WO2003055410A2 - Composition and method for treatment of otitis externa - Google Patents
Composition and method for treatment of otitis externa Download PDFInfo
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- WO2003055410A2 WO2003055410A2 PCT/US2002/038367 US0238367W WO03055410A2 WO 2003055410 A2 WO2003055410 A2 WO 2003055410A2 US 0238367 W US0238367 W US 0238367W WO 03055410 A2 WO03055410 A2 WO 03055410A2
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0046—Ear
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Definitions
- the present invention relates to the field of pharmacological compositions and methods of utilizing such compositions to both treat and prevent the occurrence of otitis externa. More specifically, the present invention relates to a means of forming a barrier upon the epithelial lining of the outer ear canal so as to prevent the alkalization thereof or the introduction of bacteria therewithin while also providing a means of distributing and delivering therapeutically active agents, effective in the treatment of otitis externa, to the epithelial lining of said canal.
- Pathological conditions can arise from, and can cause changes in surface tension values of air/liquid interfaces resident upon tissue surfaces, especially epithelial surface tissues, of and within various organs of mammalian anatomy.
- the naturally occurring "surfactant system" secreted upon the epithelial lining of the lung which is deficient in cases of R.D.S. is known to be comprised of a complex mixture of lipids, proteins and carbohydrates (as described in: Surfactants and the Lining of the Lung, The John Hopkinds University Press, Baltimore, 1988).
- the prime function of the surfactant system is to stabilize the alveoli and associated small airways against collapse by decreasing the surface tension at the air/liquid interface. It is now believed that the action of the phospholipid component of the surfactant system is the principal source of the powerful surface tension reduction effect of the naturally occurring surfactant system of the lung. More specifically, it is known that the fully saturated diacylphospholipids, principally dipalmitoyl phosphatidylcholine (DPPC), provide liquid balance and anti-collapse properties to the lung's epithelial lining and alveoli. In addition to DPPC, spreading agents, also found within the naturally occurring surfactant system, assist DPPC in rapidly forming a uniform spread film on the air/liquid surfaces of the lung.
- DPPC dipalmitoyl phosphatidylcholine
- Such spreading agents include cholesteryl esters such as, for example, cholesteryl palmitate (CP); phospholipids such as, for example, diacylophosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS), diacylphosphatidylinositols (PI), sphingomelin (Sph) and Cardiolipin (Card) and virtually and other phospholipid, and the lysophospholipids; or any of the plasmalogens, dialklylphospholipids, phosphonolipids; carbohydrates and proteins, such as, for example, albumin, pulmonary surfactant proteins A, B, C and D.
- cholesteryl esters such as, for example, cholesteryl palmitate (CP)
- phospholipids such as, for example, diacylophosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacyl
- DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure in order to restore deficient or low levels of natural surfactant.
- DPPC has been administered by means of an aqueous aerosol generator (utilized with an incubator in which the infant resided during treatment). Endotracheal administration has also been utilized.
- DPPC therapy has been typified as utilizing natural surfactants (harvested from porcine or bovine lungs), or artificial, commercially synthesized compounds.
- U.S. Patent No. 5,306,483 discloses a process to prepare lipid crystalline figures in fluorocarbon propellants for the delivery of therapeutically active substances which form amorphous fluids on delivery at the air/liquid interface of the lung and which can be utilized as an effective drug delivery system.
- said patent discloses a process comprising (a) preparing a mixture of one or more lipids of the group of phospholipids known as phosphatidylcholines and one or more spreading agents, in powder form and a therapeutically active substance and one or more fluorocarbon propellants, said lipids, spreading agents and therapeutically active substances being insoluble in the propellants; and (b) evaporating the propellants from the mixture.
