CN1509172A - 哌仑西平眼用凝胶剂 - Google Patents
哌仑西平眼用凝胶剂 Download PDFInfo
- Publication number
- CN1509172A CN1509172A CNA02810174XA CN02810174A CN1509172A CN 1509172 A CN1509172 A CN 1509172A CN A02810174X A CNA02810174X A CN A02810174XA CN 02810174 A CN02810174 A CN 02810174A CN 1509172 A CN1509172 A CN 1509172A
- Authority
- CN
- China
- Prior art keywords
- preparation
- gel
- pirenzepine
- eye
- sodium
- Prior art date
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Links
- 229960004633 pirenzepine Drugs 0.000 title claims abstract description 28
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229940100655 ophthalmic gel Drugs 0.000 title 1
- 208000001491 myopia Diseases 0.000 claims abstract description 21
- 230000004379 myopia Effects 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- -1 polyoxyethylene Polymers 0.000 claims description 12
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229960001716 benzalkonium Drugs 0.000 claims description 3
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
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- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 claims description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
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- 239000001103 potassium chloride Substances 0.000 claims description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 2
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- JJCZGVLYNIVKKD-UHFFFAOYSA-N 3-hydroxy-2-phenylpropanamide Chemical compound NC(=O)C(CO)C1=CC=CC=C1 JJCZGVLYNIVKKD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
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Abstract
本发明主要目的是提供一种用于治疗近视的水性眼用制剂，其含有与药物可接受的凝胶载体结合的哌仑西平。
Description
发明背景
发明领域
本发明涉及水性眼用药物制剂领域。
发明背景
近视即眼轴变长影响了大部分人。一般而言，近视是在小学期间开始出现的，并持续到眼睛发育完成。可预防或延迟近视发育异常的药物治疗法对于治疗近视表现出很大的改进。
如下证据促进了药物治疗法的可能用途：阿托品可预防人(DA Goss.1982.Attempts to reduce the rate of increase of myopia in young people--acritical literature review.Am.J.Optom.Physiol.Opt.59：828-841.)、树鼠(McKanna JA，and VA Casagrande.1978.Reduced lens development inlid-suture myopia.Exp.Eye Res.26：715-723.)