CN117323410A - 一种多肽药物溶液制剂及其制备方法 - Google Patents
一种多肽药物溶液制剂及其制备方法 Download PDFInfo
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- CN117323410A CN117323410A CN202310338060.3A CN202310338060A CN117323410A CN 117323410 A CN117323410 A CN 117323410A CN 202310338060 A CN202310338060 A CN 202310338060A CN 117323410 A CN117323410 A CN 117323410A
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- polypeptide
- polypeptide pharmaceutical
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- pharmaceutical formulation
- preservative
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Abstract
本发明涉及药物制剂技术领域,提供了一种多肽药物液体制剂及其制备方法。该多肽药物液体制剂包括按百分质量计的以下组分:HY30000.01‑5%;表面活性剂和/或增溶剂0.1%‑20%;渗透压调节剂0.5%‑10%;pH调节剂0.001%‑0.2%;溶剂64.8%‑99.4%。本发明所提供的多肽药物制剂提高了HY3000在液体中的稳定性,降低了患者的使用风险。
Description
技术领域
本发明涉及药物制剂技术领域,属于一种多肽药物液体制剂及其制备方法。
背景技术
在新型冠状病毒大流行的大背景下,非注射途径的预防和治疗药物显示出极大的优势和极度紧张的临床需求。鼻喷雾剂便于给药,患者顺应性高,安全风险小于注射给药,同时鼻腔给药接近新型冠状病毒入侵的人体部位,具有显著优势。
HY3000多肽药物可用于治疗和预防新型冠状病毒(Covid-19)。HY3000在液体状态下不稳定,易聚集形成沉淀或凝胶,只能以固体形式储存,在临用前配制为溶液形式给药,这增加了患者使用的风险。
因此,亟需一种多肽药物液体制剂及其制备方法,以降低上述使用风险。
发明内容
为了降低上述使用风险,本发明提供一种多肽药物液体制剂。该多肽药物液体制剂包括按百分质量计的以下组分:
可选地,所述的多肽药物制剂包括按百分质量计的以下组分:
可选地,所述表面活性剂选自磷脂类、聚山梨酯类、山梨醇脂肪酸酯类、泊洛沙姆类、聚乙二醇酯类中的一种或多种。
可选地,所述增溶剂选自环糊精、环糊精类衍生物、壳聚糖和壳聚糖衍生物中的一种或多种。
可选地,所述渗透压调节剂选自氯化钠、磷酸盐、枸橼酸盐、甘油、甘露醇、山梨醇、葡萄糖、果糖、乳糖和海藻糖中的一种或多种。
可选地,所述pH调节剂选自枸橼酸及枸橼酸盐、醋酸及醋酸盐、磷酸及磷酸盐、氢氧化钠、盐酸、乳酸和马来酸中的一种或多种。
可选地,所述溶剂为醇类有机溶剂或水。
可选地,还包括防腐剂和/或抑菌剂,所述防腐剂或所述抑菌剂选自苯扎氯铵、羟苯酯类、三氯叔丁醇、苯甲醇和苯乙醇中的一种或多种。
可选地,所述防腐剂选自三氯叔丁醇和苯甲醇中的一种或多种,所述抑菌剂选自苯扎氯铵和苯乙醇中一种或多种。
本发明的另一目的在于提供一种多肽药物制剂的制备方法。该多肽药物制剂的制备方法包括将如上任一项所述HY3000、所述表面活性剂和/或增溶剂、所述渗透压调节剂和所述防腐剂溶于10%~95%所述的溶剂中,搅拌至溶解,加入所述pH调节剂使溶液的PH值位于6~9,加入其余所述溶剂,混匀,过滤,灌装至喷雾装置中,即得所述多肽药物制剂。
本发明所提供的多肽药物制剂提高了HY3000在液体中的稳定性,降低了患者的使用风险。
附图说明
图1为实施例2提供的蛋白纤维化测试图;
图2为实施例3提供的蛋白纤维化测试图;
图3为实施例4提供的蛋白纤维化测试图;
图4为应用例提供的添加原始毒株假病毒的各多肽在不同浓度下的抑制率;
图5为应用例提供的添加变异毒株假病毒的各多肽在不同浓度下的抑制率。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂,下面结合附图对本发明的具体实施方式做详细的说明,但不能理解为对本发明的可实施范围的限定。
本发明中所涉及的HY3000为以下(1)-(8)任一所述序列的多肽或其衍生物,
(1)多肽,其包含以SEQ ID NO.1所示的氨基酸序列;
(2)多肽,其包含以SEQ ID NO.2所示的氨基酸序列;
(3)多肽,其包含以SEQ ID NO.3所示的氨基酸序列;
(4)多肽,其包含以SEQ ID NO.12所示的氨基酸序列;