- dipalmitoyl phosphatidylcholine or any of the other fully saturated Acyl chain phospholipids, 80.0 to 99.5% by weight
- other spreading agents for example, phospholipids such as, but not limited to PG, PE, PS, PI, lysophospholipids, plasmalogens, dialkylphospholipids, diether phosphonolipids, Cardiolipin, sphingomyelin, 0.5 to 20.0% weight; neutral lipids like cholesteryl esters such as, but not limited to, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate, 0.5 to 10% by weight, carbohydrates, such as, but not limited to, glucose, fructose, galactose, pneumogalactan, dextrose, 0.5 to 10% by weight; and proteins such as, but not limited to albumin, pulmonary surfactant specific proteins A, B, C, and D 0.5 to
- phospholipids such as, but not limited to PG
- the spreading agents referred to in the '483 patent are compounds such as the above-described phospholipids, lysophospholipids, plasmalogens, dialklyphospholipids, phosphonolipids, carbohydrates and proteins.
- the function of the spreading agent is to assist DPPC, or other phospholipids such as, for example, DPPG, in rapidly adsorbing and forming a spread film upon the air/liquid surfaces of the lungs.
- the '483 patent also discloses a process for preparing such lipid crystalline figures in fluorocarbon propellants without a therapeutically active substance for use as a tear (as for the eye).
- the outer ear canal or, as it is also known, the external auditory canal, is lined with epithelium. It is susceptible to the same type of skin diseases as effect skin in other parts of the mammalian anatomy, including, for example, eczema and psoriasis. Glands within the canal secrete a waxy exudate known as cerumen which aids in trapping air born debris as well as acidifying the epithelial surface. Such acidification, in turn, minimizes the overgrowth of bacteria. However, upon exposure to copious amounts of exogenous water such as, for instance, during swimming, the epithelial lining may become more alkaline, leading to an increased growth and over-growth in bacteria.
- the cerumen exudate normally secreted upon the epithelial tissue lining the external auditory canal, imparts a particularly high surface tension thereto which is useful in preventing foreign matter from reaching the tympanic membrane and effecting the middle and inner ear.
- Inflammatory by-products discussed in greater detail below, can further increase such surface tension.
- Increased surface tension is an important factor in both the symptoms and treatment of otitis externa.
- the epithelial wall lining the outer ear canal exhibits greater than usual surface tension during otitis externa due to the secretion thereupon of proteinaceous inflammatory waste material resulting from the lysis, phagocytosis and necrosis of antigenic material.
- cerumen production increases in response to inflammation of the epithelial lining of the external auditory canal.
- This material is highly viscous in nature.
- the epithelium may become extremely swollen thereby causing proximal and/or opposing walls of the auditory canal to come into close approximation of one another.
- the high surface tension thereof may cause the adhesion of such opposing and/or proximal walls so as to completely close off the external auditory canal.
- the closure of the external auditory canal is highly problematic in that both the treatment as well as the symptoms of otitis externa are negatively effected since such closure: i. blocks the transmission of sound to the middle ear; ii may result in painful increased pressure against the ear drum; and iii. inhibits and resists the application of medicine -through the external auditory meatus- to the effected tissues.
- the afore-mentioned increased surface tensions resident upon the epithelial lining of the outer ear canal tends to inhibit uniform and/or effective application of therapeutic agents effective in the treatment of the inflammatory condition as well as such agents effective in treatment of the underlying causative antigenic triggers.
- antigenic material can induce, through the inflammatory response, a marked increase in cerumen secretion from the epithelial lining of the outer ear canal.
- the inflammatory response to increased quantities of antigenic material quite often results in increased permeability of capillaries located close to the epithelial lining.
- Such increased permeability results in a localized edema or swelling of the epithelial lining of the external ear canal discussed above.
- Such edema is the direct result, in part, of various components of blood seeping into the interstitial epithelial spaces including migration of antibody laden white cells therein where pmns may complex with the antigenic trigger of the inflammatory reaction.
- a substantial quantity of the resulting waste material is often excreted onto the epithelial lining of the cerumen covered external auditory canal wherein said material, highly viscous in nature, greatly elevates there surface tension of the epithelial lining.
- the out ear canal is filled with water.
- the effect of the water upon the normally acidic epithelial lining of the external auditory canal, is to overcome the bacteriostatic low ph conditions provided by healthy cerumen production, and cause alkalinization. Rising ph level of the outer canal allow bacteria, such as, for example species of staphylococcus, streptococcus and pseudomonas to multiply, overwhelm, and invade the epithelium.
