CN116265010A - 含地夸磷索钠的药用组合物及其制备方法 - Google Patents
含地夸磷索钠的药用组合物及其制备方法 Download PDFInfo
- Publication number
- CN116265010A CN116265010A CN202111536985.6A CN202111536985A CN116265010A CN 116265010 A CN116265010 A CN 116265010A CN 202111536985 A CN202111536985 A CN 202111536985A CN 116265010 A CN116265010 A CN 116265010A
- Authority
- CN
- China
- Prior art keywords
- sodium
- pharmaceutical composition
- composition containing
- diquafosol
- diquafosol sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NMLMACJWHPHKGR-NCOIDOBVSA-N P(1),P(4)-bis(uridin-5'-yl) tetraphosphate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O NMLMACJWHPHKGR-NCOIDOBVSA-N 0.000 title claims abstract description 50
- 229950003529 diquafosol Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000003889 eye drop Substances 0.000 claims description 32
- 239000007788 liquid Substances 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 20
- 238000011049 filling Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229920001684 low density polyethylene Polymers 0.000 claims description 6
- 239000004702 low-density polyethylene Substances 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 6
- 229910021538 borax Inorganic materials 0.000 claims description 5
- 239000004328 sodium tetraborate Substances 0.000 claims description 5
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 235000010338 boric acid Nutrition 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229960002684 aminocaproic acid Drugs 0.000 claims description 2
- 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
- 235000015165 citric acid Nutrition 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004317 sodium nitrate Substances 0.000 claims description 2
- 235000010344 sodium nitrate Nutrition 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000001433 sodium tartrate Substances 0.000 claims description 2
- 229960002167 sodium tartrate Drugs 0.000 claims description 2
- 235000011004 sodium tartrates Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims 2
- 239000008121 dextrose Substances 0.000 claims 1
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- 239000000463 material Substances 0.000 description 5
