CN101272807A - 使用非离子表面活性剂促进跨膜药物输送到中耳治疗和预防中耳炎的方法 - Google Patents
使用非离子表面活性剂促进跨膜药物输送到中耳治疗和预防中耳炎的方法 Download PDFInfo
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- CN101272807A CN101272807A CNA2006800353863A CN200680035386A CN101272807A CN 101272807 A CN101272807 A CN 101272807A CN A2006800353863 A CNA2006800353863 A CN A2006800353863A CN 200680035386 A CN200680035386 A CN 200680035386A CN 101272807 A CN101272807 A CN 101272807A
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- middle ear
- antibiotic
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- prevention
- ear infection
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
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- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
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- FRMWBRPWYBNAFB-UHFFFAOYSA-M potassium salicylate Chemical compound [K+].OC1=CC=CC=C1C([O-])=O FRMWBRPWYBNAFB-UHFFFAOYSA-M 0.000 description 1
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- CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
- QPMDWIOUHQWKHV-TYYBGVCCSA-M potassium;(e)-but-2-enedioate;hydron Chemical compound [H+].[K+].[O-]C(=O)\C=C\C([O-])=O QPMDWIOUHQWKHV-TYYBGVCCSA-M 0.000 description 1
- 230000010372 presbyacusis Effects 0.000 description 1
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- 239000001294 propane Substances 0.000 description 1
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- 238000012797 qualification Methods 0.000 description 1
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- 229960004249 sodium acetate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- PRWXGRGLHYDWPS-UHFFFAOYSA-L sodium malonate Chemical compound [Na+].[Na+].[O-]C(=O)CC([O-])=O PRWXGRGLHYDWPS-UHFFFAOYSA-L 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- MSXHSNHNTORCAW-GGLLEASOSA-M sodium;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].O[C@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O MSXHSNHNTORCAW-GGLLEASOSA-M 0.000 description 1
