CN1322859C - 高氟低聚烷烃在眼科学中的应用 - Google Patents
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Abstract
本发明涉及具有通式[-RF(CH2)nCR1-CR2-]x的高氟化低聚烷烃的用途，式中：RF代表直链或支链的全氟化烷基链C2F5至C12F23，R1和R2彼此独立地选自H、CH3、C2H5和C3H7，n选自0、1和2的数值和x是2-6的数值，具有的摩尔量至少为750，在眼科学中用作治疗剂。通过本发明的用途解决了本发明的任务，所述的任务是提供一种在眼科学中应用的药理制剂，应用这种制剂时在较长的一段时间内对视网膜不造成损害或仅造成微弱的损害。
Description
本发明涉及权利要求1中高氟低聚烷烃在眼科学中的应用。
US-A-4490351公开了一种液态全氟化碳在眼科学中用于治疗和诊断的用途。当将这类物质用于临床治疗视网膜脱落和用作玻璃体充填(amponade)时，将其长时间使用，例如用作玻璃体代用品时，对眼睛带来各种损害。例如，全氟聚醚和全氟化碳已知的副作用是对视网膜和视神经的机械损伤，在这种情况下，这种化合物的高密度(约1.9克/厘米3)负有责任。
与此相反，出版物EP 0 563 446 A1、DE 195 36 504 A1和DE 197 19 280 A1公开了一种部分氟化的液体，这种液体的密度仅为1.1-1.3克/厘米3，并且可用作眼科学中视网膜扩展、玻璃体充填的助剂和用作玻璃体代用品。这种物质尽管其密度大大降低，但是也导致视网膜区域的组织发生改变并且在其他方面还存在全氟化碳已知的副作用。
最后，DE 44 05 627 A1和EP 05 45 174 A1公开了含氟代烃的通式为(RF)X-RH的低聚物，其中RF代表高氟烷基，该基团直接或通过一个连接环节连接在基团RH上，RH代表一个烷基或氢，并且x代表1-4的数值，这种低聚物由通式Y-(CF2)a-Ob-(CH2)c-CH＝CH2的化合物制备，其中Y代表氢或氟原子，a代表2-16的数值，b和c各自独立地代表0和1之间的数值，d代表0-6的数值，具有的平均低聚度为2-4。在该公开的出版物中，公开了所述物质用作润滑油(Schmiermittel)或润滑剂(Gleitmittel)和用作滑雪板涂层(Skibelag)以及用作氧载体的用途。
本发明的任务是提供一种在眼科学中应用的药理制剂，应用这种制剂时在较长的一段时间内对视网膜不造成损害或仅造成微弱的损害。
该任务是通过权利要求1中的物质的用途解决的。优选的用途和实施方案是从属权利要求的主题。
本发明中基本的和构成本发明一部分的认识是碳氟化合物在眼睛中长期使用时产生的有害作用是因其液体对组织的渗透和其低粘度和其高密度的协同作用引起的。这不仅适用于在应用时将这种物质用作眼科学中的玻璃体代用品，而且适用于将其用作液体植入物、直接用作眼泪替代液(Traenenersatzstoffe)和治疗剂或用作活性物质载体。
这些认识使得人们寻找具有足够高的密度和足够的溶解度以及同时具有最低限度的组织渗透的较高粘度的物质。
组织渗透能力由在己烷中的临界溶解温度定性确定(缩写：CST)。对于亲脂性的这一定性标准同时是对于组织渗透能力的标准。由开始的现有技术公开的也是用于眼科学中的低分子RF-RH-化合物而言，其通常的CST值在-20℃以下，与此相反，本发明的高分子低聚物化合物在+35℃以上的温度下才与己烷完全混合并且由此证明其难以或不溶解于脂类物质中，即其具有低的组织渗透能力。令人惊奇地是，与其单体的类似物相比，它们对某些非极性的物质仍具有较高的溶解能力。
本发明的物质因其具有特殊的分子形式，尽管与已知RF-RH-化合物的化学组成极其相似，但是，不具有组织渗透性，因此适合于长时间地应用于眼睛中，因为已知：已知物质对组织有害的特性是因其较高的渗透性引起的。较为理想地，在眼科学中应用时，本发明使用的治疗剂因为综合了降低的密度和提高的粘度，对眼睛不会造成机械损害，因此可用作长期的玻璃体代用品。与目前使用的硅油相比，应用本发明低聚物的优点是可用于局部缺血视网膜的调节氧治疗和由于特定的表面特性可同时用作主要的充填作用，并且将其与硅油和水相比即使在眼部下方也具有较高的密度。
出于相同的原因，本发明所述的低聚物能在迄今只能应用硅油的各种其他的眼科学领域中应用。特别是例如以植入物的形式用作容积代用品(Volumenersatzstoff)。此外，也可用于全新的眼科学领域。在本发明低聚物的应用中，在一个特别胶粘的实施方案中，可作为混浊、天生晶状体的代用品。在这种情况下，在保持四周泪囊的条件下取出天生的晶状体，向泪囊中注入高胶粘的低聚物。该液态的晶状体材料能够维持调视机能。对此，理想的做法是采用具有高支化度的低聚物，或者再进一步提高本身已经较高的低聚物的粘度，是通过按已知方法添加一定量的由水和表面活性物质组成的混合物生产凝胶进行。
