CN114763506A - 用于眼科装置的组合物 - Google Patents
用于眼科装置的组合物 Download PDFInfo
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- CN114763506A CN114763506A CN202210031539.8A CN202210031539A CN114763506A CN 114763506 A CN114763506 A CN 114763506A CN 202210031539 A CN202210031539 A CN 202210031539A CN 114763506 A CN114763506 A CN 114763506A
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- borate
- phosphate compound
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Abstract
本发明题为“用于眼科装置的组合物”。本发明涉及含硼酸盐和磷酸盐的组合物，尤其是眼睛护理组合物，该组合物实现生理上相容的pH和张力以及良好的抑菌特性。还公开了使用本发明的组合物的方法。
Description
相关申请
本申请要求2021年1月12日提交的美国临时专利申请63/136,370的权益，该申请的全部内容据此以引用方式并入本文，如同在本文完全阐述一样。
技术领域
本发明涉及含硼酸盐和磷酸盐的组合物，尤其是眼睛护理组合物，该组合物实现生理上相容的pH和张力以及良好的抑菌特性。还公开了使用本发明的组合物的方法。
背景技术
接触镜片通常作为单独包装的产品提供给消费者。包装此类接触镜片的单个单元容器通常使用缓冲盐水或去离子水作为储存或包装溶液。
此类包装溶液至少在一些情况下应为不促进有害或不期望的微生物生长的环境提供短期时段，例如，在终末期包装产品的溶液制备和灭菌之间的时段。此外，包装溶液应当对眼睛温和，因为一旦将接触镜片从包装溶液中取出并且直接放置在眼睛上(即，通过直接施加到眼睛)，至少一些包装溶液将很可能保留在接触镜片上。
接触镜片(或其它眼科装置)包装溶液还应与形成接触镜片(或其它眼科装置)的材料相容。
制备用于眼科装置的包装溶液的挑战是配制不会负面影响眼睛舒适度或溶液与形成眼科装置的材料的相容性的溶液。包括包装溶液在内的眼科组合物的一个重要组分是掺入的缓冲液，该缓冲液有助于将组合物的pH维持在可接受的生理范围内。
使用硼酸/硼酸盐作为缓冲液的益处涉及其维持制剂(添加有缓冲液)pH在生理pH(～7)附近的独特能力，具有以低浓度赋予制剂抑菌(而不是杀菌)特性的二次影响。此类“静态”特性降低了眼睛刺激的可能性。然而，降低浓度的硼酸/硼酸盐往往也会牺牲其对某些微生物(例如，铜绿假单胞菌(Pseudomonas aeruginosa))的功效。
已知磷酸盐也是能胜任的缓冲液，但是遗憾的是，已知磷酸盐也是微生物生长的促进物。
本发明人已经发现，通过适当地组合硼酸/硼酸盐和磷酸盐缓冲液可以实现充分缓冲的抑菌组合物(例如包装溶液)。更具体地，此类缓冲溶液可以通过以硼酸/硼酸盐与磷酸盐缓冲液的特定比率组合硼酸/硼酸盐与磷酸盐来实现，如下文详述的。
附图说明
图1是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的金黄色葡萄球菌(Staphylococcus aureus)的微生物菌落形成单位(CFU)的图表。
图2是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的铜绿假单胞菌的微生物菌落形成单位(CFU)的图表。
图3是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的大肠杆菌(Escherichia coli)的微生物菌落形成单位(CFU)的图表。
图4是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的枯草芽孢杆菌(Bacillus subtilis)的微生物菌落形成单位(CFU)的图表。
图5是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的鼠伤寒沙门氏菌(Salmonella typhimurium)的微生物菌落形成单位(CFU)的图表。
图6是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的白色念珠菌(Candida albicans)的微生物菌落形成单位(CFU)的图表。
图7是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的巴西曲霉(Aspergillus brasiliensis)的微生物菌落形成单位(CFU)的图表。
