触镜制备方法，包括以下步骤：Technical solution: The present invention includes a method for preparing an antibacterial contact lens based on cross-linking and copolymerization, comprising the following steps:
1)将含有抗菌单体或抗菌单体的预聚体的角膜接触镜原料单体混合物光聚合固化或热聚合固化：1) Photopolymerization or thermal polymerization curing of the corneal contact lens raw material monomer mixture containing antibacterial monomers or prepolymers of antibacterial monomers:
所述抗菌单体为包含有季铵盐官能团和两个以上不饱和键的功能单体；所述角膜接触镜原料单体混合物还含有聚合引发剂；The antibacterial monomer is a functional monomer containing a quaternary ammonium salt functional group and more than two unsaturated bonds; the contact lens raw material monomer mixture also contains a polymerization initiator;
2)将步骤1)得到的产物水化。2) hydrating the product obtained in step 1).
进一步地，所述抗菌单体为下式所述的化合物：Further, the antibacterial monomer is a compound described in the following formula:
其中：A为或Among them: A is or
其中的R3为H或C1-4烷基；Wherein R3 is H or C1-4 alkyl;
X为Cl，Br或I；X is Cl, Br or I;
R1与R2为C1-18烷基、C1-18烯烃基、苯基、苄基、—C(O)NH2、含有取代基的C1-18烯烃基、含有取代基的C1-18烷基、含有取代基的苯基或含有取代基的苄基；R1 and R2 are C1-18 alkyl, C1-18 alkenyl, phenyl, benzyl, -C(O)NH2 , C1-18 alkenyl group containing substituent, C1-18 alkyl group containing substituent, phenyl group containing substituent or benzyl group containing substituent;
其中，m、n为0～20的任意整数，取代基为以下基团中一个或多个：卤素、羟基、羧酸。Wherein, m and n are any integers from 0 to 20, and the substituents are one or more of the following groups: halogen, hydroxyl, and carboxylic acid.
本发明中的上述化合物作为角膜接触镜聚合单体的原料使用时，可以得到具有生物相容性的抗菌角膜接触镜。具体原因为，角膜接触镜聚合一般都是以自由基聚合为主，因此上述抗菌单体中的阳离子基团很容易就影响到聚合过程，降低聚合度，从而进一步影响到后面如何将角膜接触镜中残余、未反应或聚合度低的单体除去过程。同时，由于水化后的角膜接触镜是一种三维的网状结构，里面充满了大量的水分子。当单体聚合度受到影响时，就易造成聚合度低的分子被束缚在网状结构中，很难被通常的水化过程清洗干净，从而导致角膜接触镜佩戴过程中，不断有残余聚合物释放出，对眼睛造成伤害。而本专利里提出的含两个或两个以上不饱和键功能单体可以有效地避免以上弊端，究其原因如下：从某种角度看，这里提出的抗菌单体其结构类似高分子聚合过程中常用的交联剂。由于存在多个不饱和键，它可以在聚合过程中在线型分子间起架桥作用，从而使多个线型分子相互键合交联成网状结构的物质，提高了聚合度。一旦形成这种结构后，就能有效地将抗菌剂束缚在角膜接触镜中，很难再释放出，因此也就提高了角膜接触镜的生物相容性。When the above-mentioned compound in the present invention is used as a raw material for the polymerized monomer of the contact lens, a biocompatible antibacterial contact lens can be obtained. The specific reason is that the polymerization of contact lenses is generally based on free radical polymerization, so the cationic groups in the above-mentioned antibacterial monomers can easily affect the polymerization process and reduce the degree of polymerization, which further affects how to use the contact lenses later. Residual, unreacted or low degree of polymerization monomer removal process. At the same time, since the hydrated contact lens is a three-dimensional network structure, it is filled with a large number of water molecules. When the polymerization degree of the monomer is affected, it is easy to cause the molecules with low polymerization degree to be bound in the network structure, which is difficult to be cleaned by the usual hydration process, resulting in continuous residual polymer during the contact lens wearing process. Released, may cause damage to eyes. And the functional monomer containing two or more unsaturated bonds proposed in this patent can effectively avoid the above disadvantages. The reason is as follows: from a certain point of view, the structure of the antibacterial monomer proposed here is similar to the polymer polymerization process Commonly used crosslinking agents. Due to the existence of multiple unsaturated bonds, it can act as a bridge between linear molecules during the polymerization process, so that multiple linear molecules are bonded to each other and cross-linked to form a network structure, which increases the degree of polymerization. Once this structure is formed, the antibacterial agent can be effectively bound in the contact lens, and it is difficult to release it, thus improving the biocompatibility of the contact lens.
进一步地，所述的步骤1)中的角膜接触镜原料单体混合物还包括下列化合物中的一种或多种：(甲基)丙烯酸甲酯、(甲酯)丙烯酸乙酯、(甲基)丙烯酸正丁酯、(甲基)丙烯酸、(甲基)丙烯酰胺、N，N-二甲基(甲基)丙烯酰胺、(甲基)丙烯酸-2-羟乙酯、乙基乙烯基醚、正丁基乙烯基醚、甘油甲基丙烯酸酯、N-乙烯基吡咯烷酮。Further, the contact lens raw material monomer mixture in the step 1) also includes one or more of the following compounds: (meth)methyl acrylate, (methyl) ethyl acrylate, (methyl) n-butyl acrylate, (meth)acrylic acid, (meth)acrylamide, N,N-dimethyl(meth)acrylamide, 2-hydroxyethyl (meth)acrylate, ethyl vinyl ether, n-Butyl vinyl ether, glycerol methacrylate, N-vinylpyrrolidone.