(5)多肽,其包含以SEQ ID NO.13所示的氨基酸序列;
(6)多肽,其包含以SEQ ID NO.14所示的氨基酸序列;
(7)多肽,其包含在所述多肽(1)-(6)任一的氨基酸序列中取代、缺失、添加或插入1个或多个氨基酸残基的氨基酸序列,且该多肽具有针对冠状病毒的抑制活性;或
(8)多肽,其包含与所述多肽(1)-(6)任一的氨基酸序列具有至少60%、65%、70%、75%、80%、85%、90%、93%、94%或95%同一性的氨基酸序列,且该多肽具有针对冠状病毒的抑制活性;
优选地,所述多肽的序列为SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3、SEQ IDNO.12、SEQ ID NO.13或SEQ ID NO.14。
优选的,所述多肽衍生物为本申请人在先申请的专利号为“202210333422.5”的专利中所提及的衍生物。
多肽药物制剂处方组成:
优选地,多肽药物制剂处方组成:
HY3000:0.01%~5%;
增溶剂和/或表面活性剂:十二烷基磷酸胆碱0.1%~20%;
渗透压调节剂:山梨醇0.5~10%;
防腐剂:苯扎氯铵0.001%~0.5%;
pH调节剂:枸橼酸和/或氢氧化钠0.001%~0.2%;
溶剂:64.3%-99.4%。
多肽药物制剂制备方法:
将HY3000、十二烷基磷酸胆碱、山梨醇、苯扎氯铵溶于处方量10%~95%的水中,搅拌至溶解,然后加入枸橼酸和/或氢氧化钠使溶液pH值至6~9,加水至100%,混匀,过滤,灌装至喷雾装置中,即得多肽药物制剂。
按照上述多肽药物制剂处方组成和多肽药物制剂制备方法配置实施例1-4的样品和空白样品。
本申请所用到的新型冠状病毒假病毒由如下方式获得:
构建新型冠状病毒外膜S蛋白的质粒
1)将编码SARS-CoV-2原始毒株(WT)及变异毒株Omicron(BF.7)的S蛋白的后18位氨基酸的核苷酸去掉,分别得到核苷酸序列SARS-CoV-2-WT-S-del18和BF.7-S-del18,(其序列分别如SEQ ID NO:01-02所示),由苏州金唯智公司进行合成。
2)分别将1)中获得的各核苷酸序列克隆到pCAGGS表达载体上,得到表达质粒pCAGGS-SARS-CoV-2-WT-S-del18、pCAGGS-BF.7-S-del18。
SARS-CoV-2原始毒株及变异毒株假病毒的包装
a.细胞准备:在10cm细胞培养皿中铺HEK293T细胞,使第二天细胞汇合密度至80%。
b.转染:取上述步骤2)中获得的新型冠状病毒外膜S蛋白的表达质粒pCAGGS-SARS-CoV-2-WT-S-del18、pCAGGS-BF.7-S-del18各自与PEI按1:3比例混匀后转染HEK293T细胞,转染规格为30μg质粒/10cm细胞培养皿,4-6h换一次培养液(含10% FBS的DMEM培养基),37℃培养24h。
c.加毒:将慢病毒载体G*VSV-delG(购自武汉枢密脑科学技术有限公司)加入上述转染后的HEK293T细胞,37℃孵育2h,换培养液(含10% FBS的DMEM培养基),并加入VSV-G抗体(表达该抗体杂交瘤细胞购自ATCC细胞库),在培养箱中继续培养30h。
d.收毒:收上清3000rpm离心10min,在超净工作台中经0.45μm无菌滤器过滤,去除细胞碎片,得到SARS-CoV-2原始毒株(WT)及变异毒株Omicron(BF.7)的假病毒,各自进行分装,-80℃冰箱冻存。
实施例1
1.1配置样品和空白样品
按照多肽药物制剂处方组成配置处方号为2-20的多肽药物制剂为样品,不同样品的增溶剂和/或稳定性剂的种类或用量不同,配置处方号为1的多肽药物制剂为空白样品,其中含增溶剂和/或稳定性剂的量为0。
1.1.1性状:取储存温度为40℃和25℃第1、5、10、23、30天的样品和空白样品,观察其性状。
1.1.2有关物质(纯度):取储存温度为25℃第23天的样品和空白样品,采用高效液相色谱法HPLC检测杂质的生成长情况。
1.2测试结果如下表所示:
由上表可知:考察乙醇、丙二醇、甘油、聚乙二醇等常用溶剂作为增溶剂时,所制备的样品在40℃放置第5天后,样品溶液仍然出现聚集析出现象。
考察Kolliphor HS15(聚乙二醇-12-羟基硬脂酸酯)、KolliphorELP(聚氧乙烯(35)蓖麻油)、吐温80(聚氧乙烯脱水山梨醇单油酸酯,简称聚山梨酯-80)、吐温20(聚山梨酯-20)、泊洛沙姆188(α-氢-ω-羟基聚(氧乙稀)a-聚(氧丙烯)b-聚(氧乙稀))等常用表面活性剂作为稳定剂时,原料药的聚集析出问题有所改善。
采用羟丙基β环糊精作为稳定剂时,可较好的维持澄清透明的药液性状,但羟基倍他环糊精可显著加快原料药的降解,使总杂质显著增加。
采用十二烷基磷酸胆碱(DPC)作为稳定剂时,可使药液的性状较好维持澄清透明,且在已考察的方案中,使用该物料作稳定剂的样品化学稳定性表现最好。
实施例2
2.1配置样品
