CN105617353A - 一种黏菌素口服给药组合物 - Google Patents
一种黏菌素口服给药组合物 Download PDFInfo
- Publication number
- CN105617353A CN105617353A CN201610003226.6A CN201610003226A CN105617353A CN 105617353 A CN105617353 A CN 105617353A CN 201610003226 A CN201610003226 A CN 201610003226A CN 105617353 A CN105617353 A CN 105617353A
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- Prior art keywords
- colistin
- oral administration
- composition
- absorption enhancer
- sulphate
- 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
- 108010078777 Colistin Proteins 0.000 title claims abstract description 42
- 229960003346 colistin Drugs 0.000 title claims abstract description 42
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- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 title claims abstract description 42
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 title claims abstract description 42
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- ZESIAEVDVPWEKB-ORCFLVBFSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O ZESIAEVDVPWEKB-ORCFLVBFSA-N 0.000 claims description 11
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- HZYCAKGEXXKCDM-UHFFFAOYSA-N Methyl 2-(methylthio)acetate Chemical compound COC(=O)CSC HZYCAKGEXXKCDM-UHFFFAOYSA-N 0.000 claims description 7
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 4
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- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 2
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- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 2
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- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 2
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- 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
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Landscapes
- Health & Medical Sciences (AREA)
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Abstract
本发明公开了一种黏菌素口服给药组合物,属医药技术领域。该黏菌素口服给药组合物由硫酸黏菌素与吸收促进剂、辅料组成,各组分以重量份计,黏菌素1;吸收促进剂0.01~10;药学上可接受的辅料及赋形剂0~100。还可以在上述配方中加入抗菌药物,其加入量为治疗有效剂量的三分之一。该组合物大幅度提高了黏菌素的吸收度,使黏菌素口服给药治疗全身性细菌感染成为可能,可以替代注射针剂,克服了现有技术偏见。并且所述组合物含有其他抗菌药物时具有很好的体内协同作用,在减少黏菌素2/3剂量时仍能保持理想的抗细菌感染效果,从而大大降低了黏菌素的肾毒性和神经毒性。
Description
技术领域
本发明涉及一种提高黏菌素胃肠道吸收度的组合物,属医药技术领域。
背景技术
黏菌素(通常为硫酸黏菌素)是通过微生物发酵提取而得到的一种廉价抗菌药物。由于其独特的化学结构,使之对革兰氏阴性菌不易产生耐药性,是目前临床上治疗耐药细菌,特别是多药耐药细菌感染的有效药物,但本品有一定的肾毒性和神经毒性,长期使用损害人或动物健康。目前黏菌素用于治疗人或动物全身性感染时多制备成注射针剂。黏菌素从结构上看是一种碱性阳离子表面活性剂,口服后在胃肠道几乎不吸收(中国兽药典委员会编,《中华人民共和国兽药典兽药使用指南》化学药品卷,2010版,中国农业出版社),只能治疗胃肠道细菌感染,无治疗全身性细菌感染作用。用注射剂给药治疗全身性细菌感染,受试者顺应性较低,毒副作用一般比口服给药大,且注射给予黏菌素需要医护人员,且药物使用、携带均不方便。所以提高黏菌素口服给药吸收度是亟待解决的技术难题。