进一步地，所述的步骤1)中的角膜接触镜原料单体混合物中，所述的抗菌单体或抗菌单体的预聚体在角膜接触镜原料单体混合物中的比例为0.01～5％wt。Further, in the contact lens raw material monomer mixture in the step 1), the proportion of the antibacterial monomer or the prepolymer of the antibacterial monomer in the contact lens raw material monomer mixture is 0.01% to 5%. wt.
进一步地，所述步骤2)的水化具体为：将步骤1)得到的产物浸渍于水、生理盐水、缓冲生理盐水、乙醇或异丙醇中，浸渍温度为60～100℃。Further, the hydration of step 2) specifically includes: immersing the product obtained in step 1) in water, physiological saline, buffered physiological saline, ethanol or isopropanol, and the immersion temperature is 60-100°C.
进一步地，所述步骤1)在聚合容器内进行，并在聚合容器密封后，再进行光聚合固化或热聚合固化；所述光聚合固化反应条件具体为：在波长为250～398nm，强度为4～30mW/cm2的紫外灯下，固化0.5～4小时；所述热聚合固化反应条件具体为：50℃下保持18小时，70℃下保持5小时，用2个小时从70℃升温至100℃，于100℃下保持7小时。Further, the step 1) is carried out in the polymerization container, and after the polymerization container is sealed, photopolymerization curing or thermal polymerization curing is carried out; the photopolymerization curing reaction conditions are specifically: at a wavelength of 250-398nm, the intensity is 4-30mW/cm2 UV lamp, curing for 0.5-4 hours; the thermal polymerization curing reaction conditions are as follows: keep at 50°C for 18 hours, keep at 70°C for 5 hours, and take 2 hours to heat up from 70°C to 100°C, kept at 100°C for 7 hours.
进一步地，所述步骤1)中的角膜接触镜原料单体混合物还包括交联剂，所述交联剂为以下化合物中的一种或多种：二甘醇、三甘醇、丁二醇和己-1，6-二醇的二或三(甲基)丙烯酸酯。Further, the contact lens raw material monomer mixture in the step 1) also includes a crosslinking agent, and the crosslinking agent is one or more of the following compounds: diethylene glycol, triethylene glycol, butanediol and Di- or tri(meth)acrylates of hexane-1,6-diol.
本发明中，具有抗菌效果的化合物In the present invention, the compound with antibacterial effect
称为抗菌单体。抗菌单体或他们的预聚体加入量是基于初始的单体混合物重量(如果在制备聚合物时使用了适宜的稀释剂，则包含所述的稀释剂。后面无特殊说明，均指重量百分比)，其值可以随透镜组成的而变化。其最高百分比以不损害所得角膜接触镜的物理性能(如镜片透光率、透氧系数、焦度清晰度、吸脂性和生物相容性等)时抗菌单体的百分比为准，最低添加百分比以所制得镜片具有抑菌能力时的百分比为准。 called antibacterial monomers. Antibacterial monomers or their prepolymer additions are based on the initial monomer mixture weight (if a suitable diluent is used when preparing the polymer, then include said diluent. There are no special instructions below, all refer to weight percentage ), whose value can vary with the composition of the lens. Its highest percentage is subject to the percentage of antibacterial monomer when it does not damage the physical properties of the obtained contact lens (such as lens light transmittance, oxygen permeability coefficient, focus clarity, liposuction and biocompatibility, etc.), and the minimum added The percentage is based on the percentage when the prepared lens has antibacterial ability.
光聚合是指以上单体分子借光的引发(或用光敏剂)活化成自由基而进行的连锁聚合。而热聚合指在一定温度下引发单体聚合。Photopolymerization refers to the chain polymerization of the above monomer molecules activated by light (or with a photosensitizer) into free radicals. Thermal polymerization refers to the initiation of monomer polymerization at a certain temperature.
本发明中所述的空白角膜接触镜是指未加抗菌单体聚合生产的普通角膜接触镜。The blank contact lens mentioned in the present invention refers to the ordinary contact lens produced by polymerization without antibacterial monomer.
上述角膜接触镜单体混合物主要指甲基丙烯酸甲酯(MMA)与甲基丙烯酸羟乙酯(HEMA)为主体的软性隐形眼镜制剂。此外，还包括少量不饱和羧酸如甲基丙烯酸和丙烯酸、(甲基)丙烯酸取代的醇：如2-羟乙基(甲基)丙烯酸酯和2-羟乙基丙烯酸酯；乙烯基内酰胺，如N-乙烯基吡咯烷酮；以及(甲基)丙烯酰胺，如甲基丙烯酰胺和N，N-二甲基丙烯酰胺。The contact lens monomer mixture above mainly refers to a soft contact lens preparation mainly composed of methyl methacrylate (MMA) and hydroxyethyl methacrylate (HEMA). In addition, a small amount of unsaturated carboxylic acids such as methacrylic acid and acrylic acid, (meth)acrylic acid substituted alcohols: such as 2-hydroxyethyl (meth)acrylate and 2-hydroxyethyl acrylate; vinyl lactam , such as N-vinylpyrrolidone; and (meth)acrylamides, such as methacrylamide and N,N-dimethylacrylamide.