图8是示出在用本发明的某些组合物测试的第0天、第1天和第2天存在的角质镰刀菌(Fusarium keratoplasticum)的微生物菌落形成单位(CFU)的图表。
图9是下图(图表9)，呈现了每个EXP缓冲液对对照缓冲液的微生物减少百分比的比较。
图10是示出在用本发明的某些组合物测试的第1天、第2天和第3天铜绿假单胞菌CFU/mL回收计数(1350CFU/mL于PBS中的第0天递送计数)的图表。
图11是示出在用本发明的某些组合物测试的第1天、第2天和第3天铜绿假单胞菌对数减少的图表。
图12是示出在用本发明的某些组合物测试的第3天铜绿假单胞菌的计数减少百分比的图表。
发明内容
本发明涉及组合物，该组合物包含：
a.约0.1％w/v至小于或等于约0.80％w/v的硼酸盐化合物；
b.约0.3％w/v至约0.9％w/v的磷酸盐化合物；以及
c.眼科上可接受的载体，其中基于重量计，磷酸盐化合物的浓度为硼酸盐化合物的量的至少约1.5倍。
本发明还涉及制备和使用所公开的组合物的方法。
具体实施方式
如上所述，本发明涉及包含硼酸盐化合物和磷酸盐化合物以及眼科上可接受的载体的组合物。
组合物可用于储存或用作用于眼科装置的包装溶液。
组合物可用于直接施加到眼睛以获得眼睛护理益处，诸如减轻眼睛不适。
本发明的组合物和方法可包含本文所述的发明的步骤、要素及限制，或由本文所述的发明的步骤、要素及限制组成，或基本上由本文所述的发明的步骤、要素及限制组成，以及任何本文所述的另外或任选的成分、组分或限制。如本文所用，术语“包含(及其语法上的变型)”以“具有”或“包括”的涵括意义而非以“仅包含”的排它意义使用。如本文所用，术语“一种(个)”和“所述(该)”应该理解为涵盖复数形式以及单数形式。
除非另有说明，否则所有引用的文档在相关部分均以引用方式并入本文；对任何文档的引用不应该理解为是承认就本发明而言其为现有技术。此外，仅将所有以引用方式并入本文的文献以它们与本说明书一致的程度并入本文。
如本文所公开的本发明可在不存在本文未具体公开的任何化合物或元素(或者化合物或元素的组)的情况下实施。
如本文所用，“药学上可接受的”是指生物学上可耐受的并且以其它方式生物学上适用于施加到或暴露于眼睛和眼睛周围组织，而无过度的不良作用，诸如毒性、不相容性、不稳定性、刺激、过敏反应等。
除非另外指明，否则所有百分比、份数和比率均基于本发明组合物的总重量计。除非另外指明，否则所有与所列成分相关的此类重量均基于活性物质的含量，因此不包括可能包含在市售原料中的载体或副产物。
硼酸盐化合物
本发明的组合物包含硼酸盐。如本文所用，术语“硼酸盐”应指硼酸、硼酸的盐和其它药学上可接受的硼酸盐或它们的组合。合适的硼酸盐包括但不限于硼酸；药学上可接受的盐，诸如碱金属盐，诸如硼酸钠、硼酸钾；碱土金属盐，诸如硼酸钙、硼酸镁；过渡金属盐，诸如硼酸锰；以及它们的混合物。
硼酸盐化合物可以以总组合物的约0.1％，优选地约0.2％，优选地约0.25％,w/v至小于或等于0.80％(或约0.80％)，优选地0.7％(或约0.7％)，优选地0.6％(或约0.6％)，优选地0.5％(或约0.5％)，优选地0.45％(或约0.45％)，优选地0.4％(或约0.4％)，优选地0.35％(或约0.35％)，优选地0.3％(或约0.3％)的浓度存在于组合物中，在每种情况下％为％w/v。硼酸盐化合物可以以总组合物的约0.1％w/v至小于或等于0.40％(或约0.40％)w/v，优选地约0.2％w/v至小于或等于0.35％(或约0.35％)w/v，或优选地约0.25％w/v至小于或等于0.30％(或约0.30％)w/v的浓度存在于组合物中。
磷酸盐化合物
本发明的组合物包含磷酸盐化合物。如本文所用，术语“磷酸盐”应指磷酸、磷酸的盐和其它药学上可接受的磷酸盐或它们的组合。合适的磷酸盐可以作为一种或多种一元磷酸盐、二元磷酸盐等掺入。可用于组合物的磷酸盐化合物的示例是选自碱金属和/或碱土金属的药学上可接受的磷酸盐的那些。磷酸盐化合物可包括磷酸氢二钠(Na2HPO4)、磷酸二氢钠(NaH2PO4)和磷酸二氢钾(KH2PO4)中的一种或多种。
磷酸盐化合物可以以总组合物的0.3％(或约0.3％)w/v至0.9％(或约0.9％)w/v，优选地0.4％(或约0.4％)w/v至0.85％(或约0.85％)w/v，优选地0.5％(或约0.5％)w/v至0.8％(或约0.8％)w/v，或优选地0.6％(或约0.6％)w/v至0.75％(或约0.75％)w/v的浓度存在于组合物中。
磷酸盐化合物的浓度可以是基于重量计硼酸盐化合物的量的至少1.5(或约1.5)，优选地至少2.0(或约2.0)，并且优选地至少2.5(或约2.5)，但至多4，优选地至多3倍。
磷酸盐化合物与硼酸盐化合物的比率可以是基于重量计1.5:1(或约1.5:1)至3:1(或约3:1)，优选地2:1(或约2:1)至3:1(或约3:1)，或优选地2:1(或约2:1)。