- Water exposure may also act as a vector in introducing toxic and/or irritating chemicals into the ear canal wherein such chemicals act as antigens and/or break down the integrity of the epithelial lining of the external canal and allow bacterial, fungal and other microbial agents into the epithelial tissue.
- the antigenic proteins of such bacteria -or in other cases, fungal, viral or other antigenic material- may come into contact with macrophages present in such tissue.
- macrophages may induce an initial immune response by presenting such antigenic material to T-lymphocytes such as, for example, a CD4+ T lymphocyte.
- T-lymphocytes such as, for example, a CD4+ T lymphocyte.
- CD4+ lymphocytes respond, in part, by releasing a multitude of interleukins and cytokines which, in turn, promote the production of increased quantities of cerumen.
- lymphocyte leads to a cascade of inflammatory activity wherein pmns, with activated antibody, leach out of capillaries which have been made permeable thereto by histamine, into the epithelium wherein they complex with antigen for phagcytotic, lytic and macrophagic activities.
- the release of arachidonic acid from such activated mast cells, macrophages and pmns may lead to, for example, the production of luekotrienes.
- Luekotrienes have inflammatory effects similar to histamine. However, luekotrienes effect such chemotaxis and enhanced mucous production to a far greater degree than histamine.
- otitis externa has been treated with the topical application of therapeutic agents demonstrating antimicrobial activity as well as anti-inflammatory action.
- Broad spectrum topically effective antibiotic otic suspensions containing antibacterial agents such as, for example, neomycin sulfate, colistin sulfate, polymyxin b, or combinations thereof, all broad spectrum in effect, have been utilized to destroy causative bacteria.
- Anti-mycotic topically acting agents such as, for example, nystatin and clotrimazole have been employed to destroy underlying fungal disease.
- Anti-inflammatory agents often included in the above-identified topically acting suspensions, have been employed to control the inflammatory process of otits externa including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate.
- the above-described therapeutically active agents are utilized in combination to treat both the causative, triggering disorder, e.g. bacterial infection, as well as the inflammatory process itself. They are also most often utilized in drop form for topical administration to the effected ear.
- wicks comprised of absorbent material such as, for example, cotton, are utilized to draw the suspensions into the ear canal for as complete an administration as possible.
- absorbent material such as, for example, cotton
- compositions, process and method for providing a barrier upon the epithelial lining of the external auditory canal so as to protect same from the above-described deleterious effects of water and water-born toxins, irritants and antigenic materials. If would be further advantageous if such a composition, process and method was provided so as to decrease the high surface tensions associated with otitis externa so as to promote external auditory canal patency. It would be still further advantageous if a composition and method were provided for delivering therapeutically active agents, effective in the treatment of otitis externa, throughout the epithelial lining of the outer ear while simultaneously reducing the surface tension thereof .
- a composition, process and method of preventing otitis externa wherein a mixture of aerosolized lipid crystals are administered to the epithelial lining of the external auditory canal whereupon said mixture of crystals forms, on contact, a liquid barrier so as to prevent contact of said epithelial lining with exogenous fluids while simultaneously reducing the surface tension of the air/liquid interface resident thereupon.
- the propellant is selected to be one in which the one or more lipid surfactants and one or more spreading agents are not soluble so as to enable, in part, the formation of the below-described lipid crystals.
- fluorocarbon propellants may be advantageously selected.
- the lipids and the spreading agents are likewise advantageously selected to be insoluble in the propellants.
- the lipid surfactants utilized in practicing the present invention are selected to be present in said mixture in an amount sufficient to effectively reduce the surface tension of the liquid/air interface of the epithelial lining of the outer ear canal to which they are applied, while the spreading agents are selected to be present in an amount sufficient to effectively distribute the lipid surfactants upon said interface.
- the term, "effectively distribute the lipids upon said surface” refers to that weight percentage range of spreading agent that is required in order to provide adequate spreading and distribution of the lipids upon the interface resident upon the epithelial lining of the external auditory canal so as to form, in conjunction with the lipid surfactant, an amorphous spread film thereupon and thereby facilitate the afore-mentioned reduction of surface tension provided by the surfactant.
- the lipid surfactants utilized in practicing the method of the present invention are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of the mixture.