以上所得的单体混合物，主要进行自由基引发聚合，因此还需添加适量的自由基聚合引发剂(一般是反应试剂的0.01％至5％)。自由基聚合引发剂的种类，可以根据具体单体聚合的种类进行选择，比如：过氧化苯甲酰、过氧化肉桂酰、氢过氧化枯烯、二叔丁基过氧化物、过氧二碳酸双(4-叔丁基环己基)酯等有机过氧化物聚合引发剂。还可以包括偶氮系聚合引发剂：2,2’-偶氮二异丁腈、2,2’-偶氮二(2,4-二甲基戊腈)、2,2’-偶氮二(4-甲氧基-2,4-二甲基戊腈)等。一些光聚合引发剂包括：苯偶姻甲醚、苯偶姻乙醚。The above-obtained monomer mixture is mainly subjected to free radical initiation polymerization, so an appropriate amount of free radical polymerization initiator (generally 0.01% to 5% of the reactant) needs to be added. The type of free radical polymerization initiator can be selected according to the type of specific monomer polymerization, such as: benzoyl peroxide, cinnamoyl peroxide, cumene hydroperoxide, di-tert-butyl peroxide, peroxydicarbonic acid Organic peroxide polymerization initiators such as bis(4-t-butylcyclohexyl) ester. It can also include azo-based polymerization initiators: 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile), etc. Some photopolymerization initiators include: benzoin methyl ether, benzoin diethyl ether.
整个制备过程如下：首先将含有聚合引发剂、抗菌单体、和其它单体的角膜接触镜单体混合物的溶液加入到一定形状的聚合容器内(如镜片形状的容器)，密封后，进行加热或光引发自由基聚合固化。通常这种聚合容器由上、下模组合成，溶液装在两者间形成的空腔中。对于热聚合过程，可以将密闭后的容器放在热风循环式的加热柜中，按一定速度加热聚合。对于光聚合过程，需要使用透明度高的聚合容器。然后照射紫外线或可见光进行聚合。聚合结束后，将上、下模分开，取出固化后的角膜接触镜进行水化处理。这里所说的水化处理，是指将所得角膜接触镜放在水、生理盐水、缓冲生理盐水、乙醇、异丙醇中浸渍，使其溶剂膨胀，同时，洗去角膜接触镜中残余、未反应或聚合度低的单体。浸渍温度为60-100℃，浸渍过程中，浸渍液更换2-3次。The whole preparation process is as follows: first, the solution of the contact lens monomer mixture containing the polymerization initiator, antibacterial monomer, and other monomers is added into a polymerization container of a certain shape (such as a lens-shaped container), after sealing, heating Or photoinitiated free radical polymerization curing. Usually this kind of polymerization container is composed of upper and lower molds, and the solution is contained in the cavity formed between them. For the thermal polymerization process, the sealed container can be placed in a heating cabinet with hot air circulation, and the polymerization can be heated at a certain speed. For the photopolymerization process, it is necessary to use a polymerization vessel with high transparency. Polymerization is then performed by irradiating ultraviolet rays or visible light. After the polymerization is completed, the upper and lower molds are separated, and the cured contact lens is taken out for hydration treatment. The hydration treatment mentioned here refers to immersing the obtained contact lens in water, normal saline, buffered normal saline, ethanol, and isopropanol to make the solvent swell, and at the same time, to wash away the residual, untreated contact lens in the contact lens. Monomers with a low degree of reaction or polymerization. The dipping temperature is 60-100°C. During the dipping process, the dipping solution is replaced 2-3 times.
术语“抗菌”是指角膜接触镜表现出一种或多种以下性能：抑制细菌或其它微生物在透镜上生长，杀死在透镜表面上或在透镜半径延伸处的细菌或其它微生物(细菌或其它微生物在透镜上生长以及细菌或其它微生物在透镜表面上存在统称为“微生物的产生”)。本发明的透镜抑制至少20％～至少99％的细菌或真菌产生。这种细菌或其它微生物包括但是不局限于在眼睛中存在的那些生物：特别是铜绿假单胞菌、金黄色葡萄球菌、大肠杆菌、白色念珠菌。The term "antimicrobial" means that a contact lens exhibits one or more of the following properties: inhibits the growth of bacteria or other microorganisms on the lens, kills bacteria or other microorganisms (bacteria or other The growth of microorganisms on the lens and the presence of bacteria or other microorganisms on the surface of the lens are collectively referred to as "microbial growth"). The lenses of the present invention inhibit at least 20% to at least 99% of bacterial or fungal growth. Such bacteria or other microorganisms include, but are not limited to, those organisms found in the eye: especially Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans.
本发明与现有技术相比，其有益效果是：本发明方法与现有的抗菌角膜接触镜的制备方法相比，如EP2067797A1、JP11502949、JP06337378、JP6330820等相对比，最大的不同点是本发明方法采用了含有两个或两个以上的不饱和键的季胺盐类单体为抗菌主体，利用交联共聚的策略，克服了以往以单一不饱和键为主的季胺盐类单体在聚合过程中所出现的聚合度低、水化过程困难等缺点。此外，与CN1541119A、CN01822766、CN101573146及CN1281282C等提出的以银为主体的抗菌角膜接触镜制备方法相比，可以明显发现本发明的优点：(1)工艺过程简单，聚合固化后，只需2-3次水化，将角膜接触镜中残余、未反应或聚合度低的单体除去；(2)由于抗菌单体自身就是一种交联剂，因此可以不需在角膜接触镜单体混合物中再次添加其它交联剂如：二甘醇、三甘醇、丁二醇和己-1，6-二醇的二或三(甲基)丙烯酸酯等；(3)由于抗菌单体中含有两个或两个以上的不饱和键，提高了季胺盐类单体的聚合度，有效地防止了佩戴过程中，残余聚合物的释放，而造成眼睛的伤害。Compared with the prior art, the present invention has the beneficial effects that: compared with the preparation method of the existing antibacterial contact lens, such as EP2067797A1, JP11502949, JP06337378, JP6330820, etc., the biggest difference is that the present invention Methods The quaternary ammonium salt monomer containing two or more unsaturated bonds was used as the antibacterial main body, and the strategy of cross-linking and copolymerization was used to overcome the traditional quaternary ammonium salt monomer with a single unsaturated bond. During the polymerization process, there are some disadvantages such as low degree of polymerization and difficult hydration process. In addition, compared with the antibacterial contact lens preparation method based on silver proposed by CN1541119A, CN01822766, CN101573146 and CN1281282C, etc., the advantages of the present invention can be clearly found: (1) the process is simple, after polymerization and curing, only 2- 3 times of hydration to remove residual, unreacted or low-polymerization monomers in the contact lens; (2) Since the antibacterial monomer itself is a cross-linking agent, it does not need to be used in the contact lens monomer mixture Add other crosslinking agents again such as: diethylene glycol, triethylene glycol, butanediol and hexane-1,6-diol di or tri(meth)acrylate; (3) due to the two Or more than two unsaturated bonds increase the degree of polymerization of quaternary ammonium salt monomers, effectively preventing the release of residual polymers during wearing and causing eye damage.
