CN1192929A - 口服给药用制剂 - Google Patents
口服给药用制剂 Download PDFInfo
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Abstract
本发明是含有组胺加免疫球蛋白作为有效成份的口服给药用制剂。本发明的口服给药用制剂,与过去的皮下注射用制剂同样,对于各种疾病,例如支气管哮喘、过敏性鼻炎、血管舒缩性鼻炎、荨麻疹、慢性湿疹、特应性皮炎等过敏性皮肤疾病、多发性硬化症、慢性关节风湿病、全身性红斑等自身免疫性疾病、各种免疫不全综合症、以及伴随感染症、寄生虫疾病、呼吸器疾病、自身免疫性疾病、恶性肿瘤等的嗜酸性白细胞增多症和各种炎症性疾病,作为预防或治疗剂是有效的。本发明口服给药制剂与一般的注射用制剂相比,服用起来容易,实用并且有效性高。
Description
本发明涉及含有组胺加免疫球蛋白作为有效成份的口服给药用制剂。
免疫球蛋白和组胺的复合物作为组胺加免疫球蛋白制剂是公知的，因为具有恢复过敏性患者和哮喘患者降低的组胺固定能的作用，所以作为非特异性减敏疗法制剂用于治疗支气管哮喘、过敏性鼻炎、血管舒缩性鼻炎和荨麻疹、慢性湿疹、特应性皮炎等过敏性皮肤疾病。另外发现此种药剂还对组胺游离有抑制作用，而且没有作为对症疗法使用的抗组胺剂和肾上腺皮质激素制剂所具有的副作用，因而作为安全性高的医药广泛使用[医疗药日本医药品集(1996年10月版，日本医药情报中心编，药业时报社发行)，第463、464页]。
由于组胺加免疫球蛋白制剂是蛋白质制剂，所以使用时采取经皮下注射的用法，至今完全没有报导过将其口服给药时能发现有药效。
本发明人对这种组胺加免疫球蛋白进一步进行了深入研究，结果获得了惊人的发现，即本药剂经口服给药也能起到与过去的皮下给药时同样的药理作用，从而完成了本发明。
本发明的要点在于，提供含有组胺加免疫球蛋白作为有效成份的口服给药用制剂。
本发明的口服给药用制剂的有效成分即组胺加免疫球蛋白，是组胺和免疫球蛋白的复合物，可以将免疫球蛋白成分和组胺成分适宜混合进行制造。本发明中使用的免疫球蛋白，作为人体使用的医药品，当然可以将人的免疫球蛋白作为原料使用，人免疫球蛋白可以用通常的方法由血清或胎盘血浆获得。为了确保作为医药品的安全性，应当满足通常对血浆分级分离制剂制定的规格。例如使用HBs抗原、HCV抗体及HIV抗体阴性的人血浆作为原料血浆并且进行加热处理，借此能够回避肝炎病毒和爱滋病毒等混入的危险性。一般利用使病毒灭活的加热处理，例如在血浆分级分离制剂中通常使用60℃-10小时液态加热处理、60℃-10小时蒸汽化的加热处理、65℃-96小时干燥加热处理等。
在对人体以外使用的场合，可以按照作为对象的动物的种类，由人以外的动物调制免疫球蛋白加以使用。免疫球蛋白由IgG、IgA、IgM等种类构成，作为本发明中的免疫球蛋白，可以使用由各种中的一种或数种所构成。
作为组胺成分，可利用游离的组胺或其盐酸盐、磷酸盐、苦味酸盐等药学上容许的盐。
在制造本发明的口服给药用制剂时，可以将例如1至200mg、优选5至50mg的免疫球蛋白及0.01至2μg、优选0.05至0.5μg的组胺成分，适宜地溶解在生理盐水、蒸馏水等适当的溶剂中，搅拌、混合进行制造。可冷冻或冷冻干燥加以保存。
为使作为有效成分的组胺加免疫球蛋白制剂化，成为本发明的口服给药用制剂，可以将其原样或与适当的添加剂，例如乳糖、甘露醇、玉米淀粉、马铃薯淀粉、柠檬酸钙等惯用的赋形剂一起，适宜组合结晶纤维素、羟丙基纤维素等纤维素衍生物，阿拉伯胶、玉米淀粉、明胶等粘合剂，玉米淀粉、马铃薯淀粉、羧甲基纤维素钙等崩解剂，滑石、硬脂酸镁等润滑剂，其它增量剂，湿润剂，稳定剂，缓冲剂，保存剂，香料等，制成锭剂、散剂、颗粒剂或胶囊剂。也可以将组胺加免疫球蛋白制剂化成为在用时溶解于蒸馏水等当中使用的口服用液剂，可将组胺加免疫球蛋白溶液充填到管形瓶等中之后进行冷冻干燥而加以制造，也可在制剂化时根据需要加入上述各种添加剂。
组胺加人免疫球蛋白制剂的皮下给药时的给药量，在上述医疗药日本医药品集中已有记载，可以将含有人免疫球蛋白12mg及盐酸组胺0.15μg的管形瓶制剂每周1、2次皮下给药，最高可增量到3管形瓶。在本发明的口服给药制剂的场合，若按以下所列药理试验的结果，采用与皮下注射同等程度的给药量时认定有药效，但通常口服药剂与注射用制剂相比有必要比较多量的给药，因此本制剂的给药量最好按照疾病的种类、病情、患者的年龄性别、给药期间等进行适宜的设定。
实施例
以下叙述组胺加免疫球蛋白调制法的一个例子。以下的药理试验中使用小鼠作为实验动物，因此使用小鼠免疫球蛋白代替人免疫球蛋白。即，将小鼠γ-球蛋白及组胺二盐酸盐按以下的比例溶解于生理盐水中，在室温下搅拌2小时后，冷冻干燥，使用时用生理盐水溶解后口服给药。
[本发明化合物] [小鼠γ-球蛋白量] [组胺二盐酸盐量]
HG50 5.3mg 0.10μg
HG75 12.0mg 0.15μg
HG90 28.8mg 0.30μg
所制作的HG50、HG75及HG90在以下任何的药理试验中都显示出有效的作用，因此用HG75作为代表例表示所得到的结果。
[作用]
I.免疫调整作用
免疫调整作用是测定三硝基苯(TNP)特异性抗体产生反应作为指标。
(1)三硝基苯结合羊红血球(TNP-SRBC)的调制
将三硝基苯磺酸(TNBS)溶解于磷酸缓冲化生理盐水中(40mg/7.0ml，pH 7.2)，一边搅拌一边向其中滴加1ml的羊红血球。在遮光状态下一边搅拌数次一边在室温下放置20分钟，然后用生理盐水洗涤三次。以3000rpm离心分离5分钟后，用生理盐水调制成5×109/ml。