、断尾猴和小鸡(McBrien NA，Moghaddam HO，Reeder AP，and S.Moules.1991a.Structural andbiochemical changes in the sclera of experimentally myopic eyes.Biochem.Soc.Trans.19：861-865；McBrien NA，Moghaddam HO，and AP Reeder.1991b.Atropine reduces axial elongation and myopia in visually impairedchick eyes.Invest.Ophthalmol.Vis.Sci.32：1203；Tigges M，Sugrue MF，Mallorga P，Stone RA，Laties AM，Fernandes A，and PM Iuvone 1996.Effects of atropine，ATR，and pirenzepine，PIR，on ocular growth andmuscarinic cholingergic receptors in young rhesus monkeys.Invest.Ophthalmol.Vis.Sci.37：S326.)形成近视。阿托品由于包括瞳孔扩张导致的眩光视觉副作用和由于调节下降导致的视力模糊，其作为治疗的临床用途受到限制。适度的睫状肌麻痹剂如托品酰胺在许多研究中是有效的，但在另外的研究中无效(Curtin BJ and DB Karlin.1971.Axial lengthmeasurements and fundus changes of the myopic eye.Am.J.Ophthalmol.71：42-53.)。
Stone和Laties发现，阿托品、非选择性毒蕈碱拮抗剂、哌仑西平(pirenzepine)、在欧洲因其抗消化不良性质而起系统用途可购得的相对选择性M1型拮抗剂的结膜下注射可消弱近视小鸡模型的眼轴发育。而M2和M3型拮抗剂不能预防眼轴变长(Stone RA，Lin T，and AM Laties.1991.Muscarinic antagonist effects on experimental chick myopia.Exp.Eye Res.52：755-758；1990年5月11日申请的美国专利第5,112,522号)。与阿托品不同的是，选定浓度的哌仑西平可以预防近视，而不会引起不想要的副作用，如失能性瞳孔散大及睫状肌麻痹。
哌仑西平是一种相对选择性M1型毒蕈碱拮抗剂，因其可减缓及结束儿科近视形成的局部视觉用途已对其进行了调查研究。发现以达到2％浓度的溶液给药，成人志愿者感到舒适并且没有系统作用(Shedden AH，Sciberras D，Hutzelmann J，and C van Nispen. 1998.Tolerability ofpirenzepine ophthalmic solution in adult male volunteers.Invest.Ophthalmol.Vis.Sci.39：S279.)。
然而，对于哌仑西平溶液剂形的研究指出物理外形问题。哌仑西平在溶液中是稳定的，特别是在pH为5时，但是其降解产物不溶于水。从而由于溶液中哌仑西平不吸引人的外形，在溶液保存期内即使降解产物少量的累积也会产生不可接受的产物。
对于此问题没有“标准的”公式化解决方案。一种方法是使用冷藏溶液。另一种方法是使用在配药给患者之前还原的冻干产物。然而，这些方法都不是最佳的，冻干法相当程度地增加了产物成本并需要麻烦的还原过程，冷藏法也未必总是方便的。从而需要使用理想的公式化方法解决物理外形问题的哌仑西平剂形。
发明概述
综上所述，本发明主要目的是提供一种用于治疗近视的水性眼用制剂，其含有与药物可接受的凝胶载体结合的哌仑西平。
优选实施方案的详细说明
本发明用于治疗近视的眼用水性凝胶制剂含有与水溶性纤维素衍生物结合的药物有效量的哌仑西平。
本发明制剂中哌仑西平的浓度可以为约0.001～3％(w/v)，优选为约0.005～2％(w/v)。哌仑西平及其二盐酸盐在本领域是公知的。
下面是二盐酸哌仑西平的结构：
分子式：C19H21N5O2·2HCl·H2O
分子量：442.3；351.4(无水游离碱)
化学名称：二盐酸5，11-二氢-11-[(4-甲基-1-哌仑西平嗪基)乙酰]-6H-
吡啶并[2，3-b]][1，4]-苯并二氮草-6-酮一水合物
二盐酸11-[(4-甲基-1-哌仑西平嗪基)乙酰]-吡啶并
[2，3-b]][1，4]-苯并二氮草-6(5H)-酮一水合物
在本发明的制剂中使用纤维素衍生物作为凝胶剂，最优选的是羟丙基甲基纤维素。然而，可以使用在所需粘度时形成水性凝胶即可溶在水中并形成凝胶的任何衍生于纤维素的凝胶剂。此类衍生物及其性质是公知的，并已在例如美国药典(2000)中(UNITED STATESPHARMACOPEIAL CONVENTION，INC.，THE UNITED STATESPHARMACOPEIA/THE NATIONAL FORMULARY(2000))公开。此类凝胶剂包括但不限于甲基纤维素、羟丙基纤维素、羧甲基纤维素、羟乙基纤维素及纤维素胶。也可使用不同种衍生物的组合物。纤维素基凝胶剂比诸如交联的丙烯酸聚合物更有利。交联的丙烯酸聚合物例如CarbopolTM已被用于形成眼用含有盐酸毛果芸香碱的水性凝胶。然而，纤维素基凝胶剂引起不利反应的可能性更小。
本发明的制剂基本上是粘性的，足以形成粘性凝胶。在约20℃和按Brookfield RVDV分析剪切速率为1s-1时，粘度优选是在10,000～300,000厘泊(cps)范围内，最优选为15,000～200,000cps。
在眼用水性凝胶中，纤维素基凝胶剂的量按重量计优选为约0.5％～5％，最优选为约1％～5％。