本发明提出的一种交联共聚的抗菌角膜接触镜制备新路线。该路线仍是以季铵盐为抗菌主体，与前面专利所不同的是，其抗菌单体中含有两个或以上的不饱和键，从而提高聚合过程中抗菌单体与角膜接触镜单体之间的聚合度，有效地避免背景技术部分中提及的其它合成路线的缺点。The invention proposes a new route for preparing cross-linked and copolymerized antibacterial contact lenses. This route still uses quaternary ammonium salt as the antibacterial main body. The difference from the previous patents is that the antibacterial monomer contains two or more unsaturated bonds, thereby increasing the relationship between the antibacterial monomer and the contact lens monomer during the polymerization process. The degree of polymerization in between can effectively avoid the disadvantages of other synthetic routes mentioned in the background art section.
附图说明Description of drawings
图1为本发明中的角膜接触镜制备方法流程示意图；Fig. 1 is a schematic flow chart of a contact lens preparation method in the present invention;
图2为金黄色葡萄球菌分别在实施例14制得的抗菌角膜接触镜表面与空白角膜接触镜表面上的菌落照片；Fig. 2 is the colony photo of Staphylococcus aureus on the antibacterial contact lens surface and the blank contact lens surface made respectively in embodiment 14;
图3为本发明实施例26的实验结果图。Fig. 3 is a diagram of the experimental results of Example 26 of the present invention.
具体实施方式detailed description
下面对本发明技术方案进行详细说明，但是本发明的保护范围不局限于所述实施例。以下实施例中所涉试剂与菌种均购买于Sigma Aldrich公司。The technical solutions of the present invention will be described in detail below, but the protection scope of the present invention is not limited to the embodiments. The reagents and strains involved in the following examples were all purchased from Sigma Aldrich Company.
在下面的实施例中常用下列缩写：The following abbreviations are commonly used in the following examples:
HEMA 甲基丙烯酸2-羟乙酯HEMA 2-Hydroxyethyl methacrylate
DarocurTM1173 2-羟基-2-甲基-1-苯基-丙-1-酮DarocurTM 1173 2-Hydroxy-2-methyl-1-phenyl-propan-1-one
MAA 甲基丙烯酸MAA Methacrylic acid
DMA N,N-二甲基丙烯酰胺DMA N,N-Dimethacrylamide
NVP 乙烯吡咯烷酮NVP Vinylpyrrolidone
实施例1-6不同抗菌单体的合成：The synthesis of different antibacterial monomers of embodiment 1-6:
实施例1Example 1
抗菌单体1，二(2-甲基丙烯酰氧乙基)-正十六烷基-甲基溴化铵的合成Synthesis of antibacterial monomer 1, bis(2-methacryloyloxyethyl)-n-hexadecyl-methylammonium bromide
第一步，季铵化The first step, quaternization
加入15mL乙腈作为溶剂，在单口烧瓶中加入N-甲基二乙醇胺和溴代十六烷，摩尔比1:1，充N2除氧，加入一定量的阻聚剂对苯二酚，70℃下回流反应36h。待反应完成后，抽滤，洗涤，得到白色粉末状产品。Add 15mL of acetonitrile as a solvent, add N-methyldiethanolamine and hexadecane bromide in a single-necked flask, the molar ratio is 1:1, fill withN2 to remove oxygen, add a certain amount of polymerization inhibitor hydroquinone, 70°C Under reflux reaction for 36h. After the reaction is completed, filter with suction and wash to obtain a white powdery product.
第二步，酯化The second step, esterification
在单口瓶中加入20mL的二氯甲烷溶剂，再加入摩尔比1:2.2的季铵化产物和2-甲基丙烯酰氯，再加入一定量的对苯二酚，充N2除氧，冰水浴中反应4h，反应停止后，旋转蒸发，用丙酮/乙醚重结晶得到产品。Add 20mL of dichloromethane solvent into the one-necked bottle, then add the quaternized ammonium product and 2-methacryloyl chloride with a molar ratio of 1:2.2, then add a certain amount of hydroquinone, fill with N2 to deoxygenate, and put it in an ice-water bath After 4 hours of reaction, after the reaction was stopped, the product was obtained by rotary evaporation and recrystallization with acetone/ether.
实施例2Example 2
抗菌单体2，二(2-甲基丙烯酰氧乙基)-正十六烷基-甲基氯化铵的合成Synthesis of antibacterial monomer 2, bis(2-methacryloyloxyethyl)-n-hexadecyl-methylammonium chloride
第一步，季铵化The first step, quaternization
加入15mL乙腈作为溶剂，在单口烧瓶中加入N-甲基二乙醇胺和氯代十六烷，摩尔比1:1，充N2除氧，加入一定量的阻聚剂对苯二酚，80℃下回流反应28h。待反应完成后，抽滤，洗涤，得到白色粉末状产品。Add 15mL of acetonitrile as a solvent, add N-methyldiethanolamine and hexadecane chloride in a single-necked flask, the molar ratio is 1:1, fill with N2 to remove oxygen, add a certain amount of polymerization inhibitor hydroquinone, at 80°C Reflux reaction for 28h. After the reaction is completed, filter with suction and wash to obtain a white powdery product.