- VRVKOZSIJXBAJG-ODZAUARKSA-M sodium;(z)-but-2-enedioate;hydron Chemical compound [Na+].OC(=O)\C=C/C([O-])=O VRVKOZSIJXBAJG-ODZAUARKSA-M 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 229940063649 survanta Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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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
- A61K31/495—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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
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- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及用于治疗和预防中耳感染的方法，通过跨膜施用包括非离子高分子表面活性剂如烷基芳基聚醚醇(例如泰洛沙泊)的含药物跨膜载体组合物至鼓膜实施。根据本发明方法输送的药物包括用于治疗和/或者预防中耳感染及其后遗症的抗生素、抗病毒剂、抗真菌剂和抗炎剂。
Description
发明领域
[0001]本发明涉及治疗中耳炎(中耳感染)的非侵入性方法。更具体地，本发明涉及通过跨鼓膜(tympanic membrane)(鼓膜(eardrum))输送用于治疗中耳炎的药物而将所述药物施用到中耳的方法。
背景技术
[0002]每年有数百万的儿童受到中耳炎的侵袭，即中耳感染。尽管成人也易受到中耳感染，但儿童尤其具有被感染的风险，因为他们相对短的耳道可以更容易地接近炎症。接着流体可以被陷于鼓膜(tympanicmembrane)(鼓膜(eardrum))后面，这可以引起严重的疼痛，以及为微生物提供了在其中繁殖的有利环境。
[0003]鼓膜是阻止药物进入中耳的强大屏障，因此治疗中耳感染所处方的抗生素几乎总是口服的。然而，多种细菌和病毒可以引起中耳感染，并且常常不能区分什么是具体感染的原因，或者其对口服抗生素治疗是否敏感。而且，口服施用抗生素对中耳的作用可以被药物的全身分布所稀释，这也可以使患者处于与全身输送有关的副作用的风险中(例如，女性患者的酵母感染)。
[0004]遭受重复感染的儿童可能需要手术以减轻鼓膜上的流体压力。在更严重的情况下，可以将引流管放在鼓膜内。引流管本身不预防感染再发(相反，它们可以作为其它病原体进入中耳的管道)，但是它们能够减轻压力和减小流体陷于鼓膜后的程度。
[0005]引流管也提供了直接将抗生素引入中耳的潜在管道，例如通过施用抗生素滴并使许它们流入引流管。然而，该方法是侵入性的和痛苦的，这表明了对将抗生素引入中耳的可选途径的强烈需求。
发明概述
[0006]本发明提供了通过施用在跨膜载体组合物中的用于预防或者治疗中耳感染及其后遗症的药物，治疗和预防中耳炎的方法。本发明来自下述惊奇的发现：在由一种或者多种非离子高分子表面活性剂组成的载体中，药物能够被输送穿过完整的鼓膜(intact tympanic membrane)；即没有撕裂(例如，由于压力下的破裂)或者穿刺(例如，由于管的插入或者注射)的鼓膜。
[0007]根据本发明，药物作为跨膜载体组合物的活性成分被提供，所述组合物应用于耳部以便使组合物与完整的鼓膜(鼓膜)接触。跨膜载体组合物进一步包括一种或者多种非离子高分子表面活性剂(nonionicpolymer surfactants)，如聚合物链段或者嵌段共聚物，其被提供在药学上可接受的组分中。
[0008]优选的药物是那些用于治疗或者预防中耳炎(中耳感染)和其后遗症的药物。本发明尤其很好地适合于输送药物如抗生素或者抗病毒剂(取决于存在的感染源)、抗真菌剂和抗炎剂或者其它止痛药。为了预防慢性复发的中耳感染，也可以将本发明的方法用于活动性感染之间以将预防性药剂输送到中耳。
[0009]上述的本发明概述不是限制性的，并且本发明的其它特征和优点从以下对优选的实施方式的具体描述以及权利要求将是显而易见的。
发明详述
A.用于跨膜治疗中耳炎的载体
