CN116726045B - 一种氟雷拉纳组合物 - Google Patents
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- 229910052742 iron Inorganic materials 0.000 claims abstract description 72
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 20
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- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 20
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- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
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- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
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- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 229910021519 iron(III) oxide-hydroxide Inorganic materials 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- 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
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Abstract
本发明公开了一种氟雷拉纳组合物,其特征在于:含有葡庚糖酐铁溶液和氟雷拉纳,所述氟雷拉纳分散在葡庚糖酐铁溶液中,用于络合葡庚糖酐铁的葡庚糖酐酸的分子量分布范围为2000‑4000。可实现氟雷拉纳做成注射剂,并且在给药的同时补铁,提高免疫力。
Description
技术领域
本发明涉及兽药技术领域,具体涉及一种氟雷拉纳组合物。
背景技术
糖普遍具有络合金属离子的特性,在碱性条件下,糖分子被质子化而带上电荷,与聚合的FeOOH微粒以羟桥键结合,形成羟桥配合物,而后羟桥配合物中的羟基失去质子变成热力学上稳定的氧桥配合物,从而形成稳定的糖铁络合物。糖铁络合物具有以下特点:①化学性质稳定,水溶性好,无任何铁腥味,适口性好;②因聚合物比单核配合物稳定,螯合物在放置过程中趋于聚合,非糖配体与铁络合形成多核铁化合物或聚合物而不易吸收;而糖铁络合物在存放过程中形成虽为聚合态但仍可被有效吸收的多核铁化合物;③吸收快,其吸收速率比硫酸亚铁快1.8倍,并且肠道绒毛对于糖铁络合物的吸收具有特异选择性,优先于其它铁剂如FeSO4的吸收;④低聚糖配体具有较强的抗菌活性,可以解决因使用抗生素而存在的耐药性问题,尤其是DP3~DP5可以有效地抑制有害菌而有效促进有益菌的生长,从而改善动物体内的微生态平衡,故低聚糖铁络合物既能起到补铁效果,又可有效地预防腹泻,促进动物生长,提高动物免疫能力。
糖铁络合物以分子形式向人体供应,不含有Fe2+和Fe3+,且铁含量高,生物利用度高,能够被体内的还原性物质如维生素C还原成二价铁吸收。其不含铁离子,对胃肠黏膜不存腐蚀和刺激作用,小肠黏膜细胞易对其进行吸收,分子可以通过胃肠黏膜吸收阀调节血浆浓度,不易导致中毒。而且,多糖铁还可以促进机体造血,快速提高血红蛋白水平,从而有效治疗贫血。
葡庚糖酐铁分子式(FeOOH)m[HO-(C6H10O5)x-C7H13O7]n,是第四代铁,是多核的羟基氧化铁和葡庚糖苷酸的复合物,为可溶性铁,肌注葡庚糖酐铁通过网状内皮细胞(单核吞噬细胞系统)解离成铁和多糖;铁经转铁蛋白转运至骨髓合成红细胞的主要成分血红蛋白,或转为贮存铁以供机体急需。肌注葡庚糖酐铁可补充铁元素,纠正缺铁性贫血。