通常用在本发明中的适合纤维素基制剂商业上可购得。例如，适于用来制备本发明纤维素基眼用凝胶的羟丙基甲基纤维素的来源包括Ashland Distribution Co.、Asiaamerica International Inc.、Biddle SawyerCorp.、Carbomer Inc.、Colorcon Inc.、Dow Chemical Co.、FOB Chemicals、Hercules Inc.、Mutchler Inc.、Penta Mfg Co.、Spectrum Laboratory ProductsInc.、Van Waters & Rogers Inc.及Warner Jenkinson。
此制剂可以含有其它的药物非活性物质。例如，其可含有一种或多种可溶性试剂，如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60或聚山梨醇酯80。此制剂也可以含有分散剂，如卵磷脂或甘油。也可加入胶原质。其它添加剂包括环糊精，特别是α、β、γ环糊精。另外，也可加入尤其是可溶解形的维生素E或其它抗氧化剂，包括丁基羟基茴香醚(BHA)和丁基羟基甲苯(BHT)。某些非活性物的其它例子如下：氯化钠、溴化十六烷基三甲铵、乙基汞硫代水杨酸钠、氯化苯甲烷铵、硼酸、碳酸钠、氯化钾、丙二醇、聚氧乙烯、聚氧丙烯、硬脂酸40聚烃氧基酯、聚乙烯醇、泊洛沙姆188(poloxamer 188)、柠檬酸钠、硫代硫酸钠、亚硫酸氢钠、右旋糖酐70、醋酸、聚乙二醇、聚维酮(povidone)、葡萄糖、氯化镁、褐藻酸、醋酸钠、硼酸钠、乙二胺四乙酸二钠、氢氧化钠及盐酸。应用在制剂中的非活性成分最佳量可基于特定的活性药物及欲使用的药物按常规方法测定。
本发明的制剂可放在适于眼用制剂的任何所需要的配药装置中。该装置可以是眼用给药系统，如消毒眼用管，例如具有眼用尖端并含有本发明眼用制剂的常规3.5-5g的眼用管，或含有0.1-0.5g制剂的消毒一次性次或日用容器。
该药物制剂可通过各种途径给药，包括滴眼液给药、结膜下给药及玻璃体腔给药。通常哌仑西平的日剂量可以是6mg或更少/总体重，优选是4mg或更少/总体重，并且可按单剂量或分剂量给药。然而应该理解，哌仑西平实际的给药量应根据各种相关因素决定，包括待治疗的近视、给药的选择途径及患者症状的严重程度，因此上面的剂量不意于以任何方式限制本发明的范围。
与本发明背景技术中指出的在较少量水不溶性降解产物存在下保持可接受的物理外形的溶液相比，从该凝胶和溶液剂形得到的稳定性数据表现出优越性。
下面的实施例用于进一步阐明本发明的范围，而没有限制其范围。
实施例1
本发明用来治疗近视的2.0％哌仑西平水性眼用凝胶制备如下：
表1哌仑西平眼用凝胶制剂
| 成分 | 0.5％(mg/g) | 1.0％(mg/g) | 2.0％(mg/g) |
| 二盐酸哌仑西平 | 6.3 | 12.6 | 25.2 |
| (碱当量) | (5.0) | (10.0) | (20.0) |
| 羟丙基甲基纤维素(K100M，Dow Chemical Co.) | 20 | 20 | 20 |
| 醋酸钠 | 0.40 | 0.40 | 0.40 |
| 氯化苯甲烷铵 | 0.05 | 0.05 | 0.05 |
| 乙二胺四乙酸二钠 | 0.15 | 0.15 | 0.15 |
| 氯化钠 | 5.0 | 3.5 | 0.0 |
| 氢氧化钠(调节pH) | 5.0 | 5.0 | 5.0 |
| 纯化水，调节 | 1.00g | 1.00g | 1.00g |
部分1：将纯化水加热到80-90℃。加入羟丙基甲基纤维素(HPMC)，并混合至其均匀分散。用氢氧化钠将pH调节至5.0±1.0，但此步骤不是关键性的可以去掉。将混合物置于压力容器后，将其在121℃下消毒30-45分钟。在另一个实施方案中，当氧气在高压消毒中起降低粘度作用时，在氮气下进行高压消毒。将混合物冷至25～30℃，并混合几小时，从而产生均质粘性凝胶。在适合的夹套压力容器中制备混合物表明，在高压消毒后将部分1(羟丙基甲基纤维素相)冷却至10℃而不是25～30℃可很大程度地提高水合作用和生成的凝胶粘度。在25～30℃下将该凝胶保存几小时以有助于溶解，然后维持在25～30℃下保存。
部分2：混合其余的成分，并在水中溶解直到得到透明溶液。用氢氧化钠将pH调节至5.0±1.0。通过膜过滤(0.2微米)将该溶液消毒。
按游离碱计算哌仑西平的浓度。然而，我们加入的是其二盐酸盐。用氢氧化钠将pH调节至5.0±1.0，将二盐酸盐部分或全部地转化成单盐酸盐。
将消毒的部分2的溶液加到部分1的凝胶中。加入足量的消过毒的水调节混合物的最终重量。如果需要，进行最终pH调节。将此混合物混合约48小时，从而实现均质化。将生成的经消毒凝胶加到预先消毒的眼用容器内。
实施例2
将实施例1中制得的眼用哌仑西平凝胶制剂按如下给药(配药装置的眼用尖端不要与任何表面接触以避免污染)。将待给药的下眼睑向下拉，将少量的凝胶(约0.25英寸)敷在眼睑里面。每天两次将该凝胶敷在有病的眼睛上。儿科受试者的目标群对于凝胶制剂有相当的耐药性。
实施例3
粘度测量方法：在约20℃和1s-1的剪切速率下，使用Brookfield锥板型粘度计(RVDV-III+型)测量粘度。测量0.5-2g各种凝胶试样的粘度。使用CP52转子(spindle)测量粘度为5,000到小于600,000cps的凝胶，取决于凝胶的粘度可使用其它的转子。
尽管为阐明和理解起见已详细地公开了本发明，但是应该理解，本领域所属技术人员可以做出各种形式和细节的变化而不会脱离本发明真正的范围。上述引用的所有专利、专利申请和出版物据此引为参考。
