CN101031282A - Methods for transmembrane treatment and prevention of otitismedia - Google Patents

Abstract

Methods for treating and preventing middle ear infections by transmembrane administration of medicament-containing transmembrane carrier compositions, such as liposomes and other lipid vesicles, to the tympanic membrane. Medicaments useful for treating pain, inflammation or infection in the outer ear may be co-administered. If utilized for transmembrane administration, the liposomes or other lipid vesicles will usually not be sterically stabilized. The medicaments delivered according to the methods of the invention include antibiotic, anti-viral, anti-fungal and anti-inflammatory agents that are useful in treatment and/or prophylaxis of middle ear infections and their sequelae.

Description

Be used for method through film treatment and prevention of otitis media

Invention field

[0001] the present invention relates to treat the noninvasive method of otitis media (middle ear infection).More specifically, the medicine that the present invention relates to be used for the treatment of otitis media is administered to the method for middle ear, and this passes tympanum (tympanic membrane) (tympanum (eardrum)) and implement by giving described medicine.

Background technology

[0002] there are every year millions of children to be subjected to otitis media, that is, and the invasion and attack of middle ear infection.Though the adult also is vulnerable to middle ear infection, the child is in the risk especially, because their auditory meatus is short relatively, and easier the approaching of inflammation that be subjected to.Fluid can be resident in tympanum (tympanum) back subsequently, and this can cause serious pain, and is provided at the favorable environment of wherein breeding for microorganism.

[0003] tympanum is to stop medicine to introduce the barrier that is difficult to go beyond of middle ear, and therefore, the antibiotic that is used for the treatment of middle ear infection of prescribing is almost always used by oral administration.Yet many antibacterials and virus can cause middle ear infection, and usually can not distinguish reason which kind of antibacterial or virus are specific infection (particular infection) or whether it is responsive to oral antibiotic treatment.Further, the antibiotic of orally give can be distributed by the whole body of medicine to the influence of middle ear and weaken, and this also makes the patient be in whole body and carries in the risk of relevant side effect (for example, the yeast infection among women (female) patient).

[0004] suffer the child of repeated infection may need to perform the operation so that alleviate fluid pressure on the tympanum.Under serious situation more, drainage tube can be set in tympanum.The not generation again of prevention infection of described pipe itself (opposite, they can be used as the pipeline that other pathogen enters middle ear), but they can ease off the pressure and reduce fluid resident degree behind tympanum.Described pipe also provides potential pipeline for antibiotic directly enters middle ear; For example, by using several antibiotic and making them flow into drainage tube.Yet the method is invasive and is pain that this has shown antibiotic being introduced the tight demand of other approach of middle ear.

Summary of the invention

[0005] astoundingly, find that medicine can be introduced directly into middle ear by carrying through film.According to the present invention, medicine is provided as being applied to the active component through the membrane carrier compositions of tympanum (eardrum (tympanum)), for example can delivery of medicaments pass diaphragm-operated Emulsion based on lipid, lipid vesicle, liposome (liposomes), liposome (liosomes), micelle (micelles), shift body (transferomes) and polymer support.

[0006] preferred medicine is to be used for the treatment of or those medicines of prevention of otitis media (middle ear infection) and sequela thereof.The present invention is particularly suitable for carrying medicine such as antibiotic or antiviral agents (source of infection that depends on existence), antifungal agent and anti-inflammatory agent or other analgesic.In order to prevent the middle ear infection of chronic recurrence, the inventive method also can infect in activeness between (active infection) to be used, so that carry preventative medicament to middle ear.

[0007] the invention described above general introduction is not restrictive, from following the auspicious of preferred implementation is stated and claims, and further feature of the present invention and advantage will be tangible.

Invent auspicious stating

A. treat the method for otitis media through film

[0008] the invention provides the treatment and the method for prevention of otitis media, it is implemented by giving the medicine that being used in the membrane carrier compositions prevented or treated middle ear infection and sequela thereof.The present invention is derived from surprising discovery: in suitable carriers, medicine can be carried and pass tympanum and needn't puncture this film (for example, by insertion tube or injection).

[0009] " gives (transmembrane administration) through film and be meant, can pass diaphragm-operated the present invention and be applied in diaphragm-operated external ear side, so that carry medicine to middle ear through the membrane carrier compositions.Therefore, the invention provides by tympanum and give the method that medicine prevents and/or treats middle ear infection and sequela thereof through film to infected individuality.

[0010] gives following realization through film: for example,, use of the present invention to tympanum through the membrane carrier compositions by being used for any medically acceptable mode to tympanum drug administration compositions; For example, enter auditory meatus, use carrier compositions to tympanum by inserting needleless injector or dropper.Give repeatedly as required, so that reach effective dosage level in the treatment of the Antibiotique composition that gives; For example, the 5-10 that is made up of the 0.3%w/w antibiotic drips through the membrane carrier compositions and can carry twice every day, treats by invasion and attack child's otitis media.