(2)TNP特异性抗体产生
对6～8周龄的雌性BALB/c小鼠腹腔内给药109个TNP-SRBC，以采用二硝基苯-牛血清白蛋白(DNP-BSA)的酵素免疫测定法(ELISA)测定血清中的抗TNP抗体。结果在第4～6日，作为峰值，看到抗TNP-IgM及抗TNP-IgG的强的抗体产生。另外，在缺少胸腺的BALB/c先天性无胸腺小鼠中，几乎未看出两类抗体产生。
(3)被验药剂的作用测定
采用上述试验体系，对于溶解于生理盐水的本发明的组胺加小鼠γ-球蛋白(15mg/kg/day)，调查了对于由TNP-SRBC致敏日起经4天口服给药造成的抗TNP抗体产生的作用。另外，作为阳性对照，同样进行皮下注射组胺加小鼠γ-球蛋白(150mg/kg/day)作比较。将本试验体系中的结果示于图1。另外，在以下的试验结果中，使用Student’s t-test，求出与对照的平均值的明显误差，加上*号。[*：P＜0.05，**：P＜0.01，***：P＜0.001]
II.嗜酸性白细胞增多抑制作用
(1)豚草属花粉抗原诱导的嗜酸性白细胞增多模型
对于6～8周龄的雌性BALB/c小鼠，在开始日及第1日皮下注射0.1ml，再在第6、8、14日皮下注射0.2ml用生理盐水稀释1000倍的豚草属花粉浸提物，使其致敏。在第20日，于小鼠腹腔内注射稀释1000倍的豚草属抗原0.2ml的诱发反应。诱发后第24小时回收腹腔渗出细胞，吉姆萨染色后计测总细胞数、嗜酸性白细胞数、中性白细胞数、单核细胞数。结果，嗜酸性白细胞数在诱发后第24小时呈现峰值。另外，在T细胞欠缺的BALB/c先天性无胸腺小鼠中，完全没有观察到嗜酸性白细胞、中性白细胞对腹腔内的浸润。
(2)被检药剂作用的测定
使用上述的嗜酸性白细胞增多模型，每周2次(开始日及第4、7、11、14、18日)将溶解于生理盐水中的本发明的组胺加小鼠γ-球蛋白(150mg/鼠/day)作口服给药，调查对于嗜酸性白细胞增多的作用。另外，作为阳性对照，以同样的给药间隔，皮下注射组胺加小鼠γ-球蛋白(100mg/鼠/day)进行比较。将结果的一例示于图2。
III.稳定性试验
将制成冷冻干燥品的本发明的组胺加小鼠γ-球蛋白在4℃或30℃下保存6周，分别进行与试验II同样的试验，调查本制剂的稳定性。将结果的一例示于图3。
如图1的结果所表明的那样，组胺加免疫球蛋白口服给药与皮下给药时同样，对IgG、IgM抗体产生也显示出显著的增强作用。另外如图2所示，在豚草属花粉抗原诱导的嗜酸性白细胞增多模型中，通过口服给药，也有效抑制了对腹腔内的嗜酸性白细胞浸润。而在将γ-球蛋白或组胺成分各自单独口服给药时，则看不出有本药理的作用。
因而，本发明的口服给药制剂，对于应用过去的皮下注射用制剂能显示效果的各种疾病，例如支气管哮喘、过敏性鼻炎、血管舒缩性鼻炎、荨麻疹、慢性湿疹、特应性皮炎等过敏性皮肤疾病、多发性硬化症、慢性关节风湿病、全身性红斑狼疮等自身免疫性疾病、各种免疫不全综合症、以及伴随感染症、寄生虫疾病、呼吸器疾病、自身免疫性疾病、恶性肿瘤等的嗜酸性白细胞增多症和各种炎症性疾病，作为予防或治疗剂是有效的。如本发明制剂那样的可口服给药的制剂，与一般的注射用制剂相比，患者服用起来也容易，因而是实用的，并且有效性高。
图1是显示本发明的口服给药用制剂对于抗TNP抗体产生的增强作用的曲线图。
图2是显示在豚草属花粉抗原诱导的嗜酸性白细胞增多模型中本发明制剂对嗜酸性白细胞增多的抑制作用的图。
图3是显示在4℃或30℃下保存6周的本发明制剂在豚草属花粉抗原诱导的嗜酸性白细胞增多模型中对嗜酸性白细胞增多的抑制作用的图。
Claims (9)
1、含有组胺加免疫球蛋白作为有效成分的口服给药用制剂。
2、权利要求1所述的口服给药用制剂，用作过敏性疾病的治疗剂。
3、权利要求2所述的口服给药用制剂，用作支气管哮喘的治疗剂。
4、权利要求2所述的口服给药用制剂，用作过敏性鼻炎的治疗剂。
5、权利要求2所述的口服给药用制剂，用作过敏性皮肤疾病的治疗剂。
6、权利要求1所述的口服给药用制剂，用作血管舒缩性鼻炎的治疗剂。
7、权利要求1所述的口服给药用制剂，用作自身免疫性疾病的治疗剂。
8、权利要求1所述的口服给药用制剂，用作嗜酸性白细胞增多的抑制剂。
9、权利要求1所述的口服给药用制剂，用作抗炎剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31311/97 | 1997-01-30 | ||
| JP9031311A JPH10212246A (ja) | 1997-01-30 | 1997-01-30 | 経口投与用製剤 |
| JP31311/1997 | 1997-01-30 |
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| CN1192929A true CN1192929A (zh) | 1998-09-16 |
| CN1167466C CN1167466C (zh) | 2004-09-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| Country | Link |
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| US (1) | US6187803B1 (zh) |
