CN116370609B - 包含血管活性肠肽和吸收增强剂的固体组合物 - Google Patents
包含血管活性肠肽和吸收增强剂的固体组合物 Download PDFInfo
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- CN116370609B CN116370609B CN202310635587.2A CN202310635587A CN116370609B CN 116370609 B CN116370609 B CN 116370609B CN 202310635587 A CN202310635587 A CN 202310635587A CN 116370609 B CN116370609 B CN 116370609B
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- absorption enhancer
- vasoactive intestinal
- intestinal peptide
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Virology (AREA)
- Reproductive Health (AREA)
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- Oncology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了包含血管活性肠肽和吸收增强剂的固体组合物。所述血管活性肠肽为阿肽地尔，吸收增强剂为N‑(8‑(2‑羟基苯甲酰)氨基)辛酸钠。本发明的固体组合物中包含N‑(8‑(2‑羟基苯甲酰)氨基)辛酸钠，作为吸收增强剂可以改善阿肽地尔的生物利用度，与组合助剂共同使用作用效果增强。
Description
技术领域
本发明属于生物医药技术领域，具体涉及包含血管活性肠肽和吸收增强剂的固体组合物。
背景技术
阿肽地尔（Aviptadil）是一种含有28个氨基酸的直链肽，内源性阿肽地尔也被称为血管活性肠肽（Vasoactive interinal peptide，VIP）。其氨基酸序列如下所示：His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn。
阿肽地尔最初是从猪小肠中的促胰液素中分离出来的，其序列与胰高血糖素有点相似，在临床表现中可增加血管通透性，抑制胃酸分泌和胃蠕动，抑制消化道平滑肌收缩的作用，主要用于急性呼吸窘迫综合症和特发性肺纤维化治疗，在许多器官和组织中，包括心脏、甲状腺、肾、尿道和生殖器官，作为神经递质或者神经调节剂。并且对治疗肺动脉高压（PAH）也有一定的作用。
目前，阿肽地尔一直在受控的不同人类临床试验中通过静脉给药或者吸入的方式被使用。同时，目前市售的还有阿肽地尔与甲磺酸酚妥拉明的复方注射液，用于治疗勃起功能障碍。在德国、挪威等地上市，商品名Invicorp®，规格25µg/2mg（即，每个安瓿中含有25微克阿肽地尔和2毫克甲磺酸酚妥拉明）。注射液存在使用不变、注射疼痛和易出现安全性问题等。
发明内容
本发明的目的在于提供一种包含血管活性肠肽和吸收增强剂的固体组合物。
一种包含血管活性肠肽和吸收增强剂的固体组合物，包括血管活性肠肽、N-(8-(2-羟基苯甲酰)氨基)辛酸钠（SNAC）和组合助剂。
所述血管活性肠肽为阿肽地尔。
所述组合助剂为填充剂、粘合剂、崩解剂、润滑剂中的一种或几种。
所述填充剂为玉米淀粉、预胶化淀粉、微晶纤维素、乳糖、糊精、蔗糖、甘露醇、二水硫酸钙中的一种或几种。
所述粘合剂为蒸馏水、甲基纤维素、乙基纤维素、羟丙甲纤维素、聚维酮、明胶、聚乙二醇、低取代羟丙纤维素、海藻酸钠中的一种或几种。
所述崩解剂为干淀粉、羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠中的一种或几种。
所述润滑剂为二氧化硅、胶态二氧化硅、硬脂酸镁、滑石粉、硬脂富马酸钠中的一种或几种。
所述包含血管活性肠肽和吸收增强剂的固体组合物在制备治疗疾病的药物中的应用。
所述疾病包括：急性呼吸窘迫综合症、特发性肺纤维化治疗肺损伤、急性肺损伤、新型冠状病毒、成年男性勃起功能障碍。
本发明的固体组合物为胶囊剂，采用湿法制粒的制备方法，依靠液体粘合剂润湿药物粉末表面，使药粉之间产生一定的黏合力，然后通过外力作用下制成一定形状和大小的颗粒，最后通过干燥设备干燥，以固体颗粒的形式固结，形成颗粒，经湿法制粒工艺制成的颗粒外观均匀，耐磨性好。
本发明的有益效果：本发明的固体组合物中包含N-(8-(2-羟基苯甲酰)氨基)辛酸钠，作为吸收增强剂可以改善阿肽地尔的生物利用度，与组合助剂共同使用作用效果增强。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
实施例1
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
实施例2