眼科上可接受的载体
本发明的组合物包含眼科上可接受的载体。眼科上可接受的载体可以是水或水性赋形剂溶液。术语“水性”通常表示制剂，其中赋形剂为按重量计至少约50％，更优选地至少约75％，以及特别是至少约90％，并且至多约95％，或优选地约99％的水。水是蒸馏水。载体可以不含C1-4醇，诸如甲醇、乙醇、丙醇、异丙醇、丁醇等，该载体可以刺痛、刺激或以其它方式引起眼睛不适。
水可以按总组合物的重量计约96％至约99.9％，优选地约98％至约99.5％，或优选地约99.0％至约99.5％的浓度存在于眼科上可接受的载体中。
眼科上可接受的载体可以按总组合物的重量计约96％至约99.5％，优选地约98％至约99.5％，或优选地约98.5％至约99.2％的浓度存在。
组合物可以是无菌的，即使得在释放或使用之前产物中不存在微生物污染物在统计学上展示为此类产品所需的程度。可以选择对处于组合物中或眼睛上(或眼睛周围的区域上)的接触镜片没有或基本上没有有害、负面、不良影响的组合物。
根据本发明的组合物与眼睛和眼科装置生理上相容。具体地，该组合物对于与诸如接触镜片的眼科装置一起使用应该是“眼科上安全的”，这意味着用溶液处理的接触镜片对于在没有冲洗的情况下直接放置或直接施加到眼睛上通常是合适的并且安全的，也就是说，该溶液对于包括任何磨损频率的接触镜片在内的用该溶液润湿的任何施加频率的眼科装置是安全的并且舒适的。眼科上安全的组合物具有与眼睛相容的张力和pH，并且包括根据ISO标准和美国食品和药物管理局(FDA)法规的眼科上相容和非细胞毒性的材料及其量。
本发明的组合物可用张力剂调节，以近似正常泪液的渗透压，该渗透压等同于0.9％的氯化钠溶液或2.5％的甘油溶液。可以使用单独使用或与诸如甘油的其它张力剂组合使用的生理盐水将组合物制成基本上等渗，否则如果简单地与无菌水共混并制成低渗或制成高渗的诸如接触镜片的眼科装置，则可能失去其期望的光学参数。相应地，过量的盐水可能导致高渗组合物的形成，这将导致刺痛和眼睛刺激。组合物的渗透压可以是至少约200mOsm/kg，优选地约200mOsm/kg至约450mOsm/kg，优选地约205mOsm/kg至约380mOsm/kg，优选地约210毫渗摩尔每千克至约360毫渗摩尔每千克(mOsm/kg)，优选地约250mOsm/kg至约350mOsm/kg，或优选地约300mOsm/kg至约330mOsm/kg。眼科组合物通常将配制成无菌水溶液。
合适的张力调节剂的示例包括但不限于甘油、钠、钾、钙、锌和氯化镁、碱金属卤化物、右旋糖等以及它们的混合物。这些试剂可以在约0.01％w/v至约2.5％w/v，并且优选地约0.2％w/v至约1.5％w/v范围内的量单独使用。
张力调节剂可以是氯化钠，其可以按总组合物的重量计约0.4％至约0.9％，优选地约0.4％至约0.7％，或优选地约0.5％至约0.6％的浓度掺入。
本发明的组合物可以具有约5.0的pH至约8.0的pH，优选地约6.5的pH至约8.0的pH，优选地约6.5的pH至约7.5的pH，优选地约7的pH。组合物(如上所述)可以优选地具有与组合物将接触或被直接施加的人类组织的生理pH相匹配的pH。
眼科组合物的pH可以使用酸和碱来调节，诸如无机酸，诸如但不限于盐酸和碱，诸如氢氧化钠。
本发明的组合物还可用作用于包装眼科装置并且用于储存此类眼科装置的包装溶液。
如本文所用，“眼科装置”是指驻留在眼睛中或上的物体。这些装置可提供光学矫正或可以起到美容的作用。眼科装置包括但不限于软质接触镜片、眼内镜片、覆盖镜片、眼部插入物、点状塞和光学插入物。眼科装置可为接触镜片。可使用各种常规技术制造可与组合物一起使用的接触镜片，以产生具有期望的镜片后和镜片前表面的成形制品。旋转铸造方法公开于美国专利3,408,429和3,660,545中；静态铸造方法公开于美国专利4,113,224、4,197,266和5,271,875中，这些专利中的每一篇以引用方式并入本文。可用于制造合适的接触镜片的接触镜片聚合物材料包括但不限于acofilcon A、alofilcon A、alphafilconA、amifilcon A、astifilcon A、atalafilcon A、balafilcon A、bisfilcon A、bufilcon A、comfilcon、crofilcon A、cyclofilcon A、darfilcon A、deltafilcon A、delefilcon、deltafilcon B、dimefilcon A、drooxifilcon A、epsifilcon A、esterifilcon A、etafilcon A、fanfilcon A、focofilcon A、galyfilcon A、genfilcon A、govafilcon A、hefilcon A、hefilcon