- Combination of the one or more lipids, one or more spreading agents and one or more propellants results in the formation of aerosolized lipid crystals as described in more detail, below.
- a metered dose of the mixture of lipid crystals is then administered, via and aerosol dispenser, to the external auditory of a mammal upon which the present method is practiced.
- An otic administration adaptor may be advantageously selected for such administration.
- the propellant(s) are evaporated from an aerosolized mixture of lipid crystals which are then deposited upon the air/liquid interface resident upon the epithelial lining of the external auditory canal whereupon said lipid crystals form an amorphous spread film thereupon so as to effectively decrease the surface tension thereof as well as to form a barrier against exogenous fluids such as, for example, water.
- the lipid crystals deposited upon the epithelial surfaces lining the external auditory canal and the air/liquid interface thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity.
- the spreading agent combined therewith provide thorough distribution, throughout the external auditory canal, of the surfactant over and upon the air/liquid surface resident upon said lining.
- the decrease in surface tension afforded thereby tends to separate proximal and opposing epithelial walls of the external auditory canal adherent, one upon the other, so as to increase patency of said conduit and promote sound conduction therethrough when such walls are, prior to such administration, in such contact.
- said decrease in surface tension also minimizes and, in some instances, releases fluids locked within the canal due to high surface tension therewithin which might otherwise also serve to occlude, or partially occlude the external auditory canal.
- Administration of the aerosolized lipid crystals through the external auditory meatus results in deposition of said crystals upon the epithelial lining of the external auditory canal without need for the use of conduction devices such as, for example, wicks.
- a method of administering therapeutically active agents effective in the treatment of otitis externa including both agents effective in treatment of inflammation as well as those agents effective in the treatment of the agents causative thereof -directly to the effected epithelial lining- as well as a process for preparing otitis externa medicaments is disclosed.
- a mixture of one or more lipids, one or more spreading agents, one or more therapeutically active agent(s), effective in the treatment of otitis externa, and/or the underlying cause thereof, and one or more propellants -in which said lipid surfactant, spreading agent and therapeutically active agents are not soluble- is prepared.
- the one or more lipids and spreading agents are advantageously selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins.
- the one or more lipids, spreading agents, and therapeutically active agent(s) are advantageously selected to be in powder form.
- the propellants are selected so that the lipids, spreading agents and therapeutic agents are insoluble therein.
- the lipid surfactants utilized in practicing the method of the second preferred embodiment of the present invention are selected to be present in an amount sufficient to effectively reduce the surface tension of the liquid/air interface of the epithelial lining to which they are applied, while the spreading agents are present in an amount_sufficient to effectively distribute the lipids and forms an amorphous spread film upon said surface.
- the above-described clinically significant decrease in external auditory canal surface tension, formation of an amorphous spread film and delivery of therapeutically active agent can be effected by a mixture comprised of from about 99.99 to about 30 weight percent lipid surfactant and from about 70 to about 0.01 spreading agent.
- lipid surfactants are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of said mixture.
- the mixture resulting from the combination of lipid surfactant(s) spreading agent(s) and therapeutically active agent(s) and propellant forms lipid crystals which act as carriers for said therapeutically active agent.
- a metered dose of the mixture of aerosolized lipid crystals is then administered directly into the external auditory canal of a mammal upon which the method is practiced.
- a suitable bottle equipped with a metered dose valve and otic administration adaptor is advantageously utilized for this purpose.
- the propellants Upon administration of the lipid crystal mixture, the propellants carry the lipid crystals in combination with therapeutically active agent(s) effective in the treatment of inflammation as well as those agents effective in the treatment of the underlying causes thereof directly to and upon the epithelial lining of the external auditory canal.
- the lipid crystals and therapeutically active agent(s) are then deposited upon said epithelial tissue lining whereupon the mixture forms an amorphous spread film effectively carrying said therapeutically active agent effective in the treatment of the inflammation characteristic of otitis externa and/or the underlying cause thereof, therethrough and thereupon.
- the propellants carry the lipid crystals in combination with therapeutically active agent(s) effective in the treatment of inflammation as well as those agents effective in the treatment of the underlying causes thereof directly to, and upon, the epithelial lining of the external auditory canal.