按照多肽药物制剂处方组成配置处方号为21-27的多肽药物制剂为样品,不同样品含有十二烷基磷酸胆碱量不同。
2.1.1实施例的成分如下表所示:
2.1.2性状:取储存第1、5、10、20、30天的样品,观察其性状。
2.1.3淀粉样蛋白纤维化:通过硫磺素(ThT)检测各处方实施例的淀粉样蛋白纤维化聚集情况。
2.1.4有关物质(总杂质增长量):取储存第1、10、20、30天的样品,采用高效液相色谱法HPLC检测杂质增长量。
2.2稳定性检测结果
2.2.1性状
由上表可知,储存期间处方23~处方26所有产品均为无色澄清透明,性状稳定,但处方21、处方22、处方27出现可见异物或浑浊,说明十二烷基磷酸胆碱的用量对HY3000多肽的稳定性产生影响。
2.2.2淀粉样蛋白纤维化
参阅说明书图1可知,随十二烷基磷酸胆碱浓度的增大,实施例在ThT中的logtime(即样品在仪器上维持不发生淀粉样蛋白纤维化的时间,若时间越长,说明样品稳定性越好)越大,说明十二烷基磷酸胆碱对HY3000多肽的淀粉样蛋白纤维化有较明显的影响,可提高HY3000多肽的稳定性。
2.2.3有关物质(总杂质增长量)
上表中,各样品的总杂质增长量均是基于第1天相同样品的杂质含量计算得出。由上表可知,储存期间处方21~处方27所有产品的总杂质增长幅度均小于10%,检测均合格。
综合2.2.1~2.2.3稳定性各项检测结果,发现十二烷基磷酸胆碱的用量对HY3000溶液稳定性至关重要,在本实施例提供的十二烷基磷酸胆碱用量下,HY3000在水溶液中保持良好的稳定性,尤其是十二烷基磷酸胆碱在试剂中的质量分数为0.5%-1.5%的情况下,HY3000在水溶液中具有优异的稳定性
实施例3
3.1、配置样品
按照多肽药物制剂处方组成配置处方号为28-34的多肽药物制剂为样品,不同处方号的多肽药物制剂PH值不同。
3.1.1制剂pH值考察设计如下表:
3.1.2性状:取储存第1、5、10、20、30天的样品,观察其性状。
3.1.3淀粉样蛋白纤维化:通过ThT检测各处方样品的淀粉样蛋白纤维化聚集情况。
3.1.4有关物质(总杂质增长量):取储存第1、10、20、30天的样品,采用高效液相色谱法HPLC检测有关物质。
3.2稳定性检测结果
3.2.1性状
由上表可知,储存期间处方30~处方34所有样品均为无色澄清透明,性状稳定,但处方28、处方29出现可见异物或析出沉淀,说明pH值对HY3000多肽的稳定性产生影响,在pH6~9范围内,pH值越高,药液性状越稳定。
3.2.2淀粉样蛋白纤维化
参阅说明书图2可知,随pH升高,样品在ThT中的logtime越大,说明pH对HY3000多肽的淀粉样蛋白纤维化有较明显的影响。
3.2.3有关物质(总杂质增长量)
上表中,各样品的总杂质增长量均是基于第1天相同样品的杂质含量计算得出。由上表可知,储存期间处方28~处方34所有产品的总杂质增长幅度均小于10%,检测均合格,且pH值越高,总杂质增长幅度越大。
综合3.2.1~3.2.3稳定性各项检测结果,发现pH值对HY3000溶液稳定性至关重要,在pH值在6-9的范围内,HY3000在水溶液中保持良好的稳定性,尤其是PH值在7.2-8.5范围内,HY3000在水溶液中具有优异的稳定性。
实施例4
4.1配置样品
按照多肽药物制剂处方组成配置处方号为35-41的多肽药物制剂为样品,不同样品原料药浓度不同。
4.1.1原料药浓度筛选设计如下表:
4.1.2性状:取储存第1、5、10、20、30天的供试品,观察其性状。
4.1.3淀粉样蛋白纤维化:通过ThT检测各处方样品的淀粉样蛋白纤维化聚集情况。
4.1.4有关物质(总杂质增长量):取储存第1、10、20、30天的供试品,采用高效液相色谱法HPLC检测有关物质。
4.2稳定性检测结果
4.2.1性状
由上表可知,储存期间处方35~处方42所有产品均为无色澄清透明,性状稳定,说明HY3000多肽原料药的浓度在0.5~20mg/ml范围内,可维持制剂的性状。
4.2.2淀粉样蛋白纤维化
参阅说明书图3可知,随HY3000多肽原料药浓度的增大,样品在ThT中的logtime越小,说明HY3000多肽原料药浓度对HY3000多肽的淀粉样蛋白纤维化有较明显的影响。
4.2.3有关物质(总杂质增长量)
上表中,各样品的总杂质增长量均是基于第1天相同样品的杂质含量计算得出。由上表可知,储存期间处方35~处方42所有产品的总杂质增长幅度均小于10%,检测均合格。
综合4.2.1~4.2.3稳定性各项检测结果,发现HY3000多肽原料药浓度对HY3000溶液稳定性有明显影响,在实施例4提供的HY3000多肽原料药浓度下,HY3000在水溶液中保持良好的稳定性。
综上所述,本发明所提供的多肽药物制剂提高了HY3000在液体中的稳定性,降低了患者的使用风险。
应用例
HY3000多肽溶液制剂CZ430、CZ442、CZ443、CZ444、CZ445对原始毒株(SARS-CoV-2WT)及变异毒株Omicron(BF.7)的假病毒的抑制效果:
按照实验过程中动物菌株+新型冠状病毒假病毒+制剂组合的不同将实验分为以下几组:
HEK293ThACE2细胞+原始毒株或变异毒株假病毒+原料药HY3000溶液(HY3000处理组);
HEK293ThACE2细胞+原始毒株或变异毒株假病毒+制剂CZ430(CZ430处理组);
HEK293ThACE2细胞+原始毒株或变异毒株假病毒+制剂CZ442(CZ442处理组);
HEK293T hACE2细胞+原始毒株或变异毒株假病毒+制剂CZ443(CZ443处理组);
HEK293T hACE2细胞+原始毒株或变异毒株假病毒+制剂CZ444(CZ444处理组);
HEK293T hACE2细胞+原始毒株或变异毒株假病毒+制剂CZ445(CZ445处理组)。
辅料溶液的配制:
取十二烷基磷酸胆碱、山梨醇和苯乙醇,用纯水配制得到CZ430辅料溶液,含十二烷基磷酸胆碱5mg/mL,山梨醇40mg/mL,苯乙醇9mg/mL;
取羟丙基倍他环糊精、山梨醇和苯扎氯铵,用纯水配制得到CZ442辅料溶液,含羟丙基倍他环糊精100mg/mL,山梨醇50mg/mL,苯扎氯铵0.2mg/mL;
取羟丙基倍他环糊精、山梨醇和苯乙醇,用纯水配制得到CZ443辅料溶液,含羟丙基倍他环糊精100mg/mL,山梨醇50mg/mL,苯乙醇9mg/mL;
取十二烷基磷酸胆碱、山梨醇和苯扎氯铵,用纯水配制得到CZ444辅料溶液,含十二烷基磷酸胆碱5mg/mL,山梨醇50mg/mL,苯扎氯铵0.2mg/mL;
取十二烷基磷酸胆碱和山梨醇,用纯水配制得到CZ445辅料溶液,含十二烷基磷酸胆碱5mg/mL和山梨醇50mg/mL。
多肽溶液配制:分别使用纯水、CZ430辅料溶液、CZ442辅料溶液、CZ443辅料溶液、CZ444辅料溶液和CZ445辅料溶液溶解HY3000多肽制得HY3000多肽溶液和制剂CZ430、CZ442、CZ443、CZ444、CZ445母液,再用含10% FBS的DMEM培养基将母液稀释成20μM,作为进一步梯度稀释的原液。制剂CZ430母液中多肽的浓度为5mg/mL、十二烷基磷酸胆碱的浓度为5mg/mL,山梨醇的浓度为40mg/mL,苯乙醇的浓度为9mg/mL。制剂CZ442母液中多肽的浓度为5mg/mL、羟丙基倍他环糊精的浓度为100mg/mL,山梨醇的浓度为50mg/mL,苯扎氯铵的浓度为0.2mg/mL。制剂CZ443母液中多肽的浓度为5mg/mL、羟丙基倍他环糊精的浓度为100mg/mL,山梨醇的浓度为50mg/mL,苯乙醇的浓度为9mg/mL。制剂CZ444母液中多肽的浓度为5mg/mL、十二烷基磷酸胆碱的浓度为5mg/mL,山梨醇的浓度为50mg/mL,苯扎氯铵的浓度为0.2mg/mL。制剂CZ445母液中多肽的浓度为5mg/mL、十二烷基磷酸胆碱的浓度为5mg/mL、山梨醇的浓度为50mg/mL。
多肽梯度稀释液的配制:用含10% FBS的DMEM培养基将上述20μM的各多肽原液以2倍的倍比稀释,共稀释9个梯度(分别为10、5、2.5、1.25、0.625、0.3125、0.156、0.078、0.039μM),每个梯度3个复孔,每孔50μL。
假病毒用量的确定:将SARS-CoV-2原始毒株或变异毒株Omicron(BF.7)假病毒原液及一系列稀释液在HEK293ThACE2细胞上进行定量,将出现1000个FFU时的稀释度作为评价多肽抑制效果时的病毒用量(稀释倍数介于6~20倍之间)。
病毒抑制效果的测定方法为:
a.在96孔细胞培养板中铺HEK293ThACE2细胞,培养使第二天细胞汇合密度达到80-90%。
b.根据上述实验分组,取上述各多肽梯度稀释液,加入等体积(50μL)的定量的假病毒稀释液,混匀后,在37℃孵育1h。
c.将步骤a中的96孔细胞培养板上清小心弃去,加入步骤b中的多肽-假病毒混合液(100μL/孔),在培养箱中继续培养15h-24h。
d.利用高内涵显微镜统计被感染的细胞数,计算各多肽在不同浓度下的抑制率,再利用GraphPad计算出各制剂溶液的EC50(如图1、图2所示),结果见表1;并计算出制剂溶液相较于HY3000多肽溶液对SARS-CoV-2原始毒株及变异毒株Omicron(BF.7)假病毒抑制效果的提升倍数,结果见表2。
表1各制剂对SARS-CoV-2原始毒株及其变异毒株假病毒抑制效果(EC50)
表2制剂溶液相较于HY3000多肽溶液对SARS-CoV-2原始毒株及其变异毒株假病毒抑制效果的提升倍数
从表1和表2可知,各处方制剂对原始毒株和变异毒株均具有很好的抑制效果(110.15nM≤EC50≤379.35nM)。相比于HY3000多肽溶液,各处方制剂对SARS-CoV-2病毒抑制效力没有显著变化,但辅料溶液的加入能够提高HY3000的稳定性,并具备抑菌效力,具备成药性。
从图4和图5中得知,各处方制剂对原始毒株和变异毒株均具有很好的抑制效果。
>SARS-CoV-2-WT-S-del 18