[0011] those of ordinary skills are familiar with and can easily select to be suitable for being followed so that treat the dosage regimen of specific infection.Selected dosage regimen will depend on and be used to carry and use the clinical protocol of having established according to specific support provided by the invention and medicine.In one embodiment, medicine is to be provided based on the concentration at least about 0.3%w/w in the carrier of lipid.

[0012] described compositions preferably is given, through membrane carrier compositions itself as carrier; But in many embodiments, can in carrier glue or other suitable carrier, give through membrane carrier.

B. be used for the carrier based on lipid of the present invention

[0013] though the present invention is not subjected to the restriction of any theory of relevant this conveying behavioral mechanism, think at present, being suitable for carrying the carrier of medicine through film is can to interact with the passage that is rich in lipid in the tympanum (for example, Van der Waals interacts) and also may enter the carrier of described passage.Therefore, preferably be based on those carriers of lipid at present through membrane carrier, as liplid emulsions (comprising microemulsion and oil in water emulsion), and lipid vesicle, as liposome (liposomes), liposome (liosomes), micelle and transfer body (super flexible lipid vesicle).Useful non-vesicle formation in the current preparation that is preferably based on phospholipid, particularly the present invention.

[0014] same, any theory of not using its mechanism of action limits the present invention, also observes, the most effective in the acute phase of infecting through the film conveying, wherein because the pressure of middle ear increases, tympanum outwards protrudes (promptly, enter external ear), this is the symptom characteristic of acute middle ear infection.Protrusion shows that fluid is resident behind tympanum.The introducing of carrier on the tympanum opposition side that the present invention is based on lipid can produce permeable pressure head, its help medicine through film transportation, or from carrier transportation, or transport jointly with carrier based on lipid based on lipid.

[0015] most preferably, lipid vesicle is flexible through film composition, and this is that they do not comprise the stereoscopic stable composition, as cholesterol (entering external ear though three-dimensional stable vesicle can be used for giving jointly medicine, as hereinafter further argumentation of other place).Further, the medicine of carrying according to the present invention preferably carries (for example, in the double-layer of lipoid at liposome) rather than carries (for example, in the core at liposome) at aqueous phase in fat phase (lipid phase).Therefore, fat-soluble medicine (usually with than in the higher concentration of the dispersive water soluble drug of aqueous phase, provide in the double-layer of lipoid of vesicle) is preferred, though that it is used for the present invention is optional.

[0016] method for preparing liquid emulsion and vesicle is well known in the art, therefore at this present most preferred embodiment of only using among brief overview the present invention, do not have the stereoscopic stable agent and add hardly or do not add viscosity intensifier and the liposome for preparing through the membrane carrier compositions.

[0017] " liposome (liposome) " is meant spherical vesicles, limited and hold water by the double-layer of lipoid of rule.The double-layer of lipoid of liposome is made of natural or synthetic phospholipid usually, but also can be made of non-phospholipid.The double-layer of lipoid of liposome is the bilayer of rule, means that " head " and " tail " structure of lipid molecular is arranged with being adjacent to each other.

[0018] liposome of using among the present invention can be monolayer (having a double-layer of lipoid) or more preferably be multiwalled.The liposome of " multilamellar " has a plurality of layers or film.Such liposome has the multilamellar double-layer of lipoid of the aqueous fluids that carries between the double-layer of lipoid.Multilamellar liposome has two-layer at least lipid.

[0019] preferred liposome is a liposome as herein described, with common pending trial and the U.S. Patent Application Serial Number 10/366 owned together, liposome in 584, described patent application was submitted on February 12nd, 2003, and its disclosure is incorporated this paper into as a reference with integral body.Yet those of ordinary skills can know, can use other Liposomal formulation, comprise the phosphatidyl chemical compound, as phosphatidyl glycerol, phosphatidylcholine, Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, sphingolipid, cerebroside and ganglioside.Useful especially is the diacyl phosphatidyl glycerol, and wherein lipid part contains 14-18 carbon atom, a particularly 16-18 carbon atom, and is saturated.Illustrative phospholipid comprises lecithin phatidylcholine, dipalmitoyl phosphatidyl choline and distearoyl phosphatidylcholine.These lipids are also useful in the membrane carrier compositions at non-vesicle of the present invention.

[0020]---exist different---but this vesicle preferred size unanimity in every batch of prepared product if the size of liposome of using among the present invention and lipid vesicle can be different.Liposome can reach 20 μ m, 25 μ m or even 30 μ m.But in preferred embodiment, the diameter of about 95% liposome is from about 0.5 μ m to about 10 μ m.In one embodiment, in the preferred composition according to method preparation as herein described, at least 80% liposome is that about 0.5 μ m is to about 5 μ m.Given this, term " about " comprises the scope of the last of described value or following 5%.The actual diameter of liposome be hereinafter cooling curve and the function of the intensity of length and stirring or vortex hydration, when these processes be used in liposome make in the time.In other embodiments, liposome can be multi-lamellar liposome, and wherein single big liposome is enclosed one or more less liposomees.