[0010]惊奇的是，已经发现，当非离子高分子表面活性剂被用到鼓膜时，其能够帮助药物运输穿过鼓膜和进入中耳。为了达到该目的，将非离子高分子表面活性剂(例如，聚合物链段或者嵌段共聚物)提供在包括药物的药学上接受的组合物中。非离子高分子表面活性剂为本领域已知(例如，见Non-ionic Surfactants，Schick，ed.(Dekker，N.Y.，1967))。许多这样的化合物可以以这样的普通商品名经商业途径得到，如辛苯昔醇9(TritonTM X-100)及其七聚物泰洛沙泊(TritonTM WR-1339)、美罗沙波(meroxapol)、泊洛沙姆(如PluronicTM RTM，F68和F108)、polyxamine如(TetronicsTM 908，它是四官能嵌段共聚物，通过向乙二胺中顺序加入环氧丙烷和环氧乙烷获得)、磺基琥珀酸钠二烷基酯如为琥珀酸钠二辛酯的Aerosol OTTM、DuponolTM P(十二烷基硫酸钠)、TritonTM X-200(烷基芳基聚醚磺酸酯)、聚山梨醇酯20、聚山梨醇酯80、和聚山梨醇酯80(聚氧乙烯山梨糖醇酐脂肪酸酯)、聚乙氧基化蓖麻油如CremaphorTMEL、聚乙氧基化氢化蓖麻油如HCO-40。本发明最优选使用的是烷基芳基聚醚醇类型的高分子表面活性剂，例如泰洛沙泊，和其它已经被用作例如外源性肺表面活性剂的表面活性剂，如外源性牛表面活性剂(SurvantaTM贝拉康坦(beractant))，虽然非肽类表面活性剂(例如，泰洛沙泊)是最优选的。
[0011]跨膜载体组合物的非离子型表面活性剂组分以0.01％至10％w/w，优选地0.01％至0.5％w/w，最优选地0.05％至0.2％的范围存在，但是精确的配方将取决于其中包含的赋形剂、防腐剂、水、pH调节剂等的存在与含量而变化。表面活性剂最优选地为室温下的液体。
[0012]除了非离子型表面活性剂和药物，本发明的跨膜组合物可以含有常规的药物赋形剂和防腐剂。在本方面，“防腐剂”指加入跨膜载体组合物中的成分，其阻止微生物在制剂中实质生长和繁殖。优选的防腐剂包括那些水溶性的并且可以发挥抗微生物剂作用的防腐剂，如苯乙铵盐，例如苄索氯铵。
[0013]一般地，防腐剂成分的含量会在大约0.005-2.0％的范围。根据需要加入缓冲液或者酸以调节组合物的pH到优选的范围3-6，最优选地pH 4.5。跨膜载体组合物中可以存在的其它的防腐剂和赋形剂包括氯化链烷醇胺、硫酸盐(酯)、磷酸盐(酯)、苯甲酸盐、乙酸、水杨酸(salicyclic acid)、草酸邻苯二甲酸、葡糖酸、1-萘磺酸、2-萘磺酸、酒石酸、马来酸、丙二酸、琥珀酸、延胡索酸、丙酸、抗坏血酸、扁桃酸、苹果酸、柠檬酸、盐酸三乙醇铵、磷酸二氢三乙醇铵(triethanolammonium dihydrogen phosphate)、硫酸三乙醇铵、苯甲酸钠、苯甲酸钾、苯甲酸铵、乙酸钠、乙酸钾、乙酸铵、水杨酸钠、水杨酸钾、水杨酸铵、草酸钠、草酸钾、草酸铵、邻苯二甲酸钠、邻苯二甲酸钾、邻苯二甲酸铵、葡萄糖酸钠、葡萄糖酸钾、葡萄糖酸铵、1-萘磺酸铵、2-萘磺酸钾、2-萘磺酸铵、2-萘磺酸钠、酒石酸钾、马来酸钠、马来酸钾、丙二酸钠、琥珀酸钠、延胡索酸钠、丙酸钠、丙酸三乙醇铵、抗坏血酸钠、抗坏血酸三乙醇铵、抗坏血酸钾、扁桃酸钠、苹果酸钠、柠檬酸钠、柠檬酸钾、和柠檬酸三乙醇铵。也可以使用螯合剂，例如，二钠(″EDTA″)、乙二胺四乙酸三钠、乙二胺四乙酸四钠或者五乙酸二乙胺(diethyleneamine pentaacetate)。
[0014]组合物也可以含有其它活性成分，如抗炎剂、止痛剂和甾体化合物(例如，氢化可的松、地塞米松)。本领域的普通技术人员将能够鉴定用于治疗与中耳炎相关的疼痛或者炎症的合适化合物及其剂量，如0.01-0.5％的地塞米松(例如，地塞米松醇(优选的)、醋酸地塞米松或者磷酸地塞米松)。
[0015]组合物优选地以跨膜载体组合物本身为载体施用，但是在多种实施方式中，跨膜载体可以在载体凝胶或者其它合适的载体中施用。可以加入缓冲液或者酸，例如氢氧化钠或者盐酸来调节pH。
B.用于治疗和预防中耳炎的有用药物
[0016]“药物”意味着用于治疗和/或者预防中耳感染及其后遗症、以及相关的疼痛和炎症的任何生物活性化合物。因此，在本方面，特别优选的药物是用于治疗或者预防哺乳动物尤其是人类的中耳感染的抗生素。根据感染的严重性和其原因，这样的抗生素包括但不限于，阿莫西林(和其它青霉素类)、环丙沙星(和其它喹诺酮类抗生素，如氧氟沙星)、克拉维酸盐(clavulanate)(和其它β-内酰胺酶抑制剂)、头孢克洛(和其它头孢菌素类，如头孢克肟)、氮红霉素(阿奇霉素)(和其它大环内酯类抗生素，如甲红霉素)、和磺胺二甲基异噁唑(以及其它磺胺类药物，如磺胺甲基异噁唑)。在本发明所用的抗生素中，环丙沙星是目前优选的。