- the lipid crystals and therapeutically active agent(s) are then deposited upon said epithelial tissue lining whereupon the mixture forms an amorphous spread film effectively carrying said therapeutically active agent effective in the treatment of the inflammation characteristic of otitis externa and/or the underlying cause thereof, therethrough and thereupon.
- the therapeutically active agent is advantageously selected to be effective in the treatment of otitis externa as well as agents effective in the treatment of the underlying causes thereof provoking said immune responses leading to the above-described inflammatory responses.
- agents may be selected to be effective in the treatment of mycotic, viral or bacterial infections, (as well as combinations thereof) underlying and causative of said inflammatory reactions.
- the second preferred method of the present invention provides a method of administering therapeutically active agents directly to the epithelial lining of the external auditory canal wherein said therapeutically active agents provide effective treatment for the subject inflammatory condition such as, for example edema -as well as the underlying causes thereof— while, simultaneously, the mixture of lipid crystals act to directly and effectively decrease the surface tension of cerumen and, especially in instances of purulent otitis externa, the viscous mucous exudate thereupon.
- a method of administering therapeutically active agents effective in the treatment of otitis externa directly to the epithelial lining of the external auditory canal -including both agents effective in treatment of inflammation as well as those agents effective in the treatment of the agents causative thereof- while simultaneously decreasing the surface tension of an air/liquid interface resident thereupon is disclosed. Also disclosed is a process for preparing an otitis externa medicament to effect the afore- mentioned functions.
- lipid surfactants in practicing the method and process of the first alternate embodiment of the present invention, a mixture of one or more lipid surfactants, one or more therapeutically active agent(s), effective in the treatment of otitis externa, and/or the underlying cause thereof, and one or more propellants -in which said lipid surfactant and therapeutically active agents are not soluble- is prepared.
- the lipid surfactant is selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins.
- the therapeutic agent may be selected from any of the afore or below-mentioned therapeutically active agents so as to provide desired therapeutic effects (regarding treatment of inflammatory conditions and the causative agents thereof).
- the mixture of lipids is comprised of a lipid surfactant and a therapeutic agent and the lipid surfactant and therapeutic agent are selected to be present in the same weight ratios as those described above and below in regards to those embodiments incorporating surfactant/spreading agent components -the therapeutic agent being present in the same respective weight percentage range as the spreading agent in such embodiments.
- an effective result may be provided by a mixture comprised of from about 99.99 to about 30 weight percent lipid surfactant and from about 70 to about 0.01 therapeutic agent.
- Increased effectiveness is provided by a preferred mixture comprised of from about 99.99 to about 50 weight percent lipid surfactant and from about 50 to about 0.01 weight percent therapeutically active, both based on total weight of the mixture.
- it is still further preferred said mixture may be comprised of from about 80 to about 99.5 weight percent lipid surfactant and from about 20 to about .5 weight percent therapeutically active agent, based upon total weight of said mixture.
- the therapeutically active agent may be selected as a pharmacologic agent which, in addition, is also selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins.
- the therapeutically active agent acts in accordance with its own pharmacologic function, as well as providing spreading agent function.
- the therapeutic agent is selected to be present within the above-described weight ranges and in an amount sufficient to treat the aforementioned inflammatory condition and/or causative agents.
- the remainder of the mixture is comprised of one or more of the above-described lipid surfactants which act to reduce the surface tension of the liquid/air interface of the epithelial lining to which the mixture of lipid crystals is applied, while the therapeutically active agent provides treatment of the inflammatory condition effecting the external auditory canal, and/or the causative agents thereof.
- the propellant Upon evaporation of the propellant, an aerosolized mixture of lipid crystals is formed.
- the lipid crystal Upon administration of the mixture of lipid crystals and therapeutic agent to the external auditory canal via, for example, a metered dose bottle, the lipid crystal come into contact, and form an amorphous spread film upon the external auditory canal.
- the surfactant spread film reduces the surface tension of the canal while simultaneously delivering the therapeutic agent thereto.
- agents may be carried by means of the lipid crystals to the external auditory canal.