[0021] traditional liposomal of making according to any method known in the art can be with in the present invention, but preferred liposome of the present invention do not comprise the fat-soluble antiseptic found in the prior art liposome (referring to, for example, U.S. Patent number 4,761,288 and 4,897,269, all authorize Mezei, all incorporate this paper into as a reference) with integral body.On the contrary, Application No. 10/366584 (incorporating this paper into integral body) as common pending trial is described, liposome of the present invention is used waterborne-type preservation, it can be used as antimicrobial and plays a role, benzene rope ammonium salt (benzethonium salt) preferably is as benzethonium chloride (benzethonium chloride).

[0022] Given this, " antiseptic (preservative) " is meant the composition that is added into through the membrane carrier compositions, and it prevents microorganism raised growth and breeding in preparation.Further, " water solublity (water soluble) " is meant, composition has the water solubility that surpasses 100 μ g/ml (or 0.01%) in water.In other embodiments, composition can have the dissolubility above 1mg/ml (0.1%) in water.

[0023] yet, other waterborne-type preservation is also useful in the present invention, as benzoic acid and benzylkonium salts such as benzylkonium chloride.Unexpectedly finding, in order to obtain stabilized liposomes, is important to choice of preservatives, because the structure of fat-soluble antiseptic liposome because growth of microorganism can weaken and make it to stablize, produces and has low viscous unstable association thing.Other waterborne-type preservation can be employed; And advantageously selected, so that under the pH of compositions, be activated.

[0024] in preferred implementation of the present invention, the liposome of application also comprises vitamin E as fat-soluble antioxidant.Antioxidant plays free free radical scavenger, assists liposome to reach maximum stability.Methylcellulose or other viscosity intensifier be included in desire to be applied to skin in the membrane carrier compositions, purpose is to obtain enough viscosity and avoid fluid composition.In a most preferred embodiment, this compositions comprises the vitamin E as antioxidant, and comprises following or 1.5% following or 1.0% following or the 0.5% following or 0.25% following viscosity intensifier of 2%w/w.

[0025] more preferably, described compositions does not comprise any methylcellulose or any other viscosity intensifier, and what make active pharmaceutical compounds reaches best through membrane permeation.In one embodiment, at least 50% vitamin E is present in the double-layer of lipoid of liposome.In other embodiments, at least 70% or 80% or 90% or 95% vitamin E is present in the double-layer of lipoid of liposome.

[0026] " viscosity intensifier (viscosity enhancing agents) " means the adding compositions so that increase the reagent of viscosity.At 25 ℃, viscosity intensifier can increase viscosity at least 10,000 centipoise of compositions.Viscosity intensifier includes but not limited to methylcellulose, alginic acid, gelatin, Radix Acaciae senegalis (arabic gum (gum Arabic)) carbomer and cetostearyl alcohol.Do not think that phospholipid is the viscosity intensifier in this definition.Compare with there not being viscosity intensifier, viscosity intensifier can strengthen viscosity at least 10,000 centipoise, in other embodiments, do not compare with there not being viscosity intensifier in the compositions, viscosity intensifier can strengthen viscosity 20,000 or 30,000 centipoise (reaching high as 40,000 or 50,000 centipoises).

[0027] therefore, in numerous embodiments, of the present inventionly preferably contain below the 2%w/w or below 1% through the membrane carrier compositions, or 0.5% following or even 0% viscosity intensifier.For example, in numerous embodiments, compositions contains the following organic or inorganic salt of this tittle, example hydrochloric acid salt, nitrate, sulfate, phosphate, carbonate, hydrobromate or hydriodate.Compositions also preferably contain 2%w/w following or 1% following or even 0% potassium bromide, potassium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate, potassium iodide, potassium nitrate, lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium sulfate, ammonium bromide, ammonium chloride, ammonium carbonate, ammonium bicarbonate, Ammonium biphosphate, diammonium phosphate, ammonium iodide, ammonium nitrate, ammonium sulfate, sodium bromide, sodium carbonate, sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, Chile saltpeter, sodium phosphate and sodium sulfate.