另外，由此可使水溶性的物质吸收到液态植入物中，主要是拓宽其医疗应用领域。因而，使应用这种凝胶成为可能，其中，在同时的离子(玻璃体代用品)吸收能力下，这取决于额外高的粘度(液态晶状体)和限制最低可能性的机械负荷的组织。与常规的碳氟化合物凝胶相比，一个特别主要的优点是在凝胶破坏时，保留下来的介质本身会部分地保持植入物的作用，这是因为它们本身已经具有足够的粘度。
用作活性物质载体的应用是以药理活性物质在低聚物中的溶解能力为基础的，此时，一方面的溶解能力和另一方面抑制的组织渗透的异常结合显得特别重要。因此，用作活性物质载体的应用不仅是以容积代用品的形式应用的，而且即使没有该应用功能也是特别重要的。
有利的物理特性例如溶氧性以及成膜的但不起组织渗透作用的特性使得高氟低聚物具有其他的用途，例如用作眼泪替代液。
从本发明的应用角度来看，所述物质的一个主要优点是综合了碳氟化合物和硅油的已知特性，特别是硅油的高粘度和碳氟化合物的高密度和溶氧性，而且，没有其他的诸如氟硅氧烷类的已知物质已知的每性或硅油和部分氟化烷烃混合物中存在的并且会限制或排除它们在眼科学中用作治疗剂的复杂的比例。
另外，将该低聚物在眼科中应用时，具有如下的优点：它们与硅油相反，可以通过顺利的洗涤除去，原因是优选采用在眼科实践中证明是短期使用的全氟化碳，例如全氟萘烷或全氟辛烷，但是也使用部分氟化的烷烃，例如C6F13C2H5或C4F9C4H9作为生物相容的溶剂。另一方面，也可根据需要用硅油代用或反向进行，而不混合该化合物。
所述低聚化合物呈粘性至高粘性或甚至呈软膏状的稠度，其具有的密度为1.2-1.7克/厘米3。它是透光的，具有的折射率为1.30-1.45。该化合物基本上是非极性的。但是显得特别的是，与两种分子成分烷烃和全氟烷烃相比，在分离状态下由化合物型的CF2-CH2-基团表征了弱的分子极性。由物质决定的物理特性例如摩尔量、密度、折射率、粘度、透光性和溶解性根据应用目的而发生改变。这些是通过对RF-基团和RH-基团、其支化度和低聚度的选择实现的。而且，物理化学特性也可以通过添加全氟化的或部分氟化的烷烃来调节。高氟化的低聚物具有异乎寻常的耐化学稳定性和耐热稳定性并且遇酶不分解。它们在毒物学和皮肤病学方面并不令人担心。
所述物质的制备和纯化是按已知方法进行的。例如，按DE 41 39 765描述的方法制备或通过支链的全氟化烯烃与氟化钾或氟化铯在一种非质子溶剂中与卤代烯烃发生反应并且在一种非极性溶剂中用游离基引发剂低聚化获得。纯化例如是通过提取和柱色谱法进行的。
下面详细描述了高氟化低聚物的一些实施例。
实施例1
使溶解在碳氟化合物中的高氟化低聚物(C6F13CHCH2)3通过Al2O3色谱柱纯化。除去溶剂后，在真空中除去最后微量的挥发性杂质。高氟化的三聚物经核自旋谐振、红外学和质谱学检测后证明是一种单一的和高纯的物质，其具有的分子量为1055。装载活性物质的过程是小心翼翼地通过一种不与三聚物混合的溶剂在分配至饱和浓度后进行。在这种情况下，作为活性物质的β-胡萝卜素很难染色该低聚物。在121℃的高压釜中进行杀菌，不会改变该物质的物理或化学特性。该物质的核磁数据如下：
1H-NMR:CH3：0.95ppm；-CH-CF2-：2.02ppm；CH2-：1.64ppm
19F-NMR:CH3-：82.8ppm；-CH-CF2：-116.2ppm；4CF2：-123.2ppm，-124.3ppm，-124.8ppm，-127.7ppm
13C-NMR:CH3-/CH2-：25-35ppm
CF3-/CF2-：105-120ppm。
该物质的纯度主要通过下面的物理特性表征：
密度：1.661克/厘米3；
折射率nD 20：1.3351；
表面张力：19.5mN/m；
在正-己烷中的临界溶解温度CST：35℃；
粘度：220mPas。
这些低聚物适合于所有的上述和权利要求中描述的用途并且具有上述已知的优点，尤其是在长期应用领域内。
实施例2
将72克十三氟-4，4-二甲基庚烯-1溶解在100毫升正-己烷中，用1.7克二-叔丁基过氧化物在190℃的高压釜中进行低聚化，得到由二聚物和三聚物组成的反应混合物。对该混合物进行蒸馏分离，获得粘稠无色油状的三聚物，其组成为[CF3CF2CF2C(CF3)2CH2CHCH2]3，具有的平均摩尔量为1085道尔顿。根据19F-和1H-NMR以及红外探测(infrarotdektroskopischen)检测，与本发明的通式化合物对应，并证实具有高的纯度。在体外试验内进行的对应的试验说明该高氟化油适合于所要求的用途。
Claims (6)
1.一种高氟化低聚烷烃用于制备在眼科学中或眼科学的药理制剂中的治疗剂的用途，其中所述高氟化低聚烷烃是通过将十三氟-4，4-二甲基庚烯-1溶解于正己烷中并在190℃的高压釜中与二叔丁基过氧化物反应，和随后通过蒸馏分离反应混合物以便获得所述高氟化低聚烷烃的三聚体而制备的。
2.根据权利要求1的用途，用于制备玻璃体代用品和/或视网膜填充物。
3.根据权利要求1的用途，用于制备液态植入物。
4.根据权利要求1的用途，用于制备眼泪替代液。