| EP (1) | EP0864323B1 (zh) |
| JP (1) | JPH10212246A (zh) |
| KR (1) | KR100533399B1 (zh) |
| CN (1) | CN1167466C (zh) |
| AT (1) | ATE236615T1 (zh) |
| AU (1) | AU735950B2 (zh) |
| CA (1) | CA2228017A1 (zh) |
| DE (1) | DE69813070T2 (zh) |
| TW (1) | TW544316B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103002907A (zh) * | 2010-04-23 | 2013-03-27 | 普若拜特有限公司 | 湿疹治疗 |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US6566386B2 (en) | 1993-08-09 | 2003-05-20 | Nippon Zoki Pharmaceutical Co., Ltd. | Immunomodulating and antiinflammatory agent |
| JP2000143536A (ja) | 1998-11-13 | 2000-05-23 | Nippon Zoki Pharmaceut Co Ltd | 抗浮腫剤 |
| JP2000143537A (ja) * | 1998-11-13 | 2000-05-23 | Nippon Zoki Pharmaceut Co Ltd | 細胞接着分子発現抑制剤 |
| JP2005508338A (ja) * | 2001-10-04 | 2005-03-31 | プロテイン セラピューティクス、インク． | 免疫性疾患を処置するためのガンマグロブリンの使用 |
| RS20050300A (en) | 2002-10-16 | 2007-08-03 | Euro-Celtique S.A., | Antibodies that bind cell-associated ca 125/0772p and methods of use thereof |
| WO2006099175A2 (en) * | 2005-03-11 | 2006-09-21 | Euro-Celtique S.A. | Compositions comprising an anti-ca125 antibody and a cytotoxic compound and their use for the treatment of cancer |
| KR100723251B1 (ko) * | 2005-03-18 | 2007-05-29 | 전숙영 | 알레르기 질환의 치료를 위한 약학적 조성물, 그의 용도 및알레르기 질환의 치료방법 |
| RU2309732C1 (ru) * | 2006-03-13 | 2007-11-10 | Олег Ильич Эпштейн | Спрессованная твердая оральная форма лекарственного препарата и способ получения твердой оральной формы лекарственного препарата |
| KR100756974B1 (ko) * | 2006-03-16 | 2007-09-07 | 전숙영 | 알레르기 질환 및 만성염증성 질환의 치료를 위한 약학적 조성물 및 키트 |
| WO2008139487A1 (en) * | 2007-05-10 | 2008-11-20 | Rajesh Shah | Homeopathy-based formulation |
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| US3873697A (en) | 1972-11-11 | 1975-03-25 | Mack Chem Pharm | Histamine antigen |
| US4705685A (en) * | 1982-05-17 | 1987-11-10 | Mcmichael John | Methods and materials for treatment of disease states involving immunological factors |
| US4704273A (en) | 1982-05-17 | 1987-11-03 | Mcmichael John | Methods and materials for treatment of rheumatoid arthritis |
| US4705687A (en) | 1985-06-17 | 1987-11-10 | Ortho Pharmaceutical (Canada) Ltd. | Treatment of autoimmune diseases such as rheumatoid arthritis with suppressor factor |