有文献报道,中长度碳链脂肪酸、十二烷基硫酸钠可以提高一些低吸收度药物的吸收度,但这些吸收促进剂能否促进黏菌素的吸收未见报道。更重要的是黏菌素是阳离子药物,是一种阳离子表面活性剂,而前述吸收促进剂均为阴离子表面活性剂,按现有技术理论的教导,两者若在水性介质中相遇必然结合成不溶性复合物而进一步降低黏菌素的胃肠道吸收度(刘国杰主编,《药剂学》第二版,90页,人民卫生出版社,1985年)。因此,能否选择合适的药物促进剂,改变黏菌素给药形式,将其制备成口服给药组合物值得探讨和研发。
发明内容
针对目前技术现状,本发明目的在于提供一种黏菌素治疗细菌,特别是耐药细菌感染的口服给药组合物,替代注射针剂,用于人或动物疾病防控和治疗。
为实现本发明目的,本发明人通过选择药物促进剂与药物的配比,将黏菌素制备成口服给药组合物,并对其药效进行了实验。
所述黏菌素口服给药组合物由硫酸黏菌素与吸收促进剂、辅料组成,各组分以重量份计,
黏菌素1
吸收促进剂0.01~10
药学上可接受的辅料及赋形剂0~100。
还可以在上述配方中加入其它抗菌药物,其加入量为治疗有效剂量的三分之一。
所述吸收促进剂是中长度碳链的脂肪酸及其盐、十二烷基硫酸钠,其中优选癸酸钠、月桂酸钠。
所述组合物中硫酸黏菌素与吸收促进剂的优选重量份比为1:1。
所述药学上可接受的辅料及赋形剂包括但不限于淀粉、糊精、葡萄糖、柠檬酸钠、乳糖、羧甲基纤维素、硬脂酸镁、滑石粉、聚乙二醇4000-6000、包衣材料。
所述其它抗菌药物包括:青霉素类、头孢类、喹诺酮类、磺胺类、甲氧苄啶类、四环素类、大环内酯类、氨基糖苷类。其中优选阿莫西林,氨苄西林,环丙沙星,左氧氟沙星,加替沙星,司氟沙星,头孢拉定,头孢氨苄,头孢克肟,米诺环素,红霉素,阿奇霉素,磺胺甲恶唑,甲氧苄定,庆大霉素,奈替米星。
其制备方法:将上述组份分别称重,粉碎,过筛,常规方法制备成粉剂或胶囊或片剂,散剂,口服液。
本发明所述组合物中硫酸黏菌素的口服给药剂量,按体重计算为1~50mg/kg。
本发明所述的黏菌素口服给药组合物用于人或动物细菌感染,特别是耐药细菌感染。
本发明具有如下优点:所述黏菌素口服给药组合物大幅度提高了黏菌素的吸收度,使黏菌素口服给药治疗全身性细菌感染成为可能,可以替代注射针剂,克服了现有技术偏见。并且所述组合物含有其他抗菌药物时具有很好的体内协同作用,在减少黏菌素2/3剂量时仍能保持理想的抗细菌感染效果。黏菌素使用剂量的降低可大大降低黏菌素的肾毒性和神经毒性。
具体实施方式
为对本发明进行更好的说明,列举实施例,不限于下列的实施例。
实施例1.粉剂的制备
各组分按如下重量份计,按照常规方法制备成粉剂。
实施例2.粉剂的制备
各组分按如下重量份计,按照常规方法制备成粉剂。
黏菌素1
月桂酸钠1
实施例3胶囊剂的制备
各组分按如下重量份计,按照常规方法制备成胶囊。
注:所有上述处方中,各原料均过80目筛,混匀,装入20颗胶囊中。
实施例4.促进胃肠道吸收试验
动物:采用SpragueDawley大鼠,雌雄各半,体重200±20g,郑州大学实验动物中心提供。
药物:将实施例3处方1和对照处方1的胶囊内容物倒出,分别用0.5%CMC-Na研磨制成50万单位/ml的混悬液。临用前配制。
含量测定:按2010年版《中华人民共和国兽药典》一部,硫酸黏菌素项下含量测定方法测定。
给药及样品采集:将大鼠随机分为2组,分为实验组和对照组,每组10只,雌雄各半,给药前禁食12h,自由饮水。通过灌胃对实验组给予处方1的混悬液,剂量为200万单位/kg;对照组给予对照处方1制成的混悬液,剂量也是200万单位/kg。给药后1h,2h,3h由眼底静脉丛采血0.4ml,收集于肝素化离心管内,5000r·min-1离心5min,取血浆于-20℃冷冻待测。测定结果见表1.
表1.癸酸钠对硫酸黏菌素胃肠道吸收的影响(x=s,n=10)
由表1可见,对照处方1不含癸酸钠,黏菌素几乎不吸收,而含癸酸钠的处方1黏菌素有较高的吸收度。
实施例5.抗鸡大肠杆菌感染的作用
材料:致病性多药耐药大肠杆菌,由河南省农业大学惠赠;肉鸡,20日龄,体重平均450g/只,雌雄兼有,购自某养鸡场,购回后饲养5天备用。
分组:共分8个组,每组20只,其中I组为实施例3处方1给药组,II组为实施例3对照处方1给药组,III组为实施例3处方2给药组,IV组为实施例3对照处方2给药组,V组为实施例3处方3给药组,VI组为实施例3对照处方3给药组,VII组为感染不给药组,VIII组为不感染不给药组。
药物:所有药物内容物均用0.5%CMC-Na制成含25万单位/ml的黏菌素混悬液,临用现配。
攻毒与治疗:将致病性多药耐药大肠杆菌接种肉汤中,37℃培养16~18小时,用活菌计数法测定肉汤含菌量。试验用鸡(第I~VII组)于25日龄攻毒,每只鸡肌肉注射12亿个大肠杆菌(肉汤培养液约0.5ml)。攻毒后立即经口灌药,每天一次,共给药3天,观察7天,各组用药剂量及死亡率情况见表2.
表2.各组用药剂量及7天死亡情况
由表2可看出,由于癸酸钠的作用,硫酸黏菌素的吸收增加而使疗效大幅提高,并且,含有其他抗菌药物的本发明黏菌素口服给药组合物,在体内有十分显著的协同抗菌作用,而且是对多药耐药致病菌的抗菌作用。这将给治疗多药耐药细菌感染带来新的特效产品。并且还因减少了剂量,降低了硫酸黏菌素肾毒性和神经毒性带来的风险。
Claims (5)
1.一种黏菌素口服给药组合物,其特征在于,其由黏菌素与吸收促进剂、辅料组成,各组分以重量份计,
黏菌素1
吸收促进剂0.01~10
药学上可接受的辅料及赋形剂0~100;
所述吸收促进剂选十二烷基硫酸钠、癸酸钠或月桂酸钠。
2.如权利要求1所述的黏菌素口服给药组合物,其特征在于,所述组合物中硫酸黏菌素与吸收促进剂的重量比为1:1。
3.一种黏菌素口服给药组合物,其特征在于,其由硫酸黏菌素与吸收促进剂、抗菌药物,辅料组成,其中抗菌药物加入量为治疗有效剂量的三分之一,其余各组分以重量份计,
黏菌素1
吸收促进剂0.01~10
药学上可接受的辅料及赋形剂0~100;
所述吸收促进剂选十二烷基硫酸钠、癸酸钠或月桂酸钠;
所述抗菌药物选青霉素类、头孢类、喹诺酮类、磺胺类、甲氧苄啶类、四环素类、大环内酯类或氨基糖苷类。
4.如权利要求3所述的黏菌素口服给药组合物,其特征在于,所述组合物中硫酸黏菌素与吸收促进剂的重量比为1:1。
5.如权利要求3或4所述的黏菌素口服给药组合物,其特征在于,所述抗菌药物选阿莫西林,氨苄西林,环丙沙星,左氧氟沙星,加替沙星,司氟沙星,头孢拉定,头孢氨苄,头孢克肟,米诺环素,红霉素,阿奇霉素,磺胺甲恶唑,甲氧苄定,庆大霉素,奈替米星。
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