B、hefilcon D、hilafilcon A、hilafilcon B、hioxifilcon B、hioxifilcon C、hixoifilcon A、hydrofilcon A、lenefilcon A、licryfilcon A、licryfilcon B、lidofilcon A、lidofilcon B、lotrafilcon A、lotrafilcon B、mafilconA、mesifilcon A、methafilcon B、mipafilcon A、narafilcon A、narafilcon B、nelfilconA、netrafilcon A、ocufilcon A、ocufilcon B、ocufilcon C、ocufilcon D、ocufilcon E、ofilcon A、omafilcon A、oxyfilcon A、pentafilcon A、perfilcon A、pevafilcon A、phemfilcon A、polymacon、riofilcon A、samfilcon A、senofilcon A、senofilcon C、silafilcon A、siloxyfilcon A、somofilcon A、stenfilcon A、tefilcon A、tetrafilconA、trifilcon A、vasurfilcon、vifilcon和xylofilcon A。优选地，接触镜片使用选自以下(或选自由以下组成的组)的聚合物材料制造：comfilcon、etafilcon A、galyfilcon A、senofilcon A、nelfilcon A、hilafilcon、tetrafilcon A、vasurfilcon、vifilcon和polymacon。
常规的水凝胶接触镜片不含有含有机硅的组分，并且通常具有比有机硅水凝胶更高的水含量、更低的氧渗透性和模量。常规水凝胶由主要含有亲水性单体诸如甲基丙烯酸2-羟乙酯(“HEMA”)、N-乙烯基吡咯烷酮(“NVP”)或聚乙烯醇的单体混合物制备。美国专利4,495,313、4,889,664和5,039,459公开了常规水凝胶的形成。常规的水凝胶可以是离子或非离子的，并且包括polymacon、etafilcon、nelfilcon、ocufilcon lenefilcon等。这些常规水凝胶材料的氧渗透性通常低于20巴勒-30巴勒。
硅水凝胶制剂包括balafilcon samfilcon、lotrafilcon A和B、delfilcon、galyfilcon、senofilcon A、B和C、narafilcon、comfilcon、formofilcon、riofilcon、fanfilcon、stenfilcon、somofilcon、kalifilcon等。“有机硅水凝胶”是指由至少一种亲水性组分和至少一种含有机硅的组分制成的聚合物网络。有机硅水凝胶可具有在60psi-200psi、60psi-150psi或80psi-130psi范围内的模量，在20％至60％范围内的水含量。有机硅水凝胶的示例包括acquafilcon、asmofilcon、balafilcon、comfilcon、delefilcon、enfilcon、fanfilcon、formofilcon、galyfilcon、lotrafilcon、narafilcon、riofilcon、samfilcon、senofilcon、somofilcon和stenfilcon，包括所有它们的变体，以及如美国专利号4,659,782、4,659,783、5,244,981、5,314,960、5,331,067、5,371,147、5,998,498、6,087,415、5,760,100、5,776,999、5,789,461、5,849,811、5,965,631、6,367,929、6,822,016、6,867,245、6,943,203、7,247,692、7,249,848、7,553,880、7,666,921、7,786,185、7,956,131、8,022,158、8,273,802、8,399,538、8,470,906、8,450,387、8,487,058、8,507,577、8,637,621、8,703,891、8,937,110、8,937,111、8,940,812、9,056,878、9,057,821、9,125,808、9,140,825、9156,934、9,170,349、9,244,196、9,244,197、9,260,544、9,297,928、9,297,929以及WO 03/22321、WO 2008/061992和US 2010/0048847中所制备的有机硅水凝胶。这些专利据此全文以引用方式并入本文。