第二步，酯化The second step, esterification
同实施例1的第二步。With the second step of embodiment 1.
实施例3Example 3
抗菌单体3，二(2-甲基丙烯酰氧乙基)-正十二烷基-甲基溴化铵的合成Synthesis of antibacterial monomer 3, bis(2-methacryloyloxyethyl)-n-dodecyl-methylammonium bromide
第一步，同实施例一的第一步，其中溴代十六烷取代为溴代十二烷The first step is the same as the first step in Example 1, wherein hexadecane bromide is replaced by dodecyl bromide
第二步，酯化The second step, esterification
在单口瓶中加入定量的上述季铵化产物和2-甲基丙烯酰氯，投料比1:2.2，加入一定量的二氯甲烷作为溶剂，少量对苯二酚(阻聚剂)，冰水浴中反应，旋转蒸发，用环己烷/苯(1:2)重结晶得到产物。Add a certain amount of the above-mentioned quaternized product and 2-methacryloyl chloride in a single-necked bottle, the feeding ratio is 1:2.2, add a certain amount of dichloromethane as a solvent, a small amount of hydroquinone (inhibitor), and put it in an ice-water bath Reaction, rotary evaporation, recrystallization with cyclohexane/benzene (1:2) to obtain the product.
实施例4Example 4
抗菌单体4，二(2-丙烯酰氧乙基)-正十六烷基-甲基溴化铵的合成Synthesis of antibacterial monomer 4, bis(2-acryloyloxyethyl)-n-hexadecyl-methylammonium bromide
第一步，同实施例1的第一步The first step, with the first step of embodiment 1
第二步，酯化The second step, esterification
在单口瓶中加入20mL的二氯甲烷作为溶剂，再加入摩尔比1:2.2的季铵化产物和丙烯酰氯，加入定量的对苯二酚作为阻聚剂，充N2除氧，冰水浴中反应5h停止，旋转蒸发，用丙酮/乙酸乙酯重结晶得到产品。Add 20 mL of dichloromethane as a solvent in a one-necked bottle, then add quaternized ammonium products and acryloyl chloride at a molar ratio of 1:2.2, add a certain amount of hydroquinone as a polymerization inhibitor, fill with N2 to remove oxygen, and react in an ice-water bath 5h stop, rotary evaporation, recrystallization with acetone/ethyl acetate to obtain the product.
实施例5Example 5
抗菌单体5，二(2-丙烯氧乙基)-正十六烷基-甲基氯化铵的合成Synthesis of antibacterial monomer 5, bis(2-propenyloxyethyl)-n-hexadecyl-methylammonium chloride
第一步，同实施例1的第一步The first step, with the first step of embodiment 1
第二步，酯化The second step, esterification
在单口瓶中加入定量的上述季铵化产物和烯丙基氯，加入一定量的二氯甲烷作为溶剂，少量对苯二酚(阻聚剂)，冰水浴中反应，旋转蒸发，用苯/乙酸乙酯(1:1)重结晶得到产物。Add quantitative above-mentioned quaternization product and allyl chloride in one-necked bottle, add a certain amount of dichloromethane as solvent, a small amount of hydroquinone (inhibitor), react in ice-water bath, rotary evaporation, use benzene/ Recrystallization from ethyl acetate (1:1) gave the product.
实施例6Example 6
抗菌单体6，二(对苯乙烯甲基氧乙基)-正十六烷基-甲基氯化铵的合成Synthesis of antibacterial monomer 6, bis(p-styrenemethyloxyethyl)-n-hexadecyl-methylammonium chloride
第一步，同实施例1的第一步The first step, with the first step of embodiment 1
第二步，酯化The second step, esterification
在单口瓶中加入20mL的二氯甲烷溶剂，再加入摩尔比1:2.2的季铵化产物和对氯甲基苯乙烯，并加入一定量的对苯二酚作为阻聚剂，充N2除氧，冰水浴中反应3h停止，旋转蒸发，用丙酮/石油醚重结晶得到产品。Add 20mL of dichloromethane solvent into the single-necked bottle, then add the quaternized product and p-chloromethylstyrene with a molar ratio of 1:2.2, and add a certain amount of hydroquinone as a polymerization inhibitor, and fill with N2 to remove oxygen , the reaction was stopped in an ice-water bath for 3h, and the product was obtained by rotary evaporation and recrystallization with acetone/petroleum ether.
实施例7-17以HEMA为主体成分的单体混合物合成抗菌角膜接触镜Example 7-17 Synthesis of antibacterial contact lens with HEMA as the monomer mixture of the main component
实施例7Example 7
称取1g的HEMA，向其中加入引发剂0.4％的Darocur1173，0.5％抗菌单体1(见表1)，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中，在波长为398nm，强度30mW/cm2的紫外光下固化30分钟，打开模具，放入60℃生理盐水中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 1g of HEMA, add initiator 0.4% Darocur1173 therein, 0.5% antimicrobial monomer 1 (see Table 1), stir evenly, after vacuum degassing, add in the polypropylene contact lens mold, at a wavelength of 398nm , cured under ultraviolet light with an intensity of 30mW/cm2 for 30 minutes, opened the mold, put it into 60°C physiological saline for hydration, removed unreacted monomers, and obtained antibacterial contact lenses.