[0017]磺胺二甲基异噁唑和阿莫西林是也被接受用于预防复发性中耳感染的主要抗生素。广谱抗生素如阿莫西林和环丙沙星特别优选用于治疗中耳感染，尤其是在被怀疑具有抗生素抗性感染的人中。
[0018]用于同时给药或者独立于抗生素治疗使用的有用的抗炎化合物包括在口服施用中有时效果差或耐受良好的那些化合物，例如，非甾体抗炎化合物如萘普生、酮洛芬、塞来考昔(celecoxib)和吲哚美辛。当临床上有指征时，抗病毒化合物如无环鸟苷可以替代抗生素化合物或作为抗生素化合物的辅助物施用，抗真菌组分也可以如此。用于治疗和预防中耳感染及其后遗症的其它药物也可以通过将本发明的跨膜载体组合物应用到鼓膜而施用。
[0019]在一些实施方式中，本发明的跨膜载体组合物含有一种以上药物。例如，
和
都是通常开出的用于治疗中耳炎的口服施用联合制剂组合物。每种组合物含有两种活性抗生素成分，阿莫西林和克拉维酸盐。提供这样的多药剂的跨膜载体组合物特别优选用于合适的适应症。
[0020]总之，药物以期望治疗存在的疾病的任何浓度存在。一般地，0.1％至10％w/w之间的浓度是有用的，最有用的浓度落入0.2％到0.5％w/w的范围，即，0.3％到0.4％w/w将是典型的选择。
C.使用本发明的跨膜载体治疗中耳炎的方法
[0021]尽管本发明不会受到有关这种输送的作用机理的任何理论的限制，但是目前相信，存在于本发明的跨膜组合物中的非离子高分子表面活性剂改变了鼓膜的孔隙率并从而改变了其渗透性，改变的量足以允许药物穿进鼓膜。
[0022]为了达到该目的，本发明的跨膜组合物通过跨膜给药被输送到中耳中。“跨膜给药(跨膜施用，transmembrane administration)”意味着将包括药物的跨膜载体组合物应用到鼓膜的外耳侧，使得药物输送到中耳。因此，本发明提供了通过将药物跨膜施用到受侵袭个体的鼓膜，预防和/或者治疗中耳感染及其后遗症的方法。
[0023]跨膜给药通过例如下述方法实现：通过任何医学上可接受的将药物组合物施用到鼓膜的手段，将本发明的跨膜载体组合物应用到耳部，以便使组合物与鼓膜的外表面接触，例如，通过将无针注射器或者滴管插入耳道将载体组合物应用到鼓膜。注意不要刺穿或者刺伤完整的鼓膜。
[0024]根据需要重复给药以获得给定抗生素化合物和/或者其它药物(多种药物)的治疗有效剂量水平。通过以相同的一般方式施用含有止痛剂和/或者抗炎剂的本发明跨膜载体组合物，可以治疗疼痛。
[0025]基于目前利用的将抗生素通过原位鼓膜引流管引入中耳的方案，下面实施例1中所述的示例性配方(具有0.3％w/w的抗生素)的合适给药方案是，12岁以下的儿童5滴/每日2次，12岁的儿童或年龄更高者10滴/每日2次。
[0026]针对中耳感染复发的预防性治疗可以以相同的方式提供，其利用含有预防有效的抗生素或者其它药物的本发明跨膜载体组合物。
[0027]本领域普通技术人员熟悉并且能够容易地选择适于遵循的治疗特定感染的给药方案。所选择的给药方案将根据已确立的用于输送和使用按照本发明提供的具体载体和药物的临床方案。
[0028]本发明已经被充分描述，其实施通过下面的实施例被说明。然而，本发明将不限于所述实施例，而是被所附权利要求的范围所限定。
实施例1
示例性配方
[0029]下面是含有环丙沙星和泰洛沙泊的本发明跨膜载体组合物的实施例，如下(所有浓度都为重量百分比(％w/w))：盐酸环丙沙星0.35(等同于0.3％的环丙沙星碱)；一水合地塞米松醇0.1(等同于1mg的地塞米松碱)；羟乙基纤维素0.2；苯扎氯铵0.01；乙酸钠0.03；(三水合)乙酸(作为缓冲液)0.04；氯化钠0.25；EDTA 0.01；泰洛沙泊0.05；甘油1.5；硼酸0.6；NaOH/HCl，根据需要以调节pH至4.5±0.2；纯水，形成含水组合物。
[0030]将组合物灭菌并置于药学上可接受的容器中，直至应用。
实施例2
中耳炎动物(灰鼠)模型
[0031]灰鼠langer(Chinchilla langer)是适合作为研究治疗人中耳炎疗效的理想动物种类。灰鼠(毛丝鼠，Chinchilla)个头小，具有和人极其相似的听觉能力，具有和人耳蜗相似的膜结构的耳蜗，在长期的研究中没有表现出老年性耳聋，并对天然发生的中耳感染缺乏敏感性，而所述感染对豚鼠和兔是常见的。例如，见Hajek DM，Yuan Z，QuarteyMK，Giebink GS.，Otitis Media：The Chinchilla Model：Zak O，Sande M，editors，Handbook of Animal Models of Infection，San Diego，CA：Academic Press(1999)，第389-403页，其内容通过引用并入本文以说明该动物模型的性质和在本领域中的接受性。