接触镜片聚合物材料优选地是有机硅水凝胶聚合物。有机硅水凝胶可以选自以下(或选自由以下组成的组)：acquafilcon、asmofilcon、balafilcon A、comfilcon、delefilcon、enfilcon、galyfilcon、lotrafilcon、senofilcon、samfilcon、somofilcon、stenfilcon。
组合物还可以用于直接施加于眼睛作为润湿或重新润湿滴眼剂，以提供减轻眼睛不适(例如，与眼睛或通常眼睛刺激有关的燃烧感觉)。
本文所述的组合物可以不含或基本上不含防腐剂。术语“防腐剂”意指具有抗微生物特性的化合物。特定防腐剂的示例包括但不限于4-氯甲酚、4-氯二甲苯酚、苄烷铵、苯扎氯铵、苯甲酸、苯甲醇、氯己定、氯丁醇、咪脲、间甲酚、对羟基苯甲酸甲酯、苯酚0.5％、苯氧乙醇、山梨酸盐、丙酸、对羟基苯甲酸丙酯、苯甲酸钠、山梨酸、thimerosol、StabilizedOxychloro Complex(SOC-99.5％亚氯酸盐、0.5％氯酸盐和痕量的二氧化氯)、聚季铵盐化合物(诸如聚季铵盐-42、聚季铵盐-1)、过硼酸盐(例如，过硼酸钠)、双胍化合物(例如，聚六亚甲基双胍或聚氨丙基双胍)。
与防腐剂相关的术语“基本上不含”意味着防腐剂以按总组合物的重量计小于2％(或约2％)，优选地小于1.5％(或约1.5％)，并且优选地小于1％(或约1％)，优选地小于0.5％(或约0.5％)，优选地小于0.1％(或约0.1％)，优选地小于0.05％(或约0.05％)，优选地小于0.01％(或约0.01％)，优选地小于0.005％(或约0.005％)的浓度存在于本发明的组合物中。优选地，本发明的组合物不含防腐剂。
如上所述，接触镜片可以浸没在本发明的组合物中并且储存在合适的包装容器中，优选地储存在用于单个接触镜片单元的包装容器中。通常，用于储存接触镜片的包装容器包括至少密封层，该密封层密封含有浸没在本发明的组合物中的未使用的接触镜片的容器。密封容器可以是气密密封的包装容器。气密密封的包装容器可以是泡罩包装，其中含有接触镜片的凹孔被适于剥离的金属或塑料片覆盖，以便打开泡罩包装。密封容器可以由任何合适的通常惰性的包装材料形成，从而对镜片提供合理的保护程度。包装材料可以由塑料材料形成，诸如聚烷撑、PVC、聚酰胺、玻璃、玻璃态聚合物等。
也可以在本发明的组合物中采用任何水溶性缓和剂(或缓和剂，比如，例如具有诸如粘度增加能力的缓和剂特性)聚合物，条件是该缓和剂对储存的接触镜片或在用于本发明组合物的浓度下对接触镜片的佩戴者或对眼睛(或眼睛周围的区域)没有(或基本上没有)有害影响。特别有用的组分是水溶性的那些组分，例如在用于当前可用的液体水性介质的浓度下可溶。合适的水溶性缓和剂聚合物包括但不限于缓和剂聚合物，诸如聚氧化乙烯(PEO)和聚氧化丙烯(PPO)的嵌段共聚物；聚乙烯醇、聚乙烯吡咯烷酮；聚丙烯酸；聚醚，诸如聚乙二醇(例如聚乙二醇300、聚乙二醇400)和聚氧化乙烯；透明质酸和透明质酸衍生物；壳聚糖；聚山梨酸酯，诸如聚山梨酸酯80、聚山梨酸酯60和聚山梨酸酯40；葡聚糖，诸如葡聚糖70；纤维素衍生物，诸如羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素和甲基乙基纤维素；非环状聚酰胺，诸如以引用方式全文并入本文的US7,786,185中公开的重均分子量为2,500道尔顿至1,800,000道尔顿的那些；上述任何一种的盐和上述任何一种的混合物。优选地，PEO和PPO的嵌段共聚物包括泊洛沙姆和泊洛沙胺，包括以引用方式全文并入本文的美国专利6,440,366中公开的那些。优选地，水溶性缓和剂聚合物选自聚乙烯吡咯烷酮、甲基乙基纤维素、聚乙烯醇、聚甲基丙烯酸、羧甲基纤维素、甘油、丙二醇、1,3-丙二醇、聚乙二醇以及它们的混合物。
润滑剂可具有超过100,000的分子量。当甘油、丙二醇和1,3-丙二醇用作润滑剂时，它们可以具有低于100,000的分子量。
当任何水溶性聚合物用于本发明的包装溶液中时，其可以被包含并且以至多约0.5重量％、1重量％或2重量％、优选地在约0.001重量％和约2重量％之间、在约0.005重量％和约1重量％之间、在约0.01重量％和约0.5重量％之间、或在约100ppm和约0.5重量％之间的量存在，所有这些量均基于总组合物的重量。
当任何水溶性聚合物用于本发明的直接施加的眼睛护理制剂或滴眼剂中时，其可以被包含并且以至多约2重量％、5重量％或10重量％、优选地在约0.001重量％和约10重量％之间、在约0.005重量％和约2重量％之间、在约0.01重量％和约0.5重量％之间、或在约100ppm和约2重量％之间的量存在，所有这些量均基于总组合物的重量。
在不受理论限制的情况下，据信水溶性缓和剂聚合物有助于防止眼科装置粘附到其产品包装，并且当从包装中取出后放置在眼睛上时可以增强包装在组合物中的接触镜片的初始(和/或持续)舒适度。