实施例8Example 8
称取1g的HEMA，向其中加入引发剂偶氮异二丁氰(0.1％，质量比)，0.8％抗菌单体2(见表1)，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中，50℃下保持18小时，70℃下保持5小时，用2个小时从70℃升温至100℃，于100℃下保持7小时。自然冷却到室温后聚合结束。打开模具，放入100℃水中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 1g of HEMA, add initiator azoisodibutylcyanide (0.1%, mass ratio) therein, 0.8% antibacterial monomer 2 (see Table 1), stir evenly, after vacuum degassing, add to polypropylene latex In the plastic lens mold, keep it at 50°C for 18 hours, keep it at 70°C for 5 hours, raise the temperature from 70°C to 100°C in 2 hours, and keep it at 100°C for 7 hours. The polymerization ended after natural cooling to room temperature. Open the mold, put it into 100°C water for hydration, remove unreacted monomers, and obtain an antibacterial corneal contact lens.
实施例9Example 9
称取0.5g的HEMA，0.5gNVP，加入0.08g的丙烯酸甲酯，0.5％抗菌单体3(见表1)，0.4wt.％的Darocur1173作为引发剂，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中将得到的混合物装入模具中，随后在波长250nm，强度4mW/cm2的紫外光下暴露4h，使聚合物固化。打开模具，放入75℃缓冲生理盐水中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 0.5g of HEMA, 0.5gNVP, add 0.08g of methyl acrylate, 0.5% antibacterial monomer 3 (see Table 1), 0.4wt.% of Darocur1173 as initiator, stir evenly, after vacuum degassing, add to The obtained mixture was filled into a mold for a polypropylene contact lens, and then exposed to ultraviolet light with a wavelength of 250 nm and an intensity of 4 mW/cm2 for 4 hours to cure the polymer. Open the mold, put it into 75°C buffered saline for hydration, remove unreacted monomers, and obtain an antibacterial corneal contact lens.
实施例10Example 10
称取0.5g的HEMA、0.5g的VMA，0.3％抗菌单体4(见表1)，0.4％的Darocur1173作为引发剂，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中，50℃下保持23小时，70℃下保持5小时，用2个小时从70℃升温至100℃，于100℃下保持7小时。自然冷却到室温后聚合结束。打开模具，放入80℃乙醇中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 0.5g of HEMA, 0.5g of VMA, 0.3% antibacterial monomer 4 (see Table 1), 0.4% of Darocur1173 as initiator, stir, after vacuum degassing, add in the polypropylene contact lens mould, Keep at 50°C for 23 hours, keep at 70°C for 5 hours, raise the temperature from 70°C to 100°C over 2 hours, and keep at 100°C for 7 hours. The polymerization ended after natural cooling to room temperature. Open the mold, put it into 80°C ethanol for hydration, remove unreacted monomers, and obtain an antibacterial corneal contact lens.
实施例11Example 11
称取1g的HEMA、0.02g的MAA，0.6％抗菌单体5(见表1)，0.4％的Darocur1173作为引发剂，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中，50℃下保持23小时，70℃下保持5小时，用2个小时从70℃升温至100℃，于100℃下保持7小时。自然冷却到室温后聚合结束。打开模具，放入90℃异丙醇中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 1g of HEMA, 0.02g of MAA, 0.6% antibacterial monomer 5 (see Table 1), 0.4% of Darocur1173 as initiator, stir evenly, after vacuum degassing, add in the polypropylene contact lens mold, 50 It was kept at ℃ for 23 hours, kept at 70℃ for 5 hours, raised the temperature from 70℃ to 100℃ over 2 hours, and kept at 100℃ for 7 hours. The polymerization ended after natural cooling to room temperature. Open the mold, put it into isopropanol at 90°C for hydration, remove unreacted monomers, and obtain an antibacterial contact lens.
实施例12Example 12
称取1g的HEMA、0.02g的MAA，0.4％抗菌单体6(见表1)，0.4％的Darocur1173作为引发剂，搅拌均匀，真空脱气后，加到聚丙烯隐性眼镜模具中，50℃下保持23小时，70℃下保持5小时，用2个小时从70℃升温至100℃，于100℃下保持7小时。自然冷却到室温后聚合结束。打开模具，放入60℃乙醇中水化，去除未反应的单体，得到抗菌性角膜接触镜。Take by weighing 1g of HEMA, 0.02g of MAA, 0.4% antibacterial monomer 6 (see Table 1), 0.4% of Darocur1173 as initiator, stir evenly, after vacuum degassing, add in the polypropylene contact lens mold, 50 It was kept at ℃ for 23 hours, kept at 70℃ for 5 hours, raised the temperature from 70℃ to 100℃ over 2 hours, and kept at 100℃ for 7 hours. The polymerization ended after natural cooling to room temperature. Open the mold, put it into ethanol at 60°C for hydration, remove unreacted monomers, and obtain an antibacterial corneal contact lens.
实施例13Example 13
同实施例7，但抗菌单体1添加量为2％wt。Same as Example 7, but the addition of antibacterial monomer 1 is 2%wt.
实施例14Example 14
同实施例10，但抗菌单体4添加量为1％wt。Same as Example 10, but the addition of antibacterial monomer 4 is 1%wt.
实施例15Example 15
同实施例11，但抗菌单体5添加量为2％wt。Same as Example 11, but the addition of antibacterial monomer 5 is 2%wt.
实施例16Example 16
同实施例12，但抗菌单体6添加量为2％wt。Same as Example 12, but the addition of antibacterial monomer 6 is 2%wt.
实施例17Example 17
同实施例7，但抗菌单体1添加量为5％wt。Same as Example 7, but the addition of antibacterial monomer 1 is 5%wt.