Claims (20)
1.一种用于治疗近视的水性眼用凝胶制剂，其含有哌仑西平和一定量的凝胶剂，所述凝胶剂的量可有效地形成水性凝胶，所述凝胶的Brookfield RVDV粘度在约20℃和1s-1的剪切速率下为约10,000～300,000cps，其中所述的凝胶剂是水溶性纤维素衍生物。
2.如权利要求1所述的制剂，其中所述的哌仑西平的浓度为约0.001～3％(w/v)。
3.如权利要求1所述的制剂，其中所述的哌仑西平的浓度为约0.005～2％(w/v)。
4.如权利要求1所述的制剂，其中所述的水溶性纤维素衍生物在约20℃和1s-1的剪切速率下粘度为15,000～200,000cps的所述水性制剂中是可溶的。
5.如权利要求1所述的制剂，其中所述的水溶性纤维素衍生物在约20℃和1s-1的剪切速率下粘度为100,000cps的所述水性制剂中是可溶的。
6.如权利要求1所述的制剂，其中所述凝胶剂的量按重量计为约0.5～5％。
7.如权利要求1所述的制剂，其中所述凝胶剂的量按重量计为约1～5％。
8.如权利要求1所述的制剂，还包括至少一种选自如下的成分：氯化钠、溴化十六烷基三甲铵、乙基汞硫代水杨酸钠、氯化苯甲烷铵、硼酸、碳酸钠、氯化钾、丙二醇、聚氧乙烯、聚氧丙烯、硬脂酸40聚烃氧基酯、聚乙烯醇、泊洛沙姆188、柠檬酸钠、硫代硫酸钠、亚硫酸氢钠、右旋糖酐70、醋酸、聚乙二醇、聚维酮、葡萄糖、氯化镁、褐藻酸、醋酸钠、硼酸钠、乙二胺四乙酸二钠、氢氧化钠及盐酸。
9.如权利要求1所述的制剂，其中所述的凝胶剂至少是一种选自如下的成分：羟丙基甲基纤维素、甲基纤维素、羟丙基纤维素、羧甲基纤维素、羟乙基纤维素及纤维素胶。
10.如权利要求1所述的制剂，其中所述的凝胶剂是羟丙基甲基纤维素。
11.一种含有权利要求1所述制剂的眼用给药系统。
12.如权利要求11所述的眼用给药系统，其包括具有眼用尖端并含有所述水性凝胶的眼用管。
13.一种治疗近视的方法，包括将权利要求1所述的制剂给药至人类个体的眼睛，从而治疗近视。
14.如权利要求13所述的方法，其中所述的人类个体是儿科受试者。
15.如权利要求1所述的制剂在制备用于治疗近视的药物中的用途。
16.如权利要求1所述的制剂在制备用于治疗儿科受试者近视的药物中的用途。
17.一种制备如权利要求1所述制剂的方法，包括高压消毒由所述凝胶剂和水组成的混合物、消毒过滤含有所述哌仑西平和水的溶液、及在无菌条件下将它们混合。
18.如权利要求17所述的方法，其中所述的高压消毒步骤是在氮气下进行的。
19.如权利要求1所述的制剂，其中所述的制剂选自表1中的制剂。
20.如权利要求1所述消毒形式的制剂。
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| CA2573674A1 (en) * | 2004-07-16 | 2006-01-26 | Proteosys Ag | Muscarinic antagonists with parp and sir modulating activity as agents for inflammatory diseases |
| JP4963359B2 (ja) * | 2005-01-12 | 2012-06-27 | ロート製薬株式会社 | 眼局所適用製剤 |
| RU2009128703A (ru) * | 2006-12-26 | 2011-02-10 | Клт Плаг Диливери, Инк. (Us) | Имплантаты, доставляющие лекарства, для уменьшения оптических дефектов |
| US10265265B2 (en) | 2007-03-15 | 2019-04-23 | Drug Delivery Solutions Limited | Topical composition |
| EP2008651A1 (en) | 2007-06-26 | 2008-12-31 | Drug Delivery Solutions Limited | A bioerodible patch |
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| US8883214B2 (en) | 2009-01-13 | 2014-11-11 | The Regents Of The University Of California | Implantable delivery vehicle for ocular delivery of muscarinic antagonists |
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| JP6105494B2 (ja) * | 2011-03-14 | 2017-03-29 | ドラッグ デリバリー ソリューションズ リミテッド | 眼科用組成物 |
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| US11382909B2 (en) | 2014-09-05 | 2022-07-12 | Sydnexis, Inc. | Ophthalmic composition |