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
实施例3
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
实施例4
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
实施例5
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠、SNAC采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
对比例1
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将SNAC分别过30目筛，备用；处方量的阿肽地尔、SNAC采用等量递加的方式混合均匀，适量水溶液制备软材，整粒；制得的颗粒经过干燥、整粒，填充至2号明胶胶囊壳，包装，即得。
对比例2
一种阿肽地尔胶囊剂，如下所示的物质组成：
制备方法：将阿肽地尔、乳糖、交联羧甲基纤维素钠分别过30目筛，备用；处方量的阿肽地尔、乳糖、交联羧甲基纤维素钠采用等量递加的方式混合均匀，适量聚维酮水溶液制备软材，整粒；制得的颗粒经过干燥、整粒；所得颗粒与硬脂酸镁混合均匀，填充至2号明胶胶囊壳，包装，即得。
实验例：
本研究的目的是评价一系列包含阿肽地尔和SNAC的固体组合物在大鼠中的口服生物利用度。采用实施例1~5及对比例1~2中的胶囊剂样品。
动物，给药和采血：研究中使用雄性大鼠，在研究期间体重为180~250g。空腹状态下通过单次口服给药。在以下时间点采集血样：给药前、给药后0.17、0.33、0.5、0.75、1、1.5、2、2.5、3、4、6、8、24小时。
固体组合物分析：使用LC-MS方法分析口服胶囊剂中阿肽地尔的量，流动相梯度(溶剂A: 0.1%甲酸水溶液;溶剂B: 0.1%甲酸，50%乙腈)与100%溶剂A平衡1 min后开始，15min内线性上升至100% B。
结果：表1汇总了单次给药实施例1~5及对比例1~2中所示的胶囊剂后阿肽地尔的药代动力学参数。
表1：药代动力学参数汇总
结论：在本研究中，含有N-(8-(2-羟基苯甲酰)氨基) 辛酸钠的胶囊剂与未含N-(8-(2-羟基苯甲酰)氨基) 辛酸钠的胶囊剂相比，显示出改善的生物利用度，N-(8-(2-羟基苯甲酰)氨基) 辛酸钠与组合助剂复合使用协同增效。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (2)
1.一种包含血管活性肠肽和吸收增强剂的固体组合物，其特征在于，包括阿肽地尔、N-(8-(2-羟基苯甲酰)氨基)辛酸钠和组合助剂；
所述组合助剂为乳糖、聚维酮、交联羧甲基纤维素钠和硬脂酸镁。
2.权利要求1所述包含血管活性肠肽和吸收增强剂的固体组合物在制备治疗疾病的药物中的应用，其特征在于，所述疾病包括：急性呼吸窘迫综合症、特发性肺纤维化治疗肺损伤、急性肺损伤、新型冠状病毒、成年男性勃起功能障碍。
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| WO2015104596A1 (en) * | 2014-01-10 | 2015-07-16 | Ipp Dr Hayley | Vasoactive intestinal peptide |
| CN114173766A (zh) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | 包含glp-1激动剂、sglt2抑制剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015104596A1 (en) * | 2014-01-10 | 2015-07-16 | Ipp Dr Hayley | Vasoactive intestinal peptide |
| CN114173766A (zh) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | 包含glp-1激动剂、sglt2抑制剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物 |
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| Title |
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| Jihad Georges Youssef等.The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID- 19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.Critical Care Medicine .2022,1545-1554. * |
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