实施例18Example 18
同实施例8，但抗菌单体2添加量为5％wt。Same as Example 8, but the addition of antibacterial monomer 2 is 5%wt.
实施例19Example 19
同实施例9，但抗菌单体3添加量为5％wt。Same as Example 9, but the addition of antibacterial monomer 3 is 5%wt.
实施例20Example 20
同实施例10，但抗菌单体4添加量为5％wt。Same as Example 10, but the addition of antibacterial monomer 4 is 5%wt.
实施例21Example 21
同实施例11，但抗菌单体5添加量为5％wt。Same as Example 11, but the added amount of antibacterial monomer 5 is 5%wt.
实施例22Example 22
同实施例12，但抗菌单体6添加量为5％wt。Same as Example 12, but the addition of antibacterial monomer 6 is 5%wt.
实施例23角膜接触镜的抗菌性能评价Antibacterial performance evaluation of embodiment 23 corneal contact lens
金黄色葡萄球菌抗菌测试Staphylococcus aureus antibacterial test
对以上实施例1-22中所得角膜接触镜进行抗菌性能评价，基本过程参照《QB/T2591-2003抗菌塑料的抗菌性能试验方法试验》进行。通过定量接种细菌于待测角膜接触镜上，用贴膜的方法使细菌均匀接触样品，经过一定时间的培养后，测定样品中的或菌数，并计算出样品的抗细菌率。The antibacterial performance of the corneal contact lenses obtained in Examples 1-22 above was evaluated, and the basic process was carried out with reference to "QB/T2591-2003 Antibacterial Performance Test Method of Antibacterial Plastics". By quantitatively inoculating bacteria on the contact lens to be tested, the bacteria are evenly contacted with the sample by sticking a film. After a certain period of cultivation, the number of bacteria in the sample is measured, and the antibacterial rate of the sample is calculated.
具体过程如下：(1)材料准备，覆盖膜为聚乙烯薄膜，尺寸为(40±2)mm X(40±2)mm、厚度为(0.05～0.1)mm。使用前用70％乙醇溶液浸泡1分钟，再用无菌水冲洗，自然干燥。样品分为空白对照角膜接触镜A与抗菌角膜接触镜B，前者指未添加抗菌成分的角膜接触镜，测试尺寸为(50±2)mm X(50±2)mm。所有样品在试验前经高温灭菌，然后用无菌水冲洗，自然干燥。测试过程中所用洗脱液指含0.8％NaCl的生理盐水(含少量的吐温80)，培养液指营养肉汤/生理盐水溶液(1:500)；(2)金黄色葡萄球菌ATCC6538，利用接种环从金黄色葡萄球菌的培养基上取少量(刮1～2环)新鲜菌，加入到培养液中，并依次做10倍递增稀释液，选择菌液浓度为(5.0-10.0)*105cfu/mL的稀释液作为试验用菌液。(3)样品试验，分别取0.2mL试验用菌液滴加在空白对照角膜接触镜和抗菌角膜接触镜上，然后用灭菌镊子夹起灭菌覆盖膜分别覆盖在其表面，使菌均匀接触样品，置于灭菌平皿中，在37℃、相对湿度RH≥90％条件下培养24小时。结束后，取出样品，分别加入20mL洗脱液，反复洗样品与覆盖膜，充分摇匀后，取一定量接种于营养琼脂培养基中，在37℃培养24小时后活菌计数。(4)检验结果计算，抗菌率(％)＝(A组中菌落数-B组中菌落数)/A组中菌落数*100％，其中，A组中菌落数指由空白对照角膜接触镜A表面培养得到的细菌数量，B组中菌落数指由抗菌角膜接触镜B表面培养得到的细菌数量。检测结果如下表所示：The specific process is as follows: (1) Material preparation, the covering film is polyethylene film, the size is (40±2)mm X (40±2)mm, and the thickness is (0.05～0.1)mm. Soak in 70% ethanol solution for 1 minute before use, rinse with sterile water, and dry naturally. The samples are divided into blank control contact lens A and antibacterial contact lens B, the former refers to the contact lens without antibacterial ingredients, and the test size is (50±2)mm X (50±2)mm. All samples were sterilized by high temperature before testing, then rinsed with sterile water and dried naturally. The eluent used in the test process refers to the physiological saline containing 0.8% NaCl (containing a small amount of Tween 80), and the culture solution refers to nutrient broth/normal saline solution (1:500); (2) Staphylococcus aureus ATCC6538, using Take a small amount (scraping 1-2 loops) of fresh bacteria from the culture medium of Staphylococcus aureus with the inoculation loop, add them to the culture medium, and make 10-fold incremental dilutions sequentially, and select the concentration of the bacteria solution as (5.0-10.0)*10 The dilution of5 cfu/mL was used as the bacterial solution for the test. (3) For the sample test, take 0.2mL test bacteria solution and drop them on the blank control contact lens and antibacterial contact lens, and then use sterilized tweezers to pick up the sterilized covering film and cover the surface respectively, so that the bacteria can be evenly contacted The samples were placed in a sterilized plate and incubated at 37°C and relative humidity RH≥90% for 24 hours. After the end, take out the sample, add 20mL of eluent, wash the sample and the cover film repeatedly, shake well, inoculate a certain amount in the nutrient agar medium, and count the viable bacteria after culturing at 37°C for 24 hours. (4) Calculation of test results, antibacterial rate (%)=(number of colonies in group A-number of colonies in group B)/number of colonies in group A*100%, wherein, the number of colonies in group A refers to the result of blank control contact lens The number of bacteria cultured on the surface of A, and the number of colonies in group B refers to the number of bacteria cultured on the surface of antibacterial contact lens B. The test results are shown in the table below:
实施例24软镜的生物相容性评价(细胞毒性实验)Example 24 Biocompatibility Evaluation of Soft Mirrors (Cytotoxicity Test)
为了进一步对比研究含一个不饱和双键与含两个不饱和双键(本专利中提出的)的抗菌单体对后期生物相容性评价的影响，这里给出形成镜片后的细胞毒性结果。其中，一个不饱和双键的抗菌单体分子式如下：In order to further compare and study the impact of antibacterial monomers containing one unsaturated double bond and two unsaturated double bonds (proposed in this patent) on the later biocompatibility evaluation, the results of cytotoxicity after forming lenses are given here. Wherein, the antibacterial monomer molecular formula of an unsaturated double bond is as follows:
而两个不饱和双键单体以前面提到的抗菌剂1为例。两者的添加量均为2％。体外细胞毒性实验基本过程参照《GB/T16886.5-2003医疗器械生物学评价》进行，通过定量接种细胞于待测软镜及其浸提液中，经过一定时间的培养，对细胞的形态进行观察。For the two unsaturated double bond monomers, take the aforementioned antibacterial agent 1 as an example. Both are added at 2%. The basic process of the in vitro cytotoxicity test is carried out according to "GB/T16886.5-2003 Biological Evaluation of Medical Devices". The cells are quantitatively inoculated in the soft mirror and its extract to be tested, and after a certain period of cultivation, the morphology of the cells is evaluated. Observed.