[0028] in the membrane carrier compositions preferred with 2%w/w below or 1% below or even 0% other salt that exists comprise the alkanolamine chloride, sulfate, phosphate, benzoate, acetate, Salicylate, oxalates, phthalate, gluconate, 1-naphthalene sulfonic aicd salt, the 2-naphthalene sulfonate, tartrate, maleate, succinate, fumarate, propionate, Ascorbate, mandelate, malate, citrate, the triethanol ammonium chloride, the triethanol ammonium dihydric phosphate, triethanol ammonium sulfate, sodium benzoate, Potassium Benzoate, ammonium benzoate, sodium acetate, potassium acetate, ammonium acetate, sodium salicylate, potassium salicylate, ammonium salicylate, Disodium oxalate., potassium oxalate, ammonium oxalate, sodium phthalate, phthalic acid potassium, ammonium phthalate, gluconic acid sodium salt, potassium gluconate, ammonium gluconate, the 1-naphthalene sulfonic aicd ammonium, the 2-naphthalene sulfonic acid potassium, 2-LOMAR PWA EINECS 246-676-2 ammonium, the 2-sodium naphthalene sulfonate, Soluble tartar., Monosodium maleate, maleic acid potassium, sodium malonate, sodium succinate, Fumaric acid sodium, sodium propionate, the triethanol ammonium propionate, sodium ascorbate, the triethanol ammonium Ascorbate, potassium ascorbate, sodium melate, natrium malicum, sodium citrate, potassium citrate, with the triethanol ammonium citrate.

[0029] in numerous embodiments, be used for of the present inventionly having at least 10 through the membrane carrier compositions, 000 centipoise or at least 20,000 centipoise or at least 30,000 centipoise or at least 40,000 centipoise or at least 50, the viscosity of 000 centipoise or at least 60,000 centipoise or at least 70,000 centipoise, all under 58 ℃, there are not any methylcellulose or other viscosity intensifier.Owing to do not have methylcellulose and other viscosity intensifier in the formulation, increased greatly through membrane permeability.In one embodiment, oleyl alcohol can be added into strengthen medicine through membrane permeability, described oleyl alcohol but is present in the outside of liposome in compositions.

[0030] do not wish to be subjected to the restriction of any particular theory, think, what provide stability for these specific lipid bodies is the combination of waterborne-type preservation and fat-soluble antioxidant.This makes that liposome is stable and also has high viscosity.Although contain considerably less viscosity intensifier or do not contain viscosity intensifier through the membrane carrier compositions, high viscosity also is possible.Think that viscosity intensifier damages the skin movements of striding of reactive compound.In giving this reactive compound, this compositions provides the superior character of maximum percutaneous permeability, keeps enough viscosity simultaneously.

[0031] if liposome is based on the vesicle of phospholipid, preferred lipid will be phospholipon 9OH, and it obtains from soybean lecithin and purification, and chemical name is 1,2-diacyl-5N-glycerol-3-phosphatidylcholine.It is minimum 90% phosphatidylcholine and fully hydrogenation of quilt.But those of ordinary skill can know that other lipid also can be with in the present invention.For example, phosphatidylcholine can be a low-purity, perhaps can contain other lipid or carrier mass as, for example, propylene glycol/ethanol, medium chain triglyceride, oil/ethanol, phosphatidic acid, cholesterol and phosphatidylinositols.Phospholipid can be any natural or synthetic phospholipid, for example, and PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, phosphatidic acid, lysophosphatide, lecithin or soybean phospholipid or their combination.Phospholipid can be with salt or desalination, hydrogenation or partially hydrogenated, natural, synthetic or semisynthetic.The example of commercial available phospholipid include but not limited to lecithin P 123 (Pfanstiehl, Waukegen, IL), Lipoid E80 (Lipoid, Ludwigshafen, Germany); With hydrogenated soya phosphatide Phospholipon 80H ^, 80G ^, 90H ^And 100H ^(Nattermann, Munich, Germany) and 99% pure S-PC (Avanti Polar Lipids, Alabaster, AL).

[0032] randomly, the pure and mild propylene glycol of dehydration can be as the cosolvent of fat phase, and it is involved that the vitamin E acetate can be used as antioxidant.In numerous embodiments, other lipid or lipid similar substance are with in the present invention, as ceramide, lecithin, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, cuorin, trilinolein and similar compound.Non-phospholipid also can be with in the present invention.For example, useful non-phospholipid material comprise the polyoxyethylene fatty acid ester that forms lipid vesicle, polyoxyethylene fatty acid ether, diethanolamine, long-chain amide, long acyl amino acid amide, long-chain amide, polyoxyethylene sorbitan oleate, polyoxyethylene glyceryl monostearate, glyceryl monostearate, and composition thereof, analog and derivant.Vesicle also can comprise steroid and charge generation agent.Preferred steroid comprises cholesterol, hydrocortisone and composition thereof, analog and derivant.It is oleic acid, dicetyl phosphate, Palmic acid, cetyl sulfate, tretinoin, phosphatidic acid, Phosphatidylserine and their mixture that preferred negative charge produces material.In order to provide clean positive charge to vesicle when needed, can use long-chain amine for example stearylamine or oleyl amine, the long-chain pyridine compounds is hexadecylpyridinium chloride for example, and the mixture of quaternary ammonium compound or these materials is as long as the liquid vesicle can carry the water of q.s.