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 239000002997 ophthalmic solution Substances 0.000 description 4
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- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 2
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
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Images
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种含地夸磷索钠的药用组合物及其制备方法,所述的药用组合物包括地夸磷索钠、缓冲剂、等渗调节剂、pH调节剂和注射用水。本发明所公开的含地夸磷索钠药用组合物不含防腐剂、质量稳定,解决了长期存放易导致不溶析出物产生问题,避免了眼部刺激副作用。加速3个月和长期3个月稳定性试验考察结果显示,本发明所制备的含地夸磷索钠的药用组合物无不溶性析出物的产生,且质量优于国内进口的多剂量包装的参比制剂。此外,处方组成中不含防腐剂,对眼睛的刺激性更小,和已有技术中不含防腐剂的发明相比,生产效率更高,副作用更小。
Description
技术领域
本发明属药物制剂领域,具体涉及一种含地夸磷索钠的药用组合物及其制备方法。
背景技术
地夸磷索钠是一种强效的嘌呤类P2Y2受体激动剂,是一种治疗干眼症的新型药物。不同于传统的人工泪液(主要通过润滑作用改善干眼患者不适),地夸磷索钠滴眼液可通过促进黏蛋白、泪液、脂质的分泌从而提高泪膜的稳定性,同时还具有促进角膜上皮损伤修复、抑制细胞炎症反应的作用。目前,其安全性及有效性已在多个临床试验中得到证实,亚洲干眼共识协会将其作为水液缺乏型干眼的一线治疗药物,及黏蛋白缺乏型干眼的首选药物。
地夸磷索钠滴眼液最早于2010年04月16日在日本获批上市,商品名为Diquas®,规格为3%(5ml:150mg),为多剂量包装滴眼液,持证商为参天製薬株式会社(参天制药有限公司),适用于经诊断为伴随泪液异常的角结膜上皮损伤的干眼患者。该品种于2011年12月30日在韩国获批上市,商品名为DIQUAS,规格为3%(5ml:150mg)。2017年10月20日获批进口国内,商品名为丽爱思®(Diquas®),规格为3%(5ml:150mg)。
多剂量包装滴眼液可以供多次连续使用,常常发生药液染菌或病人发生交叉感染等情况,因其装量有不合理性,这将会影响到滴眼液在使用过程中的安全性和有效性。另外,国内上市的地夸磷索钠滴眼液其中含防腐剂苯扎氯铵,它可能减弱角膜上皮细胞之间的连结,破坏泪膜,使干眼症症状加剧,渗入眼内后可能导致神经毒性。
参天制药公司的专利CN103282039A、CN104203254A公开的信息显示地夸磷索钠滴眼液不稳定,易产生不溶性析出物。专利CN108403625A提供一种含有螯合剂的地夸磷索四钠滴眼液,所解决的问题是不溶性析出物的产生,通过在处方中加入第一螯合剂(选自二乙烯三胺五乙酸、乙二胺四亚甲基膦酸及其盐中的一种或多种),并配合其他药学上可添加的添加剂及pH调节剂的使用,该专利中公开的制剂中含有防腐剂苯扎氯铵,且该专利通过添加螯合剂提高制剂的稳定性,但螯合剂有一定的副作用,可能会增加对眼睛的刺激性。专利CN108853016A 公开了一种不含防腐剂和螯合剂的地夸磷索钠滴眼液,但处方中含壳聚糖,制备过程中需进行缓慢溶胀,生产效率低下,且眼部生理pH条件下存放仍有析出风险。因此减少地夸磷索钠滴眼液的析出和提高用药依从性尤为重要。
地夸磷索钠滴眼液的析出由防腐剂苯扎氯铵导致,降低其使用量甚至不使用能有效避免析出,但现市场上多剂量包装滴眼液若不添防腐剂,将会明显增加滴眼液的质量风险。地夸磷索钠滴眼液每天滴眼6次,每次1滴。通常滴眼液一滴药液的体积为50~75μl,结膜囊正常人群最多可容纳30μl,即地夸磷索钠滴眼液每次或每天分别需要150μl或900μl。为满足临床用量需求,使地夸磷索钠滴眼液的包装体积大于临床使用量即可。基于以上现状,亟需开发出一种不含防腐剂,生产效率高,质量稳定,患者依从性高的地夸磷索钠滴眼液,能更好的治疗干眼症状。
发明内容
为了克服上述现有技术的不足,本发明的目的在于提供了一种不添加防腐剂、解决产品析出问题、眼部刺激小、依从性高、质量稳定的含地夸磷索钠的药用组合物及其制备方法。
为实现上述目的,本发明采用的技术方案为:
本发明提供了一种含地夸磷索钠的药用组合物,该药用组合物包括:地夸磷索钠、缓冲剂、等渗调节剂、pH调节剂和注射用水。
根据本发明的实施方式,本发明所公开的含地夸磷索钠的药用组合物中各组分含量以100ml计,包含以下成分:活性成分地夸磷索钠3g,缓冲剂0.05g~2g,等渗调节剂0.45g~1.5g,其他为注射用水及pH调节剂。