ATGTTCGTGTTCCTCGTGCTCCTGCCTCTGGTGTCTAGCCAGTGCGTGAACCTGACCACACGGACCCAGCTCCCTCCCGCCTACACAAACTCTTTCACCCGGGGCGTGTACTACCCCGACAAGGTGTTCCGGTCTAGCGTGCTCCACTCTACACAGGACCTGTTCCTCCCTTTCTTCAGCAACGTGACATGGTTCCACGCCATCCACGTGTCTGGCACAAACGGCACAAAGCGGTTCGACAACCCCGTGCTCCCTTTCAACGACGGCGTGTACTTCGCCAGCACCGAGAAGTCTAACATTATCCGGGGCTGGATTTTCGGCACCACACTCGACTCTAAGACACAGTCCCTCCTGATTGTGAACAACGCCACAAACGTGGTGATTAAGGTGTGCGAGTTCCAGTTCTGCAACGACCCTTTCCTGGGCGTGTACTACCACAAGAACAACAAGTCTTGGATGGAGTCTGAGTTCAGAGTGTACTCTAGCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTCATGGACCTGGAGGGCAAGCAGGGCAACTTCAAGAACCTGAGAGAGTTCGTGTTCAAGAACATTGACGGCTACTTCAAGATTTACTCTAAGCACACCCCAATTAACCTCGTGAGGGACCTCCCTCAGGGCTTCTCCGCCTTAGAACCACTGGTGGACCTCCCTATTGGCATTAACATCACACGCTTCCAGACACTGCTCGCCCTCCACCGGTCTTACCTGACCCCAGGCGACTCTAGCTCTGGCTGGACAGCCGGCGCCGCCGCCTACTACGTGGGCTACCTGCAGCCTAGGACCTTCCTCCTGAAGTACAACGAGAACGGCACAATTACCGACGCCGTGGACTGCGCCCTGGACCCACTGTCCGAGACAAAGTGCACACTGAAGTCCTTCACAGTGGAGAAGGGCATTTACCAGACATCTAACTTCCGGGTGCAGCCTACAGAGTCTATTGTGCGGTTCCCAAACATCACAAACCTGTGCCCTTTCGGCGAGGTGTTCAACGCCACCCGGTTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCTCTAACTGCGTGGCCGACTACTCCGTGCTGTACAACTCCGCCTCTTTCTCTACATTCAAGTGCTACGGCGTGTCCCCTACAAAGCTGAACGACCTGTGCTTCACCAACGTGTACGCCGACTCTTTCGTGATTAGAGGCGACGAGGTGAGGCAGATTGCCCCCGGCCAGACAGGCAAGATCGCCGACTACAACTACAAGCTGCCCGACGACTTCACAGGCTGCGTGATCGCCTGGAACTCTAACAACCTGGACTCTAAGGTGGGCGGCAACTACAACTACCTGTACAGACTGTTCCGGAAGTCTAACCTGAAGCCATTCGAGAGGGACATTAGCACCGAGATTTACCAGGCCGGCTCTACCCCATGCAACGGCGTGGAGGGCTTCAACTGCTACTTCCCACTGCAGTCCTACGGCTTCCAGCCTACAAACGGCGTGGGCTACCAGCCTTACCGGGTGGTGGTGCTGTCTTTCGAGCTGCTCCACGCCCCCGCCACAGTGTGCGGCCCAAAGAAGAGCACAAACCTCGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGCCTCACAGGCACAGGCGTGCTCACCGAGTCTAACAAGAAGTTCCTCCCTTTCCAGCAGTTCGGCCGCGACATTGCCGACACCACCGACGCCGTGCGGGACCCTCAGACACTGGAAATTCTCGACATCACCCCTTGCAGCTTCGGCGGCGTGTCCGTGATCACCCCAGGCACAAACACATCTAACCAGGTGGCCGTGCTGTACCAGGACGTGAACTGCACCGAGGTGCCAGTGGCCATCCACGCCGACCAGCTCACCCCAACATGGAGGGTGTACAGCACAGGCTCTAACGTGTTCCAGACCCGGGCCGGCTGCCTCATTGGCGCCGAGCACGTGAACAACTCTTACGAGTGCGACATCCCTATTGGCGCCGGCATTTGCGCCTCTTACCAGACCCAGACAAACTCTCCACGGAGAGCCCGGTCTGTGGCCTCTCAGAGCATTATTGCCTACACCATGTCTCTGGGCGCCGAGAACTCTGTGGCCTACTCTAACAACTCTATTGCCATCCCTACAAACTTCACAATTTCTGTGACCACCGAGATTCTCCCAGTGTCTATGACCAAGACATCTGTGGACTGCACCATGTACATTTGCGGCGACTCCACCGAGTGCTCTAACCTCCTGCTCCAGTACGGCTCTTTCTGCACCCAGCTCAACCGCGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACACCCAGGAGGTGTTCGCCCAGGTGAAGCAGATTTACAAGACCCCCCCAATTAAGGACTTCGGCGGCTTCAACTTCTCTCAGATTCTCCCCGACCCATCCAAGCCTAGCAAGCGGTCCTTCATTGAGGACCTCCTGTTCAACAAGGTGACACTGGCCGACGCCGGCTTCATTAAGCAGTACGGCGACTGCCTGGGCGACATTGCCGCCCGGGACCTGATTTGCGCCCAGAAGTTCAACGGCCTCACAGTGCTCCCCCCACTGCTCACCGACGAGATGATTGCCCAGTACACATCTGCCCTCCTGGCCGGCACAATTACATCTGGCTGGACCTTCGGCGCCGGCGCCGCCCTGCAGATCCCTTTCGCCATGCAGATGGCCTACCGCTTCAACGGCATCGGCGTGACACAGAACGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCGCCATTGGCAAGATTCAGGACTCTCTGAGCAGCACAGCCAGCGCCCTGGGCAAGCTGCAGGACGTGGTGAACCAGAACGCCCAGGCCCTGAACACACTGGTGAAGCAGCTGTCTTCTAACTTCGGCGCCATTTCTAGCGTGCTGAACGACATTCTGTCGCGGCTGGACAAGGTGGAGGCCGAGGTGCAGATTGACAGGCTCATCACAGGCAGACTGCAGTCTCTGCAGACATACGTGACCCAGCAGCTGATTAGAGCCGCCGAGATTAGAGCCTCCGCCAACCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTCGGCCAGTCTAAGCGGGTGGACTTCTGCGGCAAGGGCTACCACCTCATGTCTTTCCCTCAGTCCGCCCCTCACGGCGTGGTGTTCCTCCACGTGACATACGTGCCCGCCCAGGAGAAGAACTTCACCACAGCCCCCGCCATTTGCCACGACGGCAAGGCCCACTTCCCTAGGGAGGGCGTGTTCGTGTCTAACGGCACCCACTGGTTCGTGACCCAGCGGAACTTCTACGAGCCTCAGATTATTACCACAGACAACACATTCGTGAGCGGCAACTGCGACGTGGTGATTGGCATTGTGAACAACACAGTGTACGACCCACTGCAGCCTGAGTTGGACTCTTTCAAGGAGGAACTCGACAAGTACTTCAAGAACCACACATCTCCTGACGTGGACCTGGGCGACATTAGCGGCATTAACGCCTCTGTGGTGAACATTCAGAAGGAGATTGACAGACTGAACGAGGTGGCCAAGAACCTGAACGAGTCTCTCATTGACCTGCAGGAGCTGGGCAAGTACGAGCAGTACATTAAGTGGCCTTGGTACATTTGGCTGGGCTTCATTGCCGGCCTGATCGCCATTGTGATGGTGACCATCATGCTGTGCTGCATGACATCTTGCTGCAGCTGCCTGAAGGGCTGCTGCTCTTGCGGCTCTTGCTGCAAG
>BF.7-S-del 18
ATGTTCGTGTTCCTCGTGCTCCTGCCTCTGGTGTCTAGCCAGTGCGTGAACCTGATCACACGGACCCAGAGCTACACAAACTCTTTCACCCGGGGCGTGTACTACCCCGACAAGGTGTTCCGGTCTAGCGTGCTCCACTCTACACAGGACCTGTTCCTCCCTTTCTTCAGCAACGTGACATGGTTCCACGCCATCTCTGGCACAAACGGCACAAAGCGGTTCGACAACCCCGTGCTCCCTTTCAACGACGGCGTGTACTTCGCCAGCACCGAGAAGTCTAACATTATCCGGGGCTGGATTTTCGGCACCACACTCGACTCTAAGACACAGTCCCTCCTGATTGTGAACAACGCCACAAACGTGGTGATTAAGGTGTGCGAGTTCCAGTTCTGCAACGACCCTTTCCTGGACGTGTACTACCACAAGAACAACAAGTCTTGGATGGAGTCTGAGTTCAGAGTGTACTCTAGCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTCATGGACCTGGAGGGCAAGCAGGGCAACTTCAAGAACCTGAGAGAGTTCGTGTTCAAGAACATTGACGGCTACTTCAAGATTTACTCTAAGCACACCCCAATTAACCTCGGCAGGGACCTCCCTC