[0033] other Liposomal formulation comprises non-phospholipid liposome, can be with in the present invention.For general reference, (its disclosure is incorporated this paper into to disclosed multiphasic liposomes delivery system in the U.S. Patent number of publishing on August 2nd, 1998 of authorizing Mezei 4,761,288, make easy reference), be the exemplary representative of the liposome composition that can use among the present invention.In order to be used as through membrane carrier, liposome (or other lipid vesicle of using among the present invention) is modified to the stereoscopic stable vesicle, or be provided for targeting, or offer slowly releasing properties of vesicle (or use other carrier) based on lipid, can disturb compositions through film activity, thereby not by preferably.

[0034] among the present invention advantageous applications be " stable " through the membrane carrier compositions, mean that they can be stored at least 6 months, 1 year, or 2 years, and do not change the chemical property or the physical property of compositions.

[0035] there is not theoretic restriction to incorporating the chemical compound number of using among the present invention into based on the carrier of lipid.Yet as known to persons of ordinary skill in the art, have high relatively lipid: in the liposome composition of water content, encapsulation efficiency is higher usually, and the fat-soluble medicine that carries in mutually at fat provides with the concentration of the water-soluble pesticide object height that carries than aqueous phase usually.

[0036] for example, two or more compositions can be encapsulated in the same vesicle, if perhaps various reactive compounds are inconsistent, then chemical compound can be sealed respectively, and together so that the compositions with two or more indications is provided, perhaps use the compositions of the single indication of various active compounds for treating through the membrane carrier combination of compositions.

[0037] by giving (for example to treat middle ear and auditory meatus simultaneously through the membrane carrier compositions, treat the former infection and alleviate the latter's swelling) also be possible, described compositions comprises first group of one or more reactive compound that are used for the treatment of middle ear, it is encapsulated in the vesicle, with second group of one or more reactive compound that are used for the treatment of auditory meatus, it is with the aqueous phase around encapsulated form is not dispersed in.First group of chemical compound sealing can stride across tympanum and enter middle ear; Non-encapsulated second group of chemical compound can be not like this.

[0038] gives jointly also can followingly to implement, for example, give second group of chemical compound, as making so that in the liposome of opposing degraded with slow releasing pattern.Those of ordinary skills are familiar with finishing the manufacture method of this target, described method comprises rather than is limited to: to fat add in mutually cholesterol (referring to, for example, U.S. Patent number 6,352,716, incorporate this paper into as a reference, as the example that adds the method for cholesterol for this purpose to fat in mutually) and in liposome is made application viscosity reinforcing agent (as methylcellulose).

[0039] this insoluble relatively lipid vesicle is unsuitable for carrying medicine to pass tympanum, but alternatively, can be desirably in and carry part to keep the medicine that slowly release contains second group of (or another group) chemical compound to enter auditory meatus (for example, treat inflammation wherein, or analgesic is provided).This vesicle also can have infection character or other character that helps to treat or control external ear infection speed; For example, if the positive charge that effective anti-infective cetyl trimethyl ammonium bromide is used as in the vesicle produces material, will provide second kind of advantage.In this embodiment, along with each vesicle damages (deteriorate), it plays a role as postponing the antibacterial carrier that discharges.

C. be used for the treatment of useful medicine with prevention of otitis media

[0040] " medicine (medicament) " means and is used for the treatment of and/or prevents middle ear infection and sequela thereof and relevant pain and any bioactive compound of inflammation.Given this, particularly preferred medicine is to be used for the treatment of or to prevent mammal, the particularly antibiotic of people's middle ear infection.According to the order of severity and the reason thereof that infect, this antibiotic comprises rather than is limited to, amoxicillin (with other penicillins), ciprofloxacin are (with other quinolone antibiotic, as ofloxacin), clavulanic acid (with other beta-lactamase inhibitor), cefaclor be (with other cephalosporins, as cefixime), azithromycin (with other macrolide antibiotics such as clarithromycin) and the different  azoles of sulfanilamide dimethyl (and other sulfa drugs, as the sulfamethoxazolum azoles).In the useful in the present invention antibiotic, current preferred ciprofloxacin.

[0041] different  azoles of sulfanilamide dimethyl and amoxicillin are also to be accepted the main antibiotic that is used for the prevention of recurrence middle ear infection.Broad ectrum antibiotic such as amoxicillin and ciprofloxacin are particularly preferred for treating middle ear infection, particularly suffer among the people of antibiotic resistance infection in suspection.

[0042] is used for giving jointly or is independent of those chemical compounds that useful anti-inflammatory compound that antibiotic therapy uses comprises the orally give relatively poor or suitable tolerance of efficient sometimes; For example, on-steroidal anti-inflammatory compound such as naproxen, ketoprofen, celecoxib (celecoxib) and indomethacin.When clinical the needs, antiviral compound such as acyclovir can replace Antibiotique composition, or as they adminicle and be given multi-resistance fungus component so.Also can be of the present invention through the membrane carrier compositions by using to tympanum, be used for the treatment of and prevent the other medicines of middle ear infection and sequela thereof.