根据本发明的实施方式,通过大量的实验研究和分析,预料不到的发现去除防腐剂苯扎氯铵和螯合剂,按照本发明所公开的药用组合制备的地夸磷索钠制剂质量稳定,无不溶性析出物产生,且对眼睛刺激性更小、生产效率更高。此外,本发明将装量设计为一次性使用的用量,单次使用后丢弃,可避免使用染菌后的药液且能提高患者的依从性。基于此,本发明所公开的含地夸磷索钠的药用组合物的灌装量为0.4~0.9ml/支。
根据本发明的实施方式,本发明所述的含地夸磷索钠的药用组合物中缓冲剂选自磷酸氢二钠、磷酸二氢钠、硼酸、硼砂、柠檬酸、柠檬酸钠、乙酸、乙酸钠、酒石酸、酒石酸钠、磷酸二氢钾、磷酸氢钾、碳酸钠、碳酸钾和ε-氨基己酸中的一种或多种,优选磷酸氢二钠。
根据本发明的实施方式,本发明所述的含地夸磷索钠的药用组合物中等渗调节剂选自氯化钠、氯化钾、葡萄糖、硼砂、甘油、硫酸钠、甘露醇、硝酸钠中的一种或多种,优选氯化钠和氯化钾。
根据本发明的实施方式,本发明所述的含地夸磷索钠的药用组合物中pH调节剂选自盐酸或氢氧化钠。
根据本发明的实施方式,本发明所公开的药用组合物的pH值在6.0~8.0的范围内,优选7.2~7.8。
本发明还提供了含地夸磷索钠药用组合物的制备工艺,包括:
(1)配液:在配液罐中加入处方量的注射用水,加入处方量的缓冲剂、等渗调节剂,使其溶解完全,再加入处方量的地夸磷索钠,继续搅拌使完全溶解,使用pH调节剂调节pH,补注射用水至全量;
(2)过滤除菌:将(1)中药液依次经0.45μm滤膜过滤1次、0.22μm滤膜过滤3次;
(3)灌封:通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶。
与现有技术相比,本发明的有益效果是:本发明所公开的含地夸磷索钠的药用组合物不含防腐剂、质量稳定,解决了长期存放易导致不溶析出物产生问题,避免了眼部刺激副作用。加速3个月和长期3个月稳定性试验考察结果显示,所制备的含地夸磷索钠的药用组合物无不溶性析出物的产生,且质量优于国内进口的多剂量包装的参比制剂。此外,处方组成中不含防腐剂,对眼睛的刺激性更小,和已有技术中不含防腐剂的技术相比,生产效率更高,副作用更小。
附图说明
图1为实施例6、对照例1加速试验稳定性考察对比图。
图2为实施例6、对照例1长期试验稳定性考察对比图。
具体实施方式
滴眼液中添加防腐剂可能会对患者产生不利的影响,如会对结膜、角膜等造成损伤,出现刺痛感、异物感、眼干涩等不适症状,本发明公开了一种不添加防腐剂的含地夸磷索钠的滴眼液及其制备方法。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别指出的是,所有类似的替代和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明所述药用组合及其制备方法已经通过较佳实施例进行了描述,相关人员明显在不脱离本发明内容、精神和范围内对本文所述的方法应用进行改动或适当变更与组合,来实现和应用本发明技术。本发明将通过下述实施例来说明本发明的技术方案及其所达到的效果。
实施例1、对比例1、对比例2的处方及制备工艺
处方组成
制备工艺:
(1)配液:在配液罐中加入处方量70%的注射用水,开启搅拌器搅拌,搅拌转速为120转/分钟,加入处方量的辅料,使其溶解完全,再加入处方量的地夸磷索钠,继续搅拌使完全溶解,使用pH调节剂调节pH至7.8,补注射用水至全量;
(2)过滤除菌:将(1)中药液依次经0.45μm滤膜过滤1次、0.22μm滤膜过滤3次;
(3)灌封:通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶,0.5ml/支。
实施例1、对比例1、对比例2的用药考察
将实施例1、对比例1及对比例2所得样品分别施用于10名试验室干眼患者,每天6次,一次1滴,对患者的用药感受进行考察,结果如下:
实施例1、对比例1、对比例2性状考察
将实施例1、对比例1及对比例2所得样品于25℃条件下放置3个月,目视观察其性状变化,结果如下:
由以上试验结果看出:(1)含防腐剂的滴眼液滴眼一定的时间会对眼睛产生不同程度的刺激性,给眼睛造成潜在的危害,且随着防腐剂用量的减少,刺激性越弱;(2)去除防腐剂,仅用地夸磷索钠、缓冲剂、等渗调节剂及pH调节剂制备的溶液体系较稳定,不易产生析出物。
实施例2、对比例3处方及制备工艺
现有技术文献中有不含防腐剂的地夸磷索钠滴眼液,但其制备过程耗时较长,以下实施例与对比例可显示其与本发明的生产效率情况:
处方组成
实施例2的制备工艺:
①在配液罐中加入处方量70%的注射用水,开启搅拌器搅拌,加入处方量的辅料,使其完全溶解,再加入处方量的地夸磷索钠,继续搅拌使其完全溶解,使用氢氧化钠调节pH至7.2,补注射用水至全量;②将①中药液经0.45μm滤膜过滤1次、0.22μm滤膜过滤3次;③通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶,0.4ml/支;记录整个生产过程所用的总时间。
对比例3的制备工艺:
①将处方量的硼酸、硼砂溶于30℃处方量90%的注射用水中,加入处方量的壳聚糖使其自然溶胀;再将处方量的地夸磷索钠加入上述制得的溶液中,搅拌30min,使用氢氧化钠调节pH至7.2,补注射用水至全量,继续搅拌5min;②将①溶液先用0.45μm微孔滤膜过滤1次,再用0.22μm微孔滤膜过滤1次;③通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶,0.4ml/支;记录整个生产过程所用的总时间。
实施例2、对比例3的用药对比
将实施例2、对比例3制备所用时间进行对比,并将所制备的样品分别施用于10名实验室干眼患者,对其用药感受进行记录,结果如下:
由以上实验结果可看出,本发明所提供的不含防腐剂的地夸磷索钠滴眼液,不仅生产效率明显提高,且无明显的副作用,可见其安全性更好。
实施例3、4、5及对比例4、对比例5的处方及工艺
处方组成
制备工艺:
(1)配液:在配液罐中加入处方量70%的注射用水,开启搅拌器搅拌,搅拌转速为120转/分钟,加入处方量的辅料,使其溶解完全,再加入处方量的地夸磷索钠,继续搅拌使完全溶解,使用pH调节剂调节pH至7.5,补注射用水至全量;
(2)过滤除菌:将(1)中药液依次经0.45μm滤膜过滤1次、0.22μm滤膜过滤3次;
(3)灌封:通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶,0.9ml/支。
实施例3、4、5及对比例4、对比例5的质量考察
对上述实施例3、4、5及对比例4、5进行相关质量属性考察并进行影响因素试验,考察结果如下表:
由以上结果可看出:缓冲剂、等渗调节剂在适宜的范围内(实施例3、4、5),所制得的地夸磷索钠滴眼液质量稳定,无不溶性析出物产生。用量过低不能充分发挥其在滴眼液中的作用,如pH不稳定或渗透压过低,不利于产品的稳定和用药的舒适感。用量过大可能会导致相关质量指标如渗透压过大,从而亦对眼睛产生刺激。
实施例6、对照例1处方及工艺
处方组成
制备工艺:实施例6的制备工艺参照实施例1。
实施例6、对照例1质量对比
将实施例6与对照例1进行质量对比,结果如下:
实施例6、对照例1加速试验稳定性考察
将实施例6及Diquas置于40℃/RH75%条件下放置3个月进行加速试验稳定性考察,于25℃/RH 60%条件下放置3个月进行长期试验稳定性考察,其相关质量属性变化如下:
上述结果显示,本发明生产的滴眼液质量稳定,加速3个月和长期3个月稳定性考察结果显示均未产生不溶性析出物,且本发明的地夸磷索钠滴眼液不溶性微粒和有关物质略低于参比制剂,可见本发明生产的产品质量更好。
Claims (10)
1.一种含地夸磷索钠的药用组合物,其特征在于:所述的药用组合物包括地夸磷索钠、缓冲剂、等渗调节剂、pH调节剂和注射用水。
2.根据权利要求1所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的药物组合物中各组分含量以100ml计为:地夸磷索钠3g,缓冲剂0.05g~2g,等渗调节剂0.45g~1.5g,其他为注射用水及pH调节剂。
3.根据权利要求1或2所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的含地夸磷索钠的药用组合物的灌装量为0.4~0.9ml/支。
4.根据权利要求1或2所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的缓冲剂选自磷酸氢二钠、磷酸二氢钠、硼酸、硼砂、柠檬酸、柠檬酸钠、乙酸、乙酸钠、酒石酸、酒石酸钠、磷酸二氢钾、磷酸氢钾、碳酸钠、碳酸钾和ε-氨基己酸中的一种或多种。
5.根据权利要求4所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的缓冲剂选自磷酸氢二钠。
6.根据权利要求1或2所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的等渗调节剂选自氯化钠、氯化钾、葡萄糖、硼砂、甘油、硫酸钠、甘露醇、硝酸钠中的一种或多种。
7.根据权利要求6所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的等渗调节剂选自氯化钠和氯化钾。
8.根据权利要求1或2所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的pH调节剂选自盐酸或氢氧化钠。
9.根据权利要求1或2所述的一种含地夸磷索钠的药用组合物,其特征在于,所述的药用组合物的pH值在7.2~7.8的范围内。
10.根据权利要求1所述的一种含地夸磷索钠的药用组合物的制备工艺,其特征在于,包括如下步骤:
(1)配液:在配液罐中加入处方量的注射用水,加入处方量的缓冲剂、等渗调节剂,使其溶解完全,再加入处方量的地夸磷索钠,继续搅拌使完全溶解,使用pH调节剂调节pH,补注射用水至全量;
(2)过滤除菌:将(1)中药液依次经0.45μm滤膜过滤1次、0.22μm滤膜过滤3次;
(3)灌封:通过吹、灌、封一体设备将步骤(2)所得的药液灌装至低密度聚乙烯滴眼剂瓶。
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