缓和剂聚合物可以是纤维素衍生物。纤维素衍生物可以按本发明的总组合物的重量计约0.002至约0.01，或优选地约0.004至约0.006的浓度存在。
各种其它材料可以包含在本文所述的组合物中。
在用于直接施加到眼睛的本发明组合物的情况下，可以包含表面活性剂。适合此类用途的表面活性剂包括但不限于：离子和非离子表面活性剂(尽管优选非离子表面活性剂)；RLM 100；POE 20鲸蜡硬脂醚，诸如
CS20；泊洛沙姆，诸如
F68；以及嵌段共聚物，诸如2007年12月10日提交的名称为“Use of PEO-PBO Block Copolymers inOphthalmic Compositions”的美国专利申请公布2008/0138310(该公布以引用方式并入本文)中示出的聚(氧乙烯)-聚(氧丁烯)化合物。
表面活性剂可以按本发明的总组合物的重量计约0.01％至约3％，优选地约0.01％至约1％，优选地约0.02％至约0.5％，或优选地约0.02％至约0.1％的浓度存在。
如果需要，一种或多种另外的组分可以任选地包含在组合物中。选择此类任选组分以向组合物赋予或提供至少一种有益或期望的特性。此类另外但任选的组分可以选自通常用于眼科装置护理组合物中的组分。此类任选组分的示例包括(或选自以下或选自由以下组成的组)：清洁剂(例如，在直接施加的滴眼剂或清洗[或眼睛护理溶液]中)、润湿剂、营养剂、治疗剂、螯合剂、增粘剂、接触镜片调理剂、抗氧化剂等以及它们的混合物。这些任选的组分可以各自以有效赋予或提供给组合物有益或期望特性的量包含在组合物中，此类有益或期望特性对用户是重要的。例如，此类任选的组分可以以这样的量包含在组合物中，该量类似于其它眼睛或眼科装置护理组合物产品中使用的此类组分的量。
本发明的眼科溶液中的所有组分应为水溶性的。如本文所用，水溶性意味着单独或与其它组分组合的组分在所选浓度和跨常用于制造、灭菌和储存眼科溶液的温度和pH方案下不形成人眼可见的沉淀或凝胶颗粒。
还可以将一种或多种治疗剂掺入眼科溶液中。可以使用多种治疗剂，只要所选活性剂在过氧化物存在下是惰性的。合适的治疗剂包括治疗或靶向包括眼睛的前部部分和后部部分在内的眼部环境的任何部分的那些治疗剂，并且包括药剂、维生素、营养品、它们的组合等。活性剂的合适类别包括抗组胺剂、抗生素、青光眼药物、碳酸酐酶抑制剂、抗病毒剂、抗炎剂、非甾类抗炎药物、抗真菌药物、麻醉剂、缩瞳剂、散瞳剂、免疫抑制剂、抗寄生虫药物、抗原虫药物、它们的组合等。当包含活性剂时，以足以产生期望治疗结果的量(“治疗有效量”)包含它们。
可用的任选螯合剂包括但不限于乙二胺四乙酸二钠(EDTA)、碱金属六偏磷酸盐、柠檬酸、柠檬酸钠等以及它们的混合物。
可用的任选抗氧化剂包括但不限于焦亚硫酸钠、硫代硫酸钠、N-乙酰半胱氨酸、丁基羟基茴香醚、丁羟甲苯等以及它们的混合物。
包装和储存接触镜片(或其它眼科装置)的方法包括至少将装置引入包装中，其中该装置浸没在上述组合物中。该方法可以包括在递送到客户/佩戴者之前在制造接触镜片之后立即将该装置浸没在组合物中。另选地，装置在组合物中的引入和储存(全部在包装中)可以在递送到最终客户(佩戴者)之前但在处于干燥状态的装置的制造和运输之后的中间点发生，其中通过将装置浸没在组合物中来水合干燥装置。因此，用于递送到客户的包装可以包括密封容器，该密封容器含有浸没在组合物中的一个或多个未使用的装置(例如，接触镜片)。
在一个优选的实施方案中，用于将装置包装在本发明的组合物中的步骤包括：
(1)使装置(例如，接触镜片)在模具中成型，该模具包括至少第一模具部分和第二模具部分，
(2)从模具部分取出装置并去除未反应的单体和处理剂
(3)将组合物和装置引入包装(或容器)中，以及
(4)密封包装。
该方法还可以包括对包装的内容物灭菌的步骤。灭菌可以在容器密封之前或最便利地在容器密封之后进行，并且可以通过本领域已知的任何合适的方法进行，例如通过在约120℃或更高的温度下对密封容器进行平衡高压灭菌。包装可以是塑料泡罩包装(packaging)(或包装(package))，包括用于接收装置和组合物的凹部，其中在包装内容物的灭菌之前用盖材密封该凹部。如本文所用，术语“盖材”意指箔层压复合材料，包括铝箔和聚合物的其它层，该材料被热密封以覆盖泡罩的凹面。
提供以下实施例以使本领域技术人员能够实践该组合物并且仅仅是本发明的说明。实施例不应被解读为限制权利要求中定义的本发明的范围。
实施例
实施例1
表1示出可用作眼科装置(例如，接触镜片)的储存溶液或包装溶液的组合物(即，测试Exp1-Exp5)以及对照，该组合物中的每一种可以使用常规混合技术制备。
一旦制备，就将表1的组合物中的每一种从其原始样本杯容器倒出，并且使用150mL分析过滤装置通过0.22μm膜过滤灭菌。然后将过滤的单独组合物无菌地转移到新的单独无菌样本杯中以用于储存和测试。
以下微生物用于评估微生物活性：
·金黄色葡萄球菌(Quanti-Cult PlusTM)-ATCC 6538(Remel Inc.)