[0043] in some embodiments, the medicine that contains more than one through the membrane carrier compositions of the present invention.For example, CLAMOXYL  and AUGMENTIN  are the combination formulations compositionss of orally give, and being prescribed usually is used for the treatment of otitis media.Each compositions contains two kinds of living antibiotics compositions, amoxicillin and clavulanic acids.What this multiple medicines agent was provided is to be particularly preferred for suitable indication through the membrane carrier compositions.

Embodiment 1

Demonstrative preparation A

[0044] this part provides preparation to contain the raw-material example of the present invention of ciprofloxacin through the membrane carrier compositions.Describedly comprise liposome, and contain following ingredients with w/w percentage ratio of listing through the membrane carrier compositions.

PHOSPHOLIPON ^90H 5.00 or lower

Alcohol, dehydration, USP (American Pharmacopeia) 5.00 or lower

Propylene glycol, USP 5.00

Vitamin E acetate 1.00

Benzethonium chloride 0.02

Ciprofloxacin 0.30 or therapeutic dose is provided on demand

Pure water 76.98 or more

Embodiment 2

Make the exemplary method of preparation A

[0045] this part provides and how to have made the present invention of containing ciprofloxacin example through the membrane carrier compositions.

[0046] water.This method is preferably implemented with the rustless steel vortex hydration cabin (chamber) of two band covers.In bigger one in two cabins, slowly mix pure water and benzethonium chloride, to avoid the formation of foam or blibbing.Apply heat, reach 50 ℃ ± 2 ℃ of the target temperatures of water.Cover described cabin and evaporate, and be equipped with bottom hatch door (port) and valve, flow out this container so that regulate material to prevent water.

[0047] fat phase.Second stainless steel band cover mixer used near first container.In this second cabin, the pure and mild propylene glycol of at first slow mixed dehydration is to avoid the formation of foam or blibbing.Blender above starting applies heat, reaches 58 ± 2 ℃, and target is 58 ℃.When solution reaches target temperature, add ciprofloxacin and fully dissolving.Add PHOSPHOLIPON subsequently ^90H and vitamin E acetate, and mix mutually with fat, until dissolving/fusion.In whole process, on the cabin, use covering, to prevent the alcohol evaporation.

[0048] hydration of fat phase.Open the valve on the bottom hatch door in cabin, regulate liquid stream from two containers.Water and oil phase flow and regulate tee T (in-line regulatingtee) at pipeline and locate to join, and disperse pump with biphase suction (pull) together.Mixture disperses the sieve circulation by 60 mesh (hole limit number per square inch), so that optimize the hydration of fat phase.Subsequently mixture is guided to the top, cabin, whole process circulates by pump, return capsule, 10 minutes times spent.

[0049] cooling phase.After the circulation, making cabin cover cooling, continue simultaneously slowly to mix, is 28 ℃ until the product temperature, terminal procedure.The mixing of material is preferably enough fast, does not cause the formation of surfactant foam or bubble so that thoroughly mix.Cooling procedure is preferably slow, and it is most preferred per hour cooling off about 6 ℃.

Embodiment 3

Use demonstrative preparation treatment otitis media

[0050] middle ear infection and the sequela thereof in order to treat infected individuals by giving tympanum through film, gives the patient with the medicinal liposome that contains according to the present invention.Medicine is a useful medicine in the preventing and/or treating of middle ear infection, and is antibiotic, antiviral agents or analgesic, as nonsteroid anti-inflammatory drugs.

[0051] be by for example through film, with needleless injector or be suitable for other apparatus that medical science inserts auditory meatus and be applied to tympanum through the membrane carrier compositions and realize with of the present invention.As needs, give repeatedly, to obtain the treatment effective dose level of the Antibiotique composition that given.Pain can be treated through the membrane carrier compositions by the present invention who contains pain relieving and/or antiinflammatory with identical general fashion.

[0052] based on the present scheme that is used for antibiotic being introduced middle ear by original position tympanum drainage tube, the suitable dosage regimen of the demonstrative preparation described in the embodiment 1 is: for the child below 12 years old be 5 droplets/day twice, 12 years old or more old children be 10 droplets/day twice.

[0053] prophylactic treatment at the middle ear infection recurrence can provide in an identical manner, wherein utilizes the present invention who contains effective antibiotic of prevention or other medicines through the membrane carrier compositions.

[0054] the present invention is fully described, and embodiment example is hereinafter passed through in its enforcement.Thereby these embodiment are representational to the result who implements method of the present invention and can obtain, and are not limits.

Embodiment 4

The animal of otitis media (South America chinchilla) model

[0055] South America chinchilla (Chinchilla lange) is the animal species that is suitable for ideally as the effect of the human otitis media of research treatment.Lousiness Muridae (Chinchillas) is little, have the hearing ability closely similar with the people, have the cochlea that have membrane structure similar to people's cochlea, in long term test, do not show presbyacusis, and lack susceptibility, and these are general to Cavia porcellus and rabbit to the middle ear infection of natural generation.Referring to, for example, Hajek DM, Yuan Z, Quartey MK, Giebink GS., Otitis Media:The Chinchilla Model, in:Zak O, Sande M, editors, Handbook of Animal Models of Infection, SanDiego, CA:Academic Press (1999), the 389-403 page or leaf, its content is incorporated this paper into as a reference, so that its character and this animal model degree of recognition in the art are described.