5.根据权利要求1的用途，用于制备带入药物活性物质的载体物质。
6.根据上述权利要求任一项的用途，其特征在于：将低聚烷烃用作眼科学中的药理制剂的一种成分并由此以混合物的形式使用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| DE19926890.8 | 1999-06-12 | ||
| DE19926890A DE19926890C1 (de) | 1999-06-12 | 1999-06-12 | Verwendung eines hochfluorierten oligomeren Alkans in der Ophthalmologie |
Publications (2)
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| CN1374860A CN1374860A (zh) | 2002-10-16 |
| CN1322859C true CN1322859C (zh) | 2007-06-27 |
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| CNB008116326A Expired - Lifetime CN1322859C (zh) | 1999-06-12 | 2000-04-27 | 高氟低聚烷烃在眼科学中的应用 |
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| AU (1) | AU4298300A (zh) |
| CA (1) | CA2377290C (zh) |
| DE (2) | DE19926890C1 (zh) |
| ES (1) | ES2230093T3 (zh) |
| HK (1) | HK1040931B (zh) |
| WO (1) | WO2000076491A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102010010430A1 (de) | 2010-03-05 | 2011-09-08 | Fluoron Gmbh | Füllmaterial für ophthalmologische Implantate |
| DE202010003217U1 (de) | 2010-03-05 | 2011-08-04 | Fluoron Gmbh | Füllmaterial für ophthalmologische Implantate |
| KR101656121B1 (ko) | 2010-03-17 | 2016-09-08 | 노바리크 게엠베하 | 안압 증가를 치료하기 위한 약학 조성물 |
| EP2444063A1 (en) | 2010-10-20 | 2012-04-25 | Novaliq GmbH | Liquid pharmaceutical compositions for the delivery of active ingredients |
| EP2462921A1 (en) | 2010-11-11 | 2012-06-13 | Novaliq GmbH | Liquid pharmaceutical compositions for the treatment of a posterior eye disease |
| ES2962524T3 (es) | 2011-05-25 | 2024-03-19 | Dermaliq Therapeutics Inc | Composición farmacéutica tópica a base de alcanos semifluorados |
| CA2862974C (en) | 2012-01-23 | 2021-11-16 | Novaliq Gmbh | Stabilised protein compositions based on semifluorinated alkanes |
| CN113679697A (zh) | 2012-09-12 | 2021-11-23 | 诺瓦利克有限责任公司 | 包含半氟化烷烃的混合物的组合物 |
| PT2895144T (pt) | 2012-09-12 | 2017-02-22 | Novaliq Gmbh | Composições de alcano semifluorado |
| AU2014295052B2 (en) | 2013-07-23 | 2018-08-30 | Novaliq Gmbh | Stabilized antibody compositions |
| EP3355990B1 (en) | 2015-09-30 | 2019-06-12 | Novaliq GmbH | Semifluorinated compounds and their compositions |