[0032]为了建立和评价该动物模型，直接将流感嗜血杆菌(Haemophilusinfluenzae)通过经泡(transbullar)注射接种到每只灰鼠的每只耳朵的中耳中，浓度为100菌落形成单位(cfu)，体积为0.2mL。每一灰鼠在研究前进行耳镜检查。细菌接种后大约48小时后开始施用本发明的组合物或者对照口服阿莫西林。研究期间对所有的动物每天经皮给予0.05mg/kg的丁丙诺啡叔啡2次用于止痛。
[0033]在给药期终末(细菌接种后8天)，对每只动物进行安乐死，用盐水清洗它们的耳道并检测。具体地说，收集来自每只灰鼠中耳的样品。在每个实验程序中过夜培养一个耳样品。在样品铺板后大约24小时时，对其计数并记录菌落形成单位(cfu)。
实施例3
灰鼠模型中耳炎的治疗
[0034]将实施例1所述的制剂通过管饲法经口给予三只灰鼠，每天2次，持续6天，间隔大约8小时。将2、4或者6滴制剂给予两个三只灰鼠的组，每一剂量作为这些动物的最大可行剂量。检测动物，如实施例2所述从每只动物的中耳取出样品，获得以下结果：
| 组 | 中耳中检测的环丙沙星的浓度(ng/ml) | 感染的耳朵数目/总耳朵数 |
| 1(未处理) | 无 | 7/10 |
| 2(处理) | 动物 耳朵 浓度1016 L 3096.74R 246.861017 L 324.07R 264.821018 L 612.13R 15.951019 L 1012.09R 1701.021020 L 662.51R 37.55 | 0/10 |
[0035]这些结果显示了本发明在相关动物模型中治疗中耳感染的功效。
[0036]此处说明性描述的本发明可以在本文没有具体公开的任何要素或者多种要素、限制或者多种限制不存在的情况下实施。已用的术语和描述作为描述性术语使用，并且不是限制性的，并且这样的术语和描述的使用不意图于排除所示和所述特征或其部分的任何等同物，而是承认在所要求的本发明范围内可以进行各种修改。因此，可以理解，尽管本发明已经通过优选的实施方式和任选的特征被具体公开，但是本领域普通技术人员可以对本文公开的概念进行修改和变化，并且认为这样的修改和变化在本发明范围内，如所附权利要求所限定的。
[0037]本文提到或者引用的文章、专利和专利申请以及所有其它的文件和电子可用信息的内容以整体并入本文作为参考，并入的程度与具体和单独指明每一单独出版物被并入本文作为参考相同。申请者保留将来自任何这样的文章、专利、专利申请或其它文件的任何和所有材料和信息物理上并入本申请的权利。
[0038]此处说明性描述的本发明可以在本文没有具体公开的任何要素或者多种要素、限制或者多种限制不存在的情况下适当实施。因此，例如，应该广义地和无限制地理解术语“包括(comprising)”、“包含(including)”“含有(containing)”等。另外，本文所用的术语和表述已被用作描述性术语并且不是限制性术语，并且这样的术语和表述的使用不意图于排除所示和所述特征或其部分的任何等同物，而是承认在所要求的本发明范围内可以进行各种修改。因此，可以理解，尽管本发明已经通过优选的实施方式和任选的特征被具体公开，但是本领域技术人员可以对本文包含的发明进行修改和变化，并且认为这样的修改和变化在本发明范围内。
[0039]本文中，本发明已以宽泛的和一般性的方式被描述。落入该概括性公开内容中的每一较窄的种类和亚类也形成本发明的一部分。这包括发明的这样的概括性描述，其带有附加条件或从该类中除去任何主题的负限定，不论删除的物质是否在本文中被具体地叙述。其它的实施方式在下面的权利要求中被阐述。
[0040]另外，当本发明的特征或者方面针对马库什组(Markush groups)进行描述时，本领域技术人员会意识到，本发明因此也针对该马库什组成员中的任何单独成员或亚组进行描述。
Claims (17)
1.通过向中耳跨膜施用药物治疗或者预防中耳感染及其后遗症的方法，所述方法包括：
将跨膜载体组合物施用到鼓膜的外表面，所述跨膜载体组合物包括用于治疗或者预防中耳感染及其后遗症的药物。
2.根据权利要求1所述的方法，其中所述跨膜载体是非离子高分子表面活性剂。
3.根据权利要求2所述的方法，其中所述非离子高分子表而活性剂是烷基芳基聚醚醇。
4.根据权利要求1所述的方法，其中所述药物是抗生素。
5.根据权利要求4所述的方法，其中所述抗生素选自喹诺酮类抗生素、青霉素类抗生素、大环内酯类抗生素、头孢菌素类抗生素、磺胺类抗生素、和β-内酰胺酶抑制剂。
6.根据权利要求4所述的方法，其中所述抗生素包括环丙沙星，并且其被施用以治疗或者预防中耳感染。