[0056] in order to set up and estimates animal model, to each South America chinchilla inoculation hemophilus influenza (Haemophilus influenzae), direct inoculation is to the middle ear of each ear, with the concentration of 100cfu, inject through bubbling (transbullar) with the 0.2mL volume.Before beginning one's study, give each South America chinchilla otoscopy.The present composition or contrast oral amoxicillin dosage and originate in after the microbionation about 48 hours.Give all animal buprenorphines (Buprenorphine), 0.05mg/kg, day twice subcutaneous giving is used for pain relieving during studying.

[0057] ends in administration (after the microbionation 8 days), put to death each animal, with its auditory meatus of salt water washing and detect.Particularly, collect from the sample of the middle ear of each South America chinchilla.To each test procedure, ear's sample is by overnight incubation.Behind the sample bed board about 24 hours, it is counted record colony forming unit (cfu).

Embodiment 5

The otitis media treatment (liposome lipid) of South America chinchilla model

[0058] by tube feed, gives positive control (amoxicillin), continue 6 every day twice, be separated by about 8 hours to 3 South America chinchilla per os.Give 2,4 or 6 ofloxacin 0.3% Liposomal formulations or ciprofloxacin 0.3% Liposomal formulation to 2 groups of South America chinchillas, every group of 3 South America chinchillas are as the maximum feasible dosage of these animals.

[0059] every group result (3 non-conceived jenny/groups) is as follows:

Do not treat animal: activeness infects after 6 days and still exists.

Control animal: the amoxicillin, 20mg/kg BID continues 6.After 6 days,

All animals do not exist activeness to infect.

Animal according to the inventive method treatment:

Ciprofloxacin, 4 BID continue 6.After 6 days, all animals do not exist activeness to infect.

Ofloxacin, 2 BID continue 6.After 6 days, 2 animals still exist activeness to infect; The 3rd animal do not exist activeness to infect.

Ofloxacin, 4 BID continue 6.After 6 days, 1 animal still exists activeness to infect; 2 animals do not exist activeness to infect in addition.

Embodiment 6

Otitis media treatment (non-liposome lipid) in the chinchilla model

[0060] the ciprofloxacin preparation in application liposome lipid and the non-liposome lipid is abideed by the scheme that embodiment 5 describes, and obtains following result:

Group	Preparation		Treatment	Infected ear number/total ear number
					1	Do not have		Not treatment	In 10 7
2	Component	Percentage ratio	Cipro 2 (liposome)	In 10 0
					Phospholipon 90.H	2.0
	Vitamin E	1.0
					Ethanol 1%	6.0
	Propylene glycol	5.0
					Ciprofloxacin	0.3
	Benzethonium chloride	0.02
					Boric acid powder	1.6
	Water, distillatory	84.08
						100％
	3	Component					Percentage ratio	Cipro 3 (non-liposome)	In 10 0
Mineral oil is light			9.00
		Phospholipon 90H		1.00
Span 60			2.00
		Tween 60		1.00
Propylene glycol			5.00
		Boric acid		1.90
Water, distillatory			79.78
		Benzethonium chloride		0.02
Ciprofloxacin			0.3
				100％

[0061] these results have shown the effect of the present invention in the middle ear infection of treatment relevant animal models, and being treated animal has dose dependent.

[0062] invention of the exemplary description of this paper can be implemented under the concrete disclosed any key element of Ben Wenmo or a plurality of key element, restriction or the non-existent situation of a plurality of restriction.Applied term and statement are used as descriptive term rather than restricted term; and be not intended to and when using these terms and statement, get rid of demonstration and the feature of describing or any equivalent of its part, but recognize that various modifications are possible in the claimed invention scope.Therefore, should be appreciated that, although the present invention is open particularly with optional feature quilt by embodiment preferred, but those skilled in the art can make amendment and change notion disclosed herein, and these modifications and variations are contemplated as falling with within the scope of the present invention, as defined by the appended claims.

[0063] this paper mentions and article, patent and the patent application of quoting and other all documents and electronics can get the content of information, incorporate this paper into as a reference with integral body, the degree of incorporating into specifically and is individually incorporated this paper into as a reference with integral body as indicating each indivedual publication.The applicant keeps the right that will incorporate the application into physics mode from any and all material and the information of any of these article, patent, patent application or other document.