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| CA3205816A1 (en) * | 2017-11-03 | 2019-05-09 | Alcon Inc. | Azabicyclo and diazepine derivatives for treating ocular disorders |
| EP3542788A1 (en) | 2018-03-19 | 2019-09-25 | MC2 Therapeutics Limited | Topical composition comprising calcipotriol and betamethasone dipropionate |
| EP3946357A4 (en) * | 2019-03-26 | 2023-04-05 | Winsantor, Inc. | TOPICAL FORMULATIONS FOR THE TREATMENT OF PERIPHERAL NEUROPATHIES |
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| CA3146848A1 (en) * | 2019-07-11 | 2021-01-14 | University Of Utah Research Foundation | Multi-agent ocular formulations and treatment methods |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| HU188852B (en) * | 1983-03-16 | 1986-05-28 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for producing thiazolidine derivatives active against gastric ulcer and intestinal ulcer |
| US4865599A (en) * | 1986-08-18 | 1989-09-12 | Houston Biotechnology, Inc. | Ophthalmic compositions for treating nerve degeneration |
| CA1336490C (en) * | 1988-06-03 | 1995-08-01 | Paul Michael Iuvone | Pharmacological treatment of ocular development |
| US5360801A (en) * | 1989-06-21 | 1994-11-01 | The Trustees Of The University Of Pennsylvania | Pharmacological stimulation of eye growth |
| US5122522A (en) * | 1989-06-21 | 1992-06-16 | The Trustees Of The University Of Pennsylvania | Treatment and control of ocular development |
| ES2159661T3 (es) * | 1989-06-21 | 2001-10-16 | Univ Pennsylvania | Utilizacion de un antagonista muscarinico para la preparacion de un medicamento para el tratamiento y control del desarrollo ocular. |
| US5055302A (en) * | 1990-02-22 | 1991-10-08 | Trustees Of The University Of Pennsylvania | Neuropeptide control of ocular growth |
| US5461808A (en) * | 1993-02-08 | 1995-10-31 | Fritts; Robert W. | Table top backlit display |
| US5461052A (en) * | 1993-04-30 | 1995-10-24 | The Trustees Of The University Of Pennsylvania | Prevention of myopia by tricyclic compounds |
| US5385939A (en) * | 1993-04-30 | 1995-01-31 | The Trustees Of The University Of Pennsylvania | GABA-ergic modulation of eye growth |
| US5516808A (en) * | 1994-10-27 | 1996-05-14 | Sawaya; Assad S. | Topical cellulose pharmaceutical formulation |
| US5888493A (en) * | 1996-12-05 | 1999-03-30 | Sawaya; Assad S. | Ophthalmic aqueous gel formulation and related methods |