·大肠杆菌(
Multishot 550)-NCTC 12923(ATCC 8739)(bioMérieux)
·枯草芽孢杆菌(Quanti-Cult PlusTM)-ATCC 6633(Remel Inc.)
·铜绿假单胞菌((Quanti-Cult PlusTM))-ATCC 9027(Remel Inc.)
·白色念珠菌((Quanti-Cult PlusTM))-ATCC 10231(Remel Inc.)
·鼠伤寒沙门氏菌(KWIK-STIKTM)-ATCC 14028(Microbiologics,Inc.)
·巴西曲霉((Quanti-Cult PlusTM))-ATCC 16404(Remel Inc.)
·角质镰刀菌(KWIK-STIKTM)-ATCC 36031(Microbiologics,Inc.)
对于Quanti-Cult Plus和BioBall Multishot微生物，为表1的每种组合物制备1:1(微生物样品与组合物)的溶液。200μl的接种物用于涂布铺板，一式两份。
对于剩余的KWIK-STIKTM微生物(即，在拭子/沉淀呈递中)，按照Microbiologics,Inc的说明重构。使用一般方法的一次性Hemocytometer 2-Chip说明(Bulldog Bio)产生储备溶液。基于获得的结果，进行连续稀释以获得每种缓冲液的可计数接种物。一式两份用于涂布铺板的接种物体积为100μl。
将细菌微生物铺板在胰蛋白酶大豆琼脂(TSA)培养基以及沙氏葡萄糖琼脂(SDA)或具有氯霉素的SDA中的酵母和真菌中。将TSA板在30℃-35℃下温育24小时-72小时，并将SDA板在20℃-25℃下温育48小时至4天。
在第0天、第1天和第2天进行定量分析。图1-图8总结了所获得的结果：
图1-图8中的数据表明表1的组合物提供抑菌/抑真菌能力和杀菌/杀真菌活性。下面的图9示出2天后组合物EXP1–EXP5中的每一种与对照的微生物减少百分比的比较。组合物EXP1和EXP2示出相对于对照的最等效的减少模式，并且在两天后示出针对所有微生物的停滞(即，从接种微生物的初始计数起不增加)。然而，组合物EXP 2在所有测试的微生物中示出最一致的减少％。
实施例2
表2的组合物可用作眼科装置(例如，接触镜片)的储存溶液或包装溶液，如下所述使用常规混合技术制备该组合物。
表2
*在不存在MEC和EDTA的组合物中测量—应认识到，由于这些组分的浓度，因此单独或组合的此类组分相对于剩余组分对pH和渗透压的影响较小。
一旦制备后，就将表2的组合物从其原始样本杯容器倒出，并且使用250mL快流过滤装置通过0.22μm膜过滤灭菌。然后将过滤的组合物无菌转移到无菌容器中，以使用铜绿假单胞菌ATTC培养物类型第9027号对铜绿假单胞菌(Quanti Cult plus)进行微生物生长测试。
将铜绿假单胞菌(PA)Quanti-Cult plus按照制造商说明重新悬浮，并且将大约500μL等分试样涂布铺板到两个单独的胰蛋白酶大豆琼脂(TSA)板上。将板在30℃-35℃下温育2天。使用接种环将PA从TSA板表面重新悬浮于OmniPur WFI Quality Water,SterileFiltered,Calbiochem(WFI)中。
将悬浮液用无菌移液管无菌转移到50mL离心管中。
将PA悬浮液用WFI品质无菌水连续稀释，并且使用血细胞计(一次性血细胞计，Bulldog Bio)获得1:1000稀释液，其含有大约1.0×107个细胞/mL的目标群体计数。
将1:1000PA稀释液的10μL等分试样接种到40mL表1的组合物和1xPBS对照溶液中，以获得大约2500CFU/mL的起始PA靶群体计数。(PBS＝AccuGENE 1x磷酸盐缓冲盐水，1.7mMKH2PO4,5mM Na2HPO4,150mM NaCl,pH 7.4,目录号51225,LONZA)。将100μL PBS对照溶液一式三份铺板到TSA板上，并在30℃-35℃下温育以确定第0天PA递送计数。
将表2和PBS对照的PA接种组合物在室温下储存，并且在第1天、第2天和第3天将样品一式三份地涂布铺板(100-300μL等分试样)到TSA上。然后将板在30℃-35℃下温育以在室温储存后定量PA群体计数。表1中组合物的结果表示为图10-图12(下面)中的“Exp.7”。
如图10-图12所示，与PBS对照相比，表2的组合物(示出为“Exp7”)引起PA群体计数的更大减少，并且因此提供期望的抑菌特性。PA群体的减少提供了预防自初始PA群体计数的增加或实现抑菌的进一步证据。