[0064] invention of the exemplary description of this paper can be implemented under the not concrete disclosed any key element of this paper or a plurality of key element, restriction or the non-existent situation of a plurality of restriction.Therefore, for example, term " comprises ", " comprising ", " containing " etc. will be by broad sense and unrestricted read purposefully.In addition; applied term and statement are used as descriptive term rather than restricted term; and be not intended to and when using these terms and statement, get rid of demonstration and the feature of describing or any equivalent of its part, but recognize that various modifications are possible in the claimed invention scope.Therefore, should be appreciated that, although by open particularly, those skilled in the art can make amendment and change notion disclosed herein by embodiment preferred and optional feature in the present invention, and these modifications and variations are contemplated as falling with within the scope of the present invention.

[0065] in this article, the present invention's being described with wide model with general mode.Each the narrower kind and the subclass that fall into this generality disclosure also form a part of the present invention.This such generality that comprises invention is described, and the negative qualification that it has additional conditions or removes any theme from this apoplexy due to endogenous wind is no matter whether this material of deletion is narrated in this article particularly.Other embodiment is listed in the following claims.

[0066] in addition, when feature of the present invention or aspect are described at the Ma Kushi group, those skilled in the art will know that the present invention thereby also describe at any separate member of this Ma Kushi group or subgroup member.

Claims (24)

1. the method for treatment or prevention middle ear infection and sequela thereof is implemented by giving medicine to it through film, and described method comprises:

Use through the membrane carrier compositions the described medicine that is used for the treatment of or prevents middle ear infection and sequela thereof that comprises through the membrane carrier compositions to the tympanum outer surface.

2. the method for treatment or prevention middle ear infection and sequela thereof is implemented by giving medicine to it through film, and described method comprises:

To the tympanum outer surface use non-stereoscopic stable through the membrane carrier compositions, the described medicine that is used for the treatment of or prevents middle ear infection and sequela thereof that comprises through the membrane carrier compositions.

3. according to the process of claim 1 wherein that described is lipid vesicle through membrane carrier.

4. according to the method for claim 2, being selected from by liposome (liposomes), micelle (micelles), liposome (liosomes), lipoid plastid (niosomes) and shifting the lipid vesicle group that body (transferomes) is formed of wherein said non-stereoscopic stable through membrane carrier.

5. according to the method for claim 5, wherein said non-stereoscopic stable be liposome through membrane carrier.

6. according to the method for claim 1 or 2, wherein said is liposome through the membrane carrier compositions, comprising:

Waterborne-type preservation and

Fat-soluble antioxidant;

Wherein the diameter of at least 75% described liposome is that about 0.5 μ m is to about 10 μ m;

And

The viscosity of wherein said compositions is at least 20,000 centipoise and contains the following viscosity intensifier of 2%w/w.

7. according to the process of claim 1 wherein that described medicine is an antibiotic.

8. according to the method for claim 2, wherein said medicine is an antibiotic.

9. according to Claim 8 or 9 method, wherein said antibiotic is selected from quinolone antibiotic, Penicillin antibiotics, macrolide antibiotics, cephalosporins, sulfonamides antibiotic and beta-lactamase inhibitor.

10. according to Claim 8 or 9 method, wherein said antibiotic comprises ciprofloxacin, and is given with treatment or prevention middle ear infection.

11. the method for claim 8 or 9, wherein said antibiotic comprises ofloxacin, and is given with treatment or prevention middle ear infection.

12. according to Claim 8 or 9 method, wherein said antibiotic comprises the different  azoles of sulfanilamide dimethyl, and is given with treatment or prevention middle ear infection.

13. according to Claim 8 or 9 method, wherein said antibiotic comprises the amoxicillin, and is given with treatment or prevention middle ear infection.

14. according to Claim 8 or 9 method, wherein said antibiotic is provided with the concentration of the 0.3%w/w of compositions.

15. according to the process of claim 1 wherein that described medicine is an antiviral agents.

16. according to the method for claim 2, wherein said medicine is an antiviral agents.

17. according to the method for claim 16 or 17, wherein said antiviral agents is an acyclovir.

18., also comprise giving pain, infection or the inflammation of medicine with the treatment external ear according to the method for claim 1 or 2.

19. according to the method for claim 19, the described medicine of wherein treating pain, infection or the inflammation of described external ear is provided in the lipid vesicle of stereoscopic stable.

20. according to the method for claim 20, the lipid vesicle of wherein said stereoscopic stable is liposome.

21. according to the method for claim 22, wherein said liposome is stable with cholesterol.

22. according to the method for claim 19, wherein said medicine is selected from celecoxib, naproxen, indomethacin, ketoprofen, glucamine, methanesulfonylmethawithin, pregnenolone, S-adenosylmethionine, and wherein any two or more combination.

23. according to the method for claim 20, wherein said medicine is selected from celecoxib, naproxen, indomethacin, ketoprofen, glucamine, methanesulfonylmethawithin, pregnenolone, S-adenosylmethionine, and wherein any two or more combination.

24., wherein saidly be applied to tympanum in the acute stage of middle ear infection through the membrane carrier compositions according to the method for claim 1 or claim 2.