AGGGCTTCTCCGCCTTAGAACCACTGGTGGACCTCCCTATTGGCATTAACATCACACGCTTCCAGACACTGCTCGCCCTC
CACCGGTCTTACCTGACCCCAGGCGACTCTAGCTCTGGCTGGACAGCCGGCGCCGCCGCCTACTACGTGGGCTACCTGCA
GCCTAGGACCTTCCTCCTGAAGTACAACGAGAACGGCACAATTACCGACGCCGTGGACTGCGCCCTGGACCCACTGTCCG
AGACAAAGTGCACACTGAAGTCCTTCACAGTGGAGAAGGGCATTTACCAGACATCTAACTTCCGGGTGCAGCCTACAGAG
TCTATTGTGCGGTTCCCAAACATCACAAACCTGTGCCCTTTCGACGAGGTGTTCAACGCCACCACCTTCGCCTCTGTGTA
CGCCTGGAACCGGAAGCGGATCTCTAACTGCGTGGCCGACTACTCCGTGCTGTACAACTTCGCCCCCTTCTTCGCCTTCA
AGTGCTACGGCGTGTCCCCTACAAAGCTGAACGACCTGTGCTTCACCAACGTGTACGCCGACTCTTTCGTGATTAGAGGC
AACGAGGTGAGCCAGATTGCCCCCGGCCAGACAGGCAACATCGCCGACTACAACTACAAGCTGCCCGACGACTTCACAGG
CTGCGTGATCGCCTGGAACTCTAACAAGCTGGACTCTAAGGTGGGCGGCAACTACAACTACCGGTACAGACTGTTCCGGA
AGTCTAACCTGAAGCCATTCGAGAGGGACATTAGCACCGAGATTTACCAGGCCGGCAACAAGCCATGCAACGGCGTGGCC
GGCGTGAACTGCTACTTCCCACTGCAGTCCTACGGCTTCCGGCCTACATACGGCGTGGGCCACCAGCCTTACCGGGTGGT
GGTGCTGTCTTTCGAGCTGCTCCACGCCCCCGCCACAGTGTGCGGCCCAAAGAAGAGCACAAACCTCGTGAAGAACAAGT
GCGTGAACTTCAACTTCAACGGCCTCACAGGCACAGGCGTGCTCACCGAGTCTAACAAGAAGTTCCTCCCTTTCCAGCAG
TTCGGCCGCGACATTGCCGACACCACCGACGCCGTGCGGGACCCTCAGACACTGGAAATTCTCGACATCACCCCTTGCAG
CTTCGGCGGCGTGTCCGTGATCACCCCAGGCACAAACACATCTAACCAGGTGGCCGTGCTGTACCAGGGCGTGAACTGCA
CCGAGGTGCCAGTGGCCATCCACGCCGACCAGCTCACCCCAACATGGAGGGTGTACAGCACAGGCTCTAACGTGTTCCAG
ACCCGGGCCGGCTGCCTCATTGGCGCCGAGTACGTGAACAACTCTTACGAGTGCGACATCCCTATTGGCGCCGGCATTTG
CGCCTCTTACCAGACCCAGACAAAGTCTCACCGGAGAGCCCGGTCTGTGGCCTCTCAGAGCATTATTGCCTACACCATGT
CTCTGGGCGCCGAGAACTCTGTGGCCTACTCTAACAACTCTATTGCCATCCCTACAAACTTCACAATTTCTGTGACCACC
GAGATTCTCCCAGTGTCTATGACCAAGACATCTGTGGACTGCACCATGTACATTTGCGGCGACTCCACCGAGTGCTCTAA
CCTCCTGCTCCAGTACGGCTCTTTCTGCACCCAGCTCAAGCGCGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACA
CCCAGGAGGTGTTCGCCCAGGTGAAGCAGATTTACAAGACCCCCCCAATTAAGTACTTCGGCGGCTTCAACTTCTCTCAG
ATTCTCCCCGACCCATCCAAGCCTAGCAAGCGGTCCTTCATTGAGGACCTCCTGTTCAACAAGGTGACACTGGCCGACGC