7.根据权利要求4所述的方法，其中所述抗生素包括氧氟沙星，并且其被施用以治疗或者预防中耳感染。
8.根据权利要求4所述的方法，其中所述抗生素包括磺胺二甲基异噁唑，并且其被施用以治疗或者预防中耳感染。
9.根据权利要求4所述的方法，其中所述抗生素包括阿莫西林，并且其被施用以治疗或者预防中耳感染。
10.根据权利要求4所述的方法，其中所述抗生素以所述组合物的0.1％到10％w/w的浓度被提供。
11.根据权利要求4所述的方法，其中所述抗生素以所述组合物的0.3％w/w的浓度被提供。
12.根据权利要求2所述的方法，其中所述非离子高分子表面活性剂以大约0.01％到10％w/w的浓度被提供。
13.根据权利要求2所述的方法，其中所述非离子高分子表面活性剂以大约0.05％到0.2％v/v的浓度被提供。
14.根据权利要求1所述的方法，其中所述药物是抗病毒剂。
15.根据权利要求14所述的方法，其中所述抗病毒剂是无环鸟苷。
16.根据权利要求2所述的方法，其中烷基芳基聚醚醇是泰洛沙泊。
17.根据权利要求1所述的方法，其中在中耳感染的急性期将所述跨膜载体组合物应用到所述鼓膜。
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| US8271101B2 (en) * | 2007-08-29 | 2012-09-18 | Advanced Bionics | Modular drug delivery system for minimizing trauma during and after insertion of a cochlear lead |
| CA2721927C (en) | 2008-04-21 | 2014-01-28 | Otonomy, Inc. | Auris formulations for treating otic diseases and conditions |
| US11969501B2 (en) | 2008-04-21 | 2024-04-30 | Dompé Farmaceutici S.P.A. | Auris formulations for treating otic diseases and conditions |
| CA2723458C (en) | 2008-05-14 | 2014-01-28 | Otonomy, Inc. | Controlled release corticosteroid compositions and methods for the treatment of otic disorders |
| US8648119B2 (en) | 2008-05-23 | 2014-02-11 | Otonomy, Inc. | Controlled release immunomodulator compositions and methods for the treatment of otic disorders |
| US8846770B2 (en) | 2008-06-18 | 2014-09-30 | Otonomy, Inc. | Controlled release aural pressure modulator compositions and methods for the treatment of OTIC disorders |
| US8349353B2 (en) | 2008-06-27 | 2013-01-08 | Otonomy, Inc. | Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders |
| WO2010011466A2 (en) | 2008-06-27 | 2010-01-28 | Otonomy, Inc. | Controlled-release cns modulating compositions and methods for the treatment of otic disorders |
| US20100016450A1 (en) * | 2008-07-21 | 2010-01-21 | Otonomy, Inc. | Controlled release delivery devices for the treatment of otic disorders |
| US10092580B2 (en) | 2008-07-21 | 2018-10-09 | Otonomy, Inc. | Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders |
| US8399018B2 (en) | 2008-07-21 | 2013-03-19 | Otonomy, Inc. | Controlled release ion channel modulator compositions and methods for the treatment of otic disorders |
| US8318817B2 (en) | 2008-07-21 | 2012-11-27 | Otonomy, Inc. | Controlled release antimicrobial compositions and methods for the treatment of otic disorders |
| US8496957B2 (en) | 2008-07-21 | 2013-07-30 | Otonomy, Inc | Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders |
| US8784870B2 (en) | 2008-07-21 | 2014-07-22 | Otonomy, Inc. | Controlled release compositions for modulating free-radical induced damage and methods of use thereof |
| US11033624B2 (en) | 2010-06-02 | 2021-06-15 | Novaflux Inc. | Medical item for prevention and treatment of ear infection |
| MD674Z (ro) * | 2013-03-07 | 2014-04-30 | Государственный Медицинский И Фармацевтический Университет "Nicolae Testemitanu" Республики Молдова | Metodă de tratament al otitei medii exudative la copii |
| US10166146B2 (en) | 2013-03-08 | 2019-01-01 | Mark Mitchnick | Ear medication dispenser with sensor |
| WO2015031393A1 (en) | 2013-08-27 | 2015-03-05 | Otonomy, Inc. | Treatment of pediatric otic disorders |
| US10285865B2 (en) | 2014-05-02 | 2019-05-14 | Novaflux Inc. | Drug-releasing device usable in mucosal body cavities |
| EP3512513A4 (en) | 2016-09-16 | 2020-04-15 | Otonomy, Inc. | GEL FORMULA FOR THE EAR FOR TREATING OTITIS EXTERNA |
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| US20080318918A1 (en) | 2008-12-25 |
| EP1931388A2 (en) | 2008-06-18 |
| WO2007037886A2 (en) | 2007-04-05 |
| CA2622002A1 (en) | 2007-04-05 |
| BRPI0616415A2 (pt) | 2011-06-21 |
| EA200800950A1 (ru) | 2008-08-29 |
| WO2007037886B1 (en) | 2008-01-10 |
| AU2006295248A1 (en) | 2007-04-05 |
| ZA200803370B (en) | 2009-09-30 |
| WO2007037886A3 (en) | 2007-10-25 |
| IL190079A0 (en) | 2008-08-07 |
| EP1931388A4 (en) | 2010-12-15 |
| JP2009509956A (ja) | 2009-03-12 |
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