| DE202016008739U1 (de) | 2015-09-30 | 2019-04-29 | Novaliq Gmbh | Semifluorierte Verbindungen |
| US10507132B2 (en) | 2016-06-23 | 2019-12-17 | Novaliq Gmbh | Topical administration method |
| CN109890374A (zh) | 2016-09-22 | 2019-06-14 | 诺瓦利克有限责任公司 | 用于治疗睑缘炎的药物组合物 |
| ES2965677T3 (es) | 2016-09-23 | 2024-04-16 | Novaliq Gmbh | Composiciones oftálmicas que comprenden ciclosporina |
| CA3058097C (en) | 2017-04-21 | 2024-01-02 | Novaliq Gmbh | Iodine compositions |
| WO2018206656A1 (en) | 2017-05-12 | 2018-11-15 | Novaliq Gmbh | Pharmaceutical compositions comprosing semifluorinated alkanes for the treatment of contact lense-related conditions |
| EP3687496A1 (en) | 2017-09-27 | 2020-08-05 | Novaliq GmbH | Ophthalmic compositions comprising latanoprost for use in the treatment of ocular diseases |
| US11896559B2 (en) | 2017-10-04 | 2024-02-13 | Novaliq Gmbh | Opthalmic compositions comprising F6H8 |
| WO2019166631A1 (en) | 2018-03-02 | 2019-09-06 | Novaliq Gmbh | Pharmaceutical compositions comprising nebivolol |
| WO2019206956A1 (en) | 2018-04-27 | 2019-10-31 | Novaliq Gmbh | Ophthalmic compositions comprising tafluprost for the treatment of glaucoma |
| AU2019358249B2 (en) | 2018-10-12 | 2024-02-22 | Novaliq Gmbh | Ophthalmic composition for treatment of dry eye disease |
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| US5441733A (en) * | 1992-04-01 | 1995-08-15 | Pharmpur Gmbh | Treatment agent for ophthalmology and use thereof |
| DE19536504A1 (de) * | 1995-09-29 | 1997-04-03 | H Prof Dr Meinert | Fluorierte Alkane und ihre Verwendung |
| EP0877010A1 (de) * | 1997-05-07 | 1998-11-11 | PHARMPUR GmbH | Fluorierte Alkane und ihre Verwendungen |
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| US4490351A (en) * | 1982-03-15 | 1984-12-25 | Children's Hospital Medical Center | Methods of treating disorders of an eye with liquid perfluorocarbons |
| DE4139765A1 (de) * | 1991-12-03 | 1993-06-09 | Hoechst Ag, 6230 Frankfurt, De | Oligomere von fluorierten olefinen |
| DE4405627A1 (de) * | 1994-02-22 | 1995-08-24 | Hoechst Ag | Fluorkohlenwasserstoffe enthaltende Ölemulsionen |