CGGCTTCATTAAGCAGTACGGCGACTGCCTGGGCGACATTGCCGCCCGGGACCTGATTTGCGCCCAGAAGTTCAACGGCC
TCACAGTGCTCCCCCCACTGCTCACCGACGAGATGATTGCCCAGTACACATCTGCCCTCCTGGCCGGCACAATTACATCT
GGCTGGACCTTCGGCGCCGGCGCCGCCCTGCAGATCCCTTTCGCCATGCAGATGGCCTACCGCTTCAACGGCATCGGCGT
GACACAGAACGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCGCCATTGGCAAGATTCAGGACTCTC
TGAGCAGCACAGCCAGCGCCCTGGGCAAGCTGCAGGACGTGGTGAACCACAACGCCCAGGCCCTGAACACACTGGTGAAG
CAGCTGTCTTCTAAGTTCGGCGCCATTAGCAGCGTGCTGAACGACATTCTGTCGCGGCTGGACAAGGTGGAGGCCGAGGT
GCAGATTGACAGGCTCATCACAGGCAGACTGCAGTCTCTGCAGACATACGTGACCCAGCAGCTGATTAGAGCCGCCGAGA
TTAGAGCCTCCGCCAACCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTCGGCCAGTCTAAGCGGGTGGACTTCTGCGGC
AAGGGCTACCACCTCATGTCTTTCCCTCAGTCCGCCCCTCACGGCGTGGTGTTCCTCCACGTGACATACGTGCCCGCCCA
GGAGAAGAACTTCACCACAGCCCCCGCCATTTGCCACGACGGCAAGGCCCACTTCCCTAGGGAGGGCGTGTTCGTGTCTA
ACGGCACCCACTGGTTCGTGACCCAGCGGAACTTCTACGAGCCTCAGATTATTACCACAGACAACACATTCGTGAGCGGC
AACTGCGACGTGGTGATTGGCATTGTGAACAACACAGTGTACGACCCACTGCAGCCTGAGTTGGACTCTTTCAAGGAGGA
ACTCGACAAGTACTTCAAGAACCACACATCTCCTGACGTGGACCTGGGCGACATTAGCGGCATTAACGCCTCTGTGGTGA
ACATTCAGAAGGAGATTGACAGACTGAACGAGGTGGCCAAGAACCTGAACGAGTCTCTCATTGACCTGCAGGAGCTGGGC
AAGTACGAGCAGTACATTAAGTGGCCTTGGTACATTTGGCTGGGCTTCATTGCCGGCCTGATCGCCATTGTGATGGTGAC
CATCATGCTGTGCTGCATGACATCTTGCTGCAGCTGCCTGAAGGGCTGCTGCTCTTGCGGCTCTTGCTGCAAG
Claims (10)
1.一种多肽药物制剂,其特征在于,包括按百分质量计的以下组分:
2.如权利要求1所述的多肽药物制剂,其特征在于,包括按百分质量计的以下组分:
3.如权利要求1所述的多肽药物制剂,其特征在于,所述表面活性剂选自磷脂类、聚山梨酯类、山梨醇脂肪酸酯类、泊洛沙姆类、聚乙二醇酯类中的一种或多种。
4.如权利要求1所述的多肽药物制剂,其特征在于,所述增溶剂选自环糊精、环糊精类衍生物、壳聚糖和壳聚糖衍生物中的一种或多种。
5.如权利要求1所述的多肽药物制剂,其特征在于,所述渗透压调节剂选自氯化钠、磷酸盐、枸橼酸盐、甘油、甘露醇、山梨醇、葡萄糖、果糖、乳糖和海藻糖中的一种或多种。
6.如权利要求1所述的多肽药物制剂,其特征在于,所述pH调节剂选自枸橼酸及枸橼酸盐、醋酸及醋酸盐、磷酸及磷酸盐、氢氧化钠、盐酸、乳酸和马来酸中的一种或多种。
7.如权利要求1所述的多肽药物制剂,其特征在于,所述溶剂为醇类有机溶剂或水。
8.如权利要求1所述的多肽药物制剂,其特征在于,还包括防腐剂和/或抑菌剂,所述防腐剂或所述抑菌剂选自苯扎氯铵、羟苯酯类、三氯叔丁醇、苯甲醇和苯乙醇中的一种或多种。
9.如权利要求8所述的多肽药物制剂,其特征在于,所述防腐剂选自三氯叔丁醇和苯甲醇中的一种或多种,所述抑菌剂选自苯扎氯铵和苯乙醇中一种或多种。
10.一种多肽药物制剂的制备方法,其特征在于,将如权利要求1-9任一项所述的HY3000、所述表面活性剂和/或增溶剂、所述渗透压调节剂和所述防腐剂溶于10%~95%所述的溶剂中,搅拌至溶解,加入所述pH调节剂使溶液的PH值位于6~9,加入其余所述溶剂,混匀,过滤,灌装至喷雾装置中,即得所述多肽药物制剂。
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