具体过程如下：(1)材料准备：24孔板，镊子，空白对照软镜A、抗菌软镜B(一个饱和键，制备过程中加入的抗菌单体结构式为和抗菌软镜C(前面提到的抗菌剂1)，实验前将所有材料在121℃下高压灭菌25min，灭菌水反复清洗，自然干燥。实验过程中的完全培养基指的是89％DMEM、10％胎牛血清和1％的青霉素和链霉素。将软镜A、B和C用镊子取出放入24孔板中，加入1mL完全培养基，37℃±2℃浸提24h，将浸提液取出加入新的孔中，将L929细胞用胰蛋白酶消化下来，并用完全培养基调整细胞悬液浓度为5×105个/mL，在含浸提液和镜片的孔中加入细胞悬液和完全培养基，置于37℃培养箱下培养24h，观察细胞形态并拍摄照片如图3所示。需要指出的，以上软镜A、B与C均事先经过相同流程的水化处理，清洗至抗菌剂不浸出。换句话说，去除未反应的单体过程相同。如浸提液中再出现残留的抗菌剂就是软镜不断释放造成的。可以看出经过24小时培养后，空白对照软镜A表面的细胞状态良好，而抗菌软镜B表面见不到明显存活的细胞，其浸提液中细胞几乎凋亡。与之鲜明对比的是，同样经过24小时培养后，抗菌软镜C表面的细胞存活率可以达到百分之五十，其浸提液中细胞的状态良好，只有个别凋亡。由此可以看出本专利提出的基于交联共聚的抗菌角膜接触镜制备方法的优越性。The specific process is as follows: (1) material preparation: 24-well plate, tweezers, blank control soft mirror A, antibacterial soft mirror B (a saturated bond, the antibacterial monomer structural formula added in the preparation process is And antibacterial soft mirror C (antibacterial agent 1 mentioned above), all materials were autoclaved at 121°C for 25 minutes before the experiment, washed repeatedly with sterilized water, and dried naturally. The complete medium during the experiment refers to 89% DMEM, 10% fetal bovine serum and 1% penicillin and streptomycin. Take out the soft mirrors A, B, and C with tweezers and put them into a 24-well plate, add 1mL of complete medium, extract at 37°C±2°C for 24 hours, take out the extract and add it to a new well, and use trypsin on the L929 cells Digest it, and adjust the concentration of the cell suspension to 5×105 cells/mL with the complete medium, add the cell suspension and complete medium to the wells containing the leaching solution and the lens, and culture in a 37°C incubator for 24h, observe The cell morphology and photographs are shown in Figure 3. It should be pointed out that the above soft mirrors A, B and C have all undergone the same process of hydration beforehand, and are cleaned until the antibacterial agent is not leached. In other words, the process of removing unreacted monomer is the same. If the residual antibacterial agent appears in the extract, it is caused by the continuous release of the soft lens. It can be seen that after 24 hours of culture, the cells on the surface of the blank control soft mirror A are in good condition, but no obvious surviving cells can be seen on the surface of the antibacterial soft mirror B, and the cells in its extract are almost apoptotic. In sharp contrast, after 24 hours of culture, the survival rate of cells on the surface of the antibacterial soft mirror C can reach 50%, and the cells in the extract are in good condition, with only a few cells undergoing apoptosis. From this we can see the superiority of the antibacterial contact lens preparation method based on cross-linking copolymerization proposed by this patent.
上述实例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人能够了解本发明的内容并具以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰，都应涵盖在本发明的保护范围之内。The above examples are only to illustrate the technical conception and characteristics of the present invention, and its purpose is to enable those skilled in the art to understand and implement the content of the present invention, and not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention shall fall within the protection scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410413666.XACN104193890B (en) | 2014-08-20 | 2014-08-20 | Preparation method of antibacterial corneal contact lenses based on crosslinking copolymerization |
| Application Number | Priority Date | Filing Date | Title |
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| CN201410413666.XACN104193890B (en) | 2014-08-20 | 2014-08-20 | Preparation method of antibacterial corneal contact lenses based on crosslinking copolymerization |
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| CN104193890Btrue CN104193890B (en) | 2017-02-15 |
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| CN201410413666.XAActiveCN104193890B (en) | 2014-08-20 | 2014-08-20 | Preparation method of antibacterial corneal contact lenses based on crosslinking copolymerization |
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