| US6164282A (en) * | 1999-01-27 | 2000-12-26 | Allergan Sales, Inc. | Methods for restoring and/or enhancing accommodation in pseudo phakia |
-
2002
- 2002-05-01 CN CNA02810174XA patent/CN1509172A/zh active Pending
- 2002-05-01 CA CA002447562A patent/CA2447562A1/en not_active Abandoned
- 2002-05-01 BR BR0210013-4A patent/BR0210013A/pt not_active IP Right Cessation
- 2002-05-01 NZ NZ529615A patent/NZ529615A/en unknown
- 2002-05-01 KR KR10-2003-7015393A patent/KR20040018380A/ko not_active Application Discontinuation
- 2002-05-01 IL IL15890402A patent/IL158904A0/xx unknown
- 2002-05-01 JP JP2002592928A patent/JP2004531569A/ja not_active Withdrawn
- 2002-05-01 MX MXPA03010655A patent/MXPA03010655A/es not_active Application Discontinuation
- 2002-05-01 HU HU0304071A patent/HUP0304071A2/hu unknown
- 2002-05-01 EP EP02734130A patent/EP1397132A4/en not_active Withdrawn
- 2002-05-01 RU RU2003136735/15A patent/RU2297831C2/ru not_active IP Right Cessation
- 2002-05-01 WO PCT/US2002/013823 patent/WO2002096418A1/en active IP Right Grant
- 2002-05-01 PL PL02366924A patent/PL366924A1/xx not_active Application Discontinuation
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2003
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- 2003-11-24 NO NO20035224A patent/NO20035224D0/no not_active Application Discontinuation
- 2003-12-18 ZA ZA200309791A patent/ZA200309791B/xx unknown
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2004
- 2004-01-23 EC EC2004004862A patent/ECSP044862A/es unknown
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| US20040137069A1 (en) | 2004-07-15 |
| NZ529615A (en) | 2005-07-29 |
| RU2297831C2 (ru) | 2007-04-27 |
| EP1397132A1 (en) | 2004-03-17 |
| RU2003136735A (ru) | 2005-03-27 |
| IL158904A0 (en) | 2004-05-12 |
| BR0210013A (pt) | 2004-08-10 |
| WO2002096418A1 (en) | 2002-12-05 |
| EP1397132A4 (en) | 2006-12-13 |
| JP2004531569A (ja) | 2004-10-14 |
| ECSP044862A (es) | 2004-03-23 |
| PL366924A1 (en) | 2005-02-07 |
| KR20040018380A (ko) | 2004-03-03 |
| HUP0304071A2 (hu) | 2004-04-28 |
| US20060188576A1 (en) | 2006-08-24 |
| MXPA03010655A (es) | 2007-06-22 |
| CA2447562A1 (en) | 2002-12-05 |
| ZA200309791B (en) | 2004-10-04 |
| NO20035224D0 (no) | 2003-11-24 |
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