申请人发现,葡庚糖酐铁溶液如图1所示,具有胶体性质,粘度适中,粒径小,因此我们希望能将其作为分散载体,用于分散不溶于水的活性成分,做成复方制剂,在治疗的同时,可实现补铁的效果,增加免疫力。
氟雷拉纳是一种广谱性杀虫剂,对蜱目、蚤目、虱目、半翅目和双翅目等害虫均具有良好的杀虫活性,其毒力高于或与常用杀虫剂相当。氟雷拉纳不仅与现有杀虫剂无显著的交互抗性,甚至对部分抗性害虫也具有较好的杀虫活性。氟雷拉纳不同于水,目前剂型多为咀嚼片,宠物给药存在困难。
发明内容
针对现有技术问题,本发明的目的在于提供一种氟雷拉纳组合物。可实现氟雷拉纳做成注射剂,并且在给药的同时补铁,提高免疫力。
为实现以上目的,本发明通过以下技术方案予以实现:、一种氟雷拉纳组合物,其特征在于:含有葡庚糖酐铁溶液和氟雷拉纳,所述氟雷拉纳分散在葡庚糖酐铁溶液中,用于络合葡庚糖酐铁的葡庚糖酐酸的分子量分布范围为2000-4000。
上述方案中:所述所述葡庚糖酐铁分子量分布的Tf值为1.15-1.30。
上述方案中:该组合物的剂型为注射剂,每1ml注射剂中含有葡庚糖酐铁180±5mg。
上述方案中:所述氟雷拉纳的量为100mg/ml。
上述方案中:还包括药学添加剂,所述药学添加剂为消泡剂、pH调节剂和防腐剂。
上述方案中:按照如下方法制备:
1)取助溶表面活性剂、消泡剂加入纯水中,搅拌溶解,得到组分A;所述助溶表面活性剂为十二烷基磺酸钠、聚乙烯吡咯烷酮的混合物;
2)将氟雷拉纳加入能溶于水的有机溶剂中,超声搅拌溶解,得到组分B;能溶于水的有机溶剂为DMSO;
3)将组分B缓慢滴加入组分A,同时开启超声和搅拌,得纳米混悬剂;
4)将纳米混悬剂静置,沉淀,然后过滤,洗涤,得到微米到纳米级的活性成分;
5)将所需量的葡庚糖酐铁胶体溶液的部分置于容器中,加入所需量的活性成分,超声搅拌混匀,
6)加入药学添加剂,继续超声搅拌混匀,然后高速剪切均匀分散匀浆10min;
7)将余量的葡庚糖酐铁加入,高速剪切或球磨,均匀分散。
8)加水至所需最终浓度。
上述方案中:步骤(6)中的药学添加剂还包括表面活性剂。
PH调节剂为盐酸、柠檬酸、甲磺酸或氢氧化钠。
与现有技术相比,本发明具有以下优点:
本发明的采用分子量2000-4000的葡庚糖酐制备的葡庚糖酐铁,粘度适中,粒径小,为可溶性铁胶体,有利于形成注射制剂,有利于非水溶性活性成分的分散,在不添加表面活性剂的情况下,使得其能稳定的分散在葡庚糖酐铁胶体内,并且葡庚糖酐铁胶体能对活性成分进行包裹,形成稳定的注射制剂,并达到药物的缓释作用,实现非水溶性的氟雷拉纳成分做成注射剂。再给药的同时还能补铁,提高动物免疫力。
附图说明
图1为本发明制备的铁1的照片。
具体实施方式
下面将结合实施例,对本发明做进一步的描述。
实施例1
葡庚糖酐铁的制备参考CN114249844 A的制备方法:葡庚糖苷酸分子量分别为2000、3000、4000、5000),得葡庚糖苷酸分子量为2000的葡庚糖酐铁记做铁1,铁的浓度200±5mg/ml,葡庚糖苷酸分子量为4000的葡庚糖酐铁记做铁2,铁的浓度200±5mg/ml,葡庚糖苷酸分子量为5000的葡庚糖酐铁记做铁3,葡庚糖苷酸分子量为4000的葡庚糖酐铁记做铁7,铁的浓度200±5mg/ml。游离铁小于0.2%。葡庚糖酐铁分子量分布的Tf值均在1.151.30。
也可以参考US3536696的制备方法,葡庚糖苷酸分子量分别为2000、4000、5000),得葡庚糖苷酸分子量为2000的葡庚糖酐铁记做铁4,铁的浓度200±5mg/ml,葡庚糖苷酸分子量为3000的葡庚糖酐铁记做铁5,铁的浓度200±5mg/ml,葡庚糖苷酸分子量为5000的葡庚糖酐铁记做铁6,铁的浓度200±5mg/ml。游离铁小于0.2%。葡庚糖酐铁分子量分布的Tf值均在1.15 1.30。
实施例8
氟雷拉纳与葡庚糖酐铁的复方制剂
1、1ML制剂中(注射剂)
制备方法:
取120mg十二烷基磺酸钠,240mg聚乙烯吡咯烷酮K30和200mg西甲硅油加入240ml纯化水中,420R/min搅拌溶解,为组分A。