| FR2716678B1 (fr) * | 1994-02-25 | 1996-05-15 | Opsia | Nouveaux composés organiques fluorés, applications en particulier ophtalmologiques et procédé de fabrication. |
| DE19861012A1 (de) * | 1998-03-18 | 1999-09-30 | Pharm Pur Gmbh | Behandlungsmittel für die Ophthalmologie |
-
1999
- 1999-06-12 DE DE19926890A patent/DE19926890C1/de not_active Expired - Lifetime
-
2000
- 2000-04-27 AU AU42983/00A patent/AU4298300A/en not_active Abandoned
- 2000-04-27 CA CA2377290A patent/CA2377290C/en not_active Expired - Lifetime
- 2000-04-27 EP EP00922666A patent/EP1185256B1/de not_active Expired - Lifetime
- 2000-04-27 AT AT00922666T patent/ATE278396T1/de not_active IP Right Cessation
- 2000-04-27 CN CNB008116326A patent/CN1322859C/zh not_active Expired - Lifetime
- 2000-04-27 DE DE50008127T patent/DE50008127D1/de not_active Expired - Lifetime
- 2000-04-27 WO PCT/EP2000/003817 patent/WO2000076491A1/de active IP Right Grant
- 2000-04-27 HK HK02102747.0A patent/HK1040931B/zh not_active IP Right Cessation
- 2000-04-27 ES ES00922666T patent/ES2230093T3/es not_active Expired - Lifetime
- 2000-04-27 US US10/018,398 patent/US7026359B1/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5441733A (en) * | 1992-04-01 | 1995-08-15 | Pharmpur Gmbh | Treatment agent for ophthalmology and use thereof |
| DE19536504A1 (de) * | 1995-09-29 | 1997-04-03 | H Prof Dr Meinert | Fluorierte Alkane und ihre Verwendung |
| EP0877010A1 (de) * | 1997-05-07 | 1998-11-11 | PHARMPUR GmbH | Fluorierte Alkane und ihre Verwendungen |
Also Published As
| Publication number | Publication date |
|---|---|
| DE50008127D1 (de) | 2004-11-11 |
| AU4298300A (en) | 2001-01-02 |
| HK1040931B (zh) | 2005-02-25 |
| HK1040931A1 (zh) | 2002-06-28 |
| CN1374860A (zh) | 2002-10-16 |
| DE19926890C1 (de) | 2000-07-27 |
| ES2230093T3 (es) | 2005-05-01 |
| CA2377290A1 (en) | 2000-12-21 |
| EP1185256A1 (de) | 2002-03-13 |
| CA2377290C (en) | 2010-07-20 |
| ATE278396T1 (de) | 2004-10-15 |
| WO2000076491A1 (de) | 2000-12-21 |
| EP1185256B1 (de) | 2004-10-06 |
| US7026359B1 (en) | 2006-04-11 |
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