实施例3
表3的组合物可用作眼科装置(例如，接触镜片)的储存溶液或包装溶液，如下所述使用常规混合技术制备该组合物。
表3
优选的实施方案：
1.一种组合物，包含：
a.约0.1％w/v至小于或等于约0.80％w/v的硼酸盐化合物；
b.约0.3％w/v至约0.9％w/v的磷酸盐化合物；以及
c.眼科上可接受的载体
其中基于重量计，所述磷酸盐化合物的浓度为所述硼酸盐化合物的量的至少约1.5倍。
2.根据实施方案1所述的组合物，其中所述组合物包含约0.2％w/v至小于或等于0.7％w/v的硼酸盐化合物。
3.根据实施方案1和/或2所述的组合物，其中所述组合物包含约0.25％w/v至小于或等于0.45％w/v的硼酸盐化合物。
4.根据前述实施方案中任一项所述的组合物，其中所述组合物包含约0.25％w/v至小于或等于0.4％w/v的硼酸盐化合物。
5.根据前述实施方案中任一项所述的组合物，其中所述组合物包含约0.4％w/v至约0.85％w/v的磷酸盐化合物。
6.根据前述实施方案中任一项所述的组合物，其中所述组合物包含约0.5％w/v至约0.8％w/v的磷酸盐化合物。
7.根据前述实施方案中任一项所述的组合物，其中基于重量计，所述磷酸盐化合物为所述硼酸盐化合物的量的至少约2.5倍。
8.根据前述实施方案中任一项所述的组合物，其中基于重量计，所述磷酸盐化合物与所述硼酸化合物的比率为约1.5:1至约3:1。
9.根据前述实施方案中任一项所述的组合物，其中基于重量计，所述磷酸盐化合物与所述硼酸化合物的比率为约2:1至约3:1。
10.根据前述实施方案中任一项所述的组合物，其中所述组合物基本上不含防腐剂。
11.根据前述实施方案中任一项所述的组合物，其中所述组合物不含防腐剂。
12.根据前述实施方案中任一项所述的组合物，还包含缓和剂聚合物。
13.根据前述实施方案中任一项所述的组合物，其中所述缓和剂聚合物选自聚氧化乙烯(PEO)和聚氧化丙烯(PPO)的嵌段共聚物、聚乙烯醇、聚乙烯吡咯烷酮、聚丙烯酸、聚醚、透明质酸和透明质酸衍生物、壳聚糖、聚山梨酸酯、葡聚糖、纤维素衍生物、无环聚酰胺、它们的盐以及它们的混合物。
14.根据前述实施方案中任一项所述的组合物，还包含另外的组分，所述另外的组分选自清洁剂、润湿剂、营养剂、治疗剂、螯合剂、增粘剂、接触镜片调理剂、抗氧化剂等以及它们的混合物。
Claims (14)
1.一种组合物，包含：
a.约0.1％w/v至小于或等于约0.80％w/v的硼酸盐化合物；
b.约0.3％w/v至约0.9％w/v的磷酸盐化合物；以及
c.眼科上可接受的载体，
其中基于重量计，所述磷酸盐化合物的浓度为所述硼酸盐化合物的量的至少约1.5倍。
2.根据权利要求1所述的组合物，其中所述组合物包含约0.2％w/v至小于或等于0.7％w/v的硼酸盐化合物。
3.根据权利要求2所述的组合物，其中所述组合物包含约0.25％w/v至小于或等于0.45％w/v的硼酸盐化合物。
4.根据权利要求3所述的组合物，其中所述组合物包含约0.25％w/v至小于或等于0.4％w/v的硼酸盐化合物。
5.根据权利要求1所述的组合物，其中所述组合物包含约0.4％w/v至约0.85％w/v的磷酸盐化合物。
6.根据权利要求5所述的组合物，其中所述组合物包含约0.5％w/v至约0.8％w/v的磷酸盐化合物。
7.根据权利要求1所述的组合物，其中基于重量计，所述磷酸盐化合物为所述硼酸盐化合物的量的至少约2.5倍。
8.根据权利要求7所述的组合物，其中基于重量计，所述磷酸盐化合物与所述硼酸化合物的比率为约1.5:1至约3:1。
9.根据权利要求7所述的组合物，其中基于重量计，所述磷酸盐化合物与所述硼酸化合物的比率为约2:1至约3:1。
10.根据权利要求1所述的组合物，其中所述组合物基本上不含防腐剂。
11.根据权利要求10所述的组合物，其中所述组合物不含防腐剂。
12.根据权利要求1所述的组合物，还包含缓和剂聚合物。
13.根据权利要求12所述的组合物，其中所述缓和剂聚合物选自聚氧化乙烯(PEO)和聚氧化丙烯(PPO)的嵌段共聚物、聚乙烯醇、聚乙烯吡咯烷酮、聚丙烯酸、聚醚、透明质酸和透明质酸衍生物、壳聚糖、聚山梨酸酯、葡聚糖、纤维素衍生物、无环聚酰胺、它们的盐以及它们的混合物。
14.根据权利要求1所述的组合物，还包含另外的组分，所述另外的组分选自清洁剂、润湿剂、营养剂、治疗剂、螯合剂、增粘剂、接触镜片调理剂、抗氧化剂等以及它们的混合物。
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