取2.5g氟雷拉纳加入60ml DMSO中,超声溶解,为组分B。
将组分B以30ml/min下滴加入组分A,同时开启超声,420R/min搅拌30min,得纳米混悬剂。
将纳米混悬剂静置,沉淀,然后过滤,洗涤,得到微米到纳米级的活性成分,检测其D90小于1微米。
将所需量的葡庚糖酐铁胶体溶液的部分(三分之一)置于烧杯中,加入所需量的活性成分,超声搅拌混匀,
按照上表加入药学添加剂,继续超声搅拌混匀,然后高速剪切均匀分散匀浆10min。将余量的葡庚糖酐铁加入,高速剪切或球磨,均匀分散。加水至所需最终浓度。即葡庚糖酐铁胶体溶液的中铁的浓度180±5mg/ml。
实施例2-11
其它与实施例2-1相同,不同的是制备方法按照如下方法:
1)将氟雷拉纳分别球磨至D90小于1μm、0.5微米、2微米。
2)将所需量的葡庚糖酐铁胶体溶液的部分置于烧杯中,分别加入不同粒径的所需量的活性成分,超声搅拌混匀,
3)加入药学添加剂(包括防腐剂、消泡剂、pH调节剂),继续超声搅拌混匀,然后高速剪切均匀分散匀浆10min,
4)将余量的葡庚糖酐铁加入,高速剪切或球磨,均匀分散。
5)加水至所需最终浓度,即葡庚糖酐铁胶体溶液的中铁的浓度180±5mg/ml。发现氟雷拉纳也不能很好的分散,始终有沉淀。
实施例2-12
其它与实施例2-11,不同的是在步骤3)添加表面活性剂单山梨聚糖酯2mg,能分散,放置3个月后无沉淀。
2、取实施例2-1到2-10的组合物进行稳定性试验
试验结果如下表
从表中可以看出:本发明的铁1、铁2、铁4、铁7在制备组合物时,无需添加表面活性剂,能很好的分散氟雷拉纳,而铁3、铁6、右旋糖酐铁在分散时,如不加表面活性剂,均不能得到均一体系,产品在放置产生沉淀。本发明的铁1、铁2、铁4、铁7添加表面活性剂的情况下也能起到很好的分散作用。2-11分散时都不能分散,直接有沉淀。2-12能分散,且能稳定放置一年。
3、生物学试验
将本发明实施例2-1、2-2、2-5、2-6、2-7制备得到的组合物用以生物学试验。
30只健康的比格犬,雌雄各半,平均体重9-10kg,分成6组,每组5只。分别用6个房间分开关狗狗,然后1-5组,分别肌肉注射本发明2-1、2-2、2-5、2-6、2-7制备得到的组合物注射液1ml/10kg,第6组口服氟雷拉纳咀嚼片,25mg氟雷拉纳/kg,用药期间正常饮食喝水。服药后0天、1天、2天、3天、4天、7天、14天、21天、28天、42天、56天、70天、84天and 91天分别采集血样检测。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (3)
1.一种氟雷拉纳组合物,其特征在于:含有葡庚糖酐铁溶液和氟雷拉纳,所述氟雷拉纳分散在葡庚糖酐铁溶液中,用于络合葡庚糖酐铁的葡庚糖酐酸的分子量分布范围为2000-4000;所述葡庚糖酐铁分子量分布的分子量分布指数为1.15-1.30;
按照如下方法制备:
1)取助溶表面活性剂、消泡剂加入纯水中,搅拌溶解,得到组分A;所述助溶表面活性剂为十二烷基磺酸钠、聚乙烯吡咯烷酮的混合物;
2)将氟雷拉纳加入能溶于水的有机溶剂中,超声搅拌溶解,得到组分B;能溶于水的有机溶剂为DMSO;
3)将组分B缓慢滴加入组分A,同时开启超声和搅拌,得纳米混悬剂;
4)将纳米混悬剂静置,沉淀,然后过滤,洗涤,得到D90小于1微米以下的活性成分;
5)将所需量的葡庚糖酐铁胶体溶液的部分置于容器中,加入所需量的活性成分,超声搅拌混匀,
6)加入药学添加剂,继续超声搅拌混匀,然后高速剪切均匀分散匀浆10min;所述药学添加剂为消泡剂、pH调节剂和防腐剂,调节pH到5-6;
7)将余量的葡庚糖酐铁加入,高速剪切或球磨,均匀分散;
8)加水至所需最终浓度。
2.根据权利要求1所述氟雷拉纳组合物,其特征在于:该组合物的剂型为注射剂,每1ml注射剂中含有葡庚糖酐铁180±5mg。
3.根据权利要求1所述氟雷拉纳组合物,其特征在于:所述氟雷拉纳的量为100mg/ml。
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