| US5112738A (en) | 1985-07-03 | 1992-05-12 | Miles Inc. | Histamine derivatives, immunogen conjugates and antibodies raised thereto |
| US4812449A (en) | 1986-07-03 | 1989-03-14 | Scripps Clinic And Research Foundation | In situ active compound assembly |
| US5244902A (en) | 1989-08-21 | 1993-09-14 | Beth Israel Hospital Association | Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses |
| IT1237475B (it) | 1989-10-06 | 1993-06-07 | Allergeni modificati chimicamente e procedimento per la loro preparazione | |
| US5192773A (en) | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| JP3193205B2 (ja) | 1993-08-09 | 2001-07-30 | 日本臓器製薬株式会社 | 好酸球増多抑制剤 |
| JPH0959180A (ja) * | 1995-08-11 | 1997-03-04 | Nippon Zoki Pharmaceut Co Ltd | 活性化免疫グロブリン |
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1997
- 1997-01-30 JP JP9031311A patent/JPH10212246A/ja not_active Withdrawn
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1998
- 1998-01-23 TW TW087100904A patent/TW544316B/zh not_active IP Right Cessation
- 1998-01-23 KR KR1019980002115A patent/KR100533399B1/ko not_active IP Right Cessation
- 1998-01-23 CN CNB981051375A patent/CN1167466C/zh not_active Expired - Fee Related
- 1998-01-26 US US09/013,202 patent/US6187803B1/en not_active Expired - Fee Related
- 1998-01-26 CA CA002228017A patent/CA2228017A1/en not_active Abandoned
- 1998-01-29 AU AU52790/98A patent/AU735950B2/en not_active Ceased
- 1998-01-30 DE DE69813070T patent/DE69813070T2/de not_active Expired - Fee Related
- 1998-01-30 EP EP98101614A patent/EP0864323B1/en not_active Expired - Lifetime
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103002907A (zh) * | 2010-04-23 | 2013-03-27 | 普若拜特有限公司 | 湿疹治疗 |
| CN105412912A (zh) * | 2010-04-23 | 2016-03-23 | 普若拜特有限公司 | 湿疹治疗 |
Also Published As
| Publication number | Publication date |
|---|---|
| US6187803B1 (en) | 2001-02-13 |
| KR100533399B1 (ko) | 2007-03-15 |
| CN1167466C (zh) | 2004-09-22 |
| AU735950B2 (en) | 2001-07-19 |
| CA2228017A1 (en) | 1998-07-30 |
| KR19980070794A (ko) | 1998-10-26 |
| EP0864323A1 (en) | 1998-09-16 |
| TW544316B (en) | 2003-08-01 |
| ATE236615T1 (de) | 2003-04-15 |
| DE69813070D1 (de) | 2003-05-15 |
| AU5279098A (en) | 1998-08-06 |
| DE69813070T2 (de) | 2003-12-04 |
| EP0864323B1 (en) | 2003-04-09 |
| JPH10212246A (ja) | 1998-08-11 |
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