- agents are contemplated to be antibiotics, antiviral agents, anti-inflammatory agents (steroid and non-steroid) anti- histamines and decongestants as well as combinations thereof.
- agents are also contemplated to include gene therapy modalities including, for example, nucelic acids and vectors thereof.
- the lipid surfactants utilized in practicing the method of the present invention may be advantageously selected to be phospholipids, neutral lipids or mixtures thereof.
- the phospholipids utilized may be further advantageously selected to be any phospholipid of the class known as phosphatidlycholine including any fully saturated diacyl phosphatidlycholine including 1 ,2 dipalmitoyl phosphatidylcholine
- DPPC diacylphosphatidylglycerol
- a diacylphosphatidylethanolamine a diacylphosphatidylserine
- a diacylphosphatidylinositol sphingomyelin, Cardiolipin, lysophospholipid; a plasmalogen; a diether phosphonolipid; or a dialklyphospholipid.
- the lipids utilized in practicing the method and process of the present invention may also be advantageously selected to be either plant or animal sterols.
- cholesterol may be selected.
- fatty acids such as, for example, palmitic acid and oleic acid may also be selected.
- cholesteryl esters utilized in practicing the method and process of the present invention may be advantageously selected to be, for example, cholesteryl palmitate, cholesteryl oleate or cholesteryl stearate.
- Carbohydrates utilized in the present invention may be advantageously selected to be, for example, glucose, fructose, galactose, pneumogalactan, or dextrose.
- Proteins especially suited and advantageously selected for use in the present invention include albumin, pulmonary surfactant specific proteins A or B or C or D, their synthetic analogs, and mixtures thereof.
- the propellants may be advantageously selected to be a fluorocarbon such as, for example, chlorofluorocarbon propellants, hydrofluorocarbons or mixtures thereof.
- the present invention contemplates carbon dioxide as a suitable propellant.
- the present invention contemplates the use of carbon dioxide as a propellant as a suitable propellant.
- the present invention may incorporate and select any pharmaceutical grade, hypo-allergenic propellant in which the other components of the mixture are not soluble -the propellant, lipids, spreading agents and therapeutically active agents must be selected so none of the afore-mentioned surfactants, spreading agents or therapeutically active agents are soluble, and thus dissolved, within the propellant.
- the propellant is thus selected in order to enable the formation of the aerosolized mixture of lipid crystals, discussed below.
- the mixture is advantageously prepared to yield crystalline forms that demonstrate a particle size equal to or less than 16 microns in diameter.
- the diminutive nature of the crystalline particles is, as discussed in detail below, highly advantageous in enabling dispersion and application of the aerosolized mixture.
- therapeutically active agent includes any substance which is capable of altering a biologic, physiologic and/or immunologic function, in nature or degree and includes those substances generally referred to as pharmacologic agents and drugs, including gene therapy agents and the vectors thereof, in order to provide treatment of the symptoms or underlying causes of the subject inflammation;
- propellant includes all those non-toxic as well as hypo-allergenic propellants in which the afore-mentioned surfactants, spreading agents and therapeutic agents are not soluble such as, for example, "fluorocarbons,” and carbon dioxide.
- flurocarbons includes the class of both chlorofluorocarbons and hydrofluorocarbons
- lipids includes the class of phospholipids including, but not limited to PC, PG, PE, PI and Cardiolipin
- spreading agent(s) refer to and includes PG, PE, PS, PI, Sph., Card., lysophospholipids, plasmalogens, dialkylphospholipids, and all others in the class phospholipid as well as cholesteryl esters (like CP), proteins, and carbohydrates.
- the phrase "spreading agent(s)" refers to compounds, as listed above, which assist the one or more lipid such as, for example, DPPC, in rapidly adsorbing and forming an amorphous spread film on air/liquid interfaces such as that found upon the epithelial lined lumen of the external auditory canal.
- the compounds referred to as “spreading agent(s)" together with the one or more lipids, are responsible for achieving and maintaining biophysical properties including, but not limited to, reduction of intermolecular attractive forces, surface tension, and the resultant attractive forces generated thereby, that tend to cause opposed surfaces, such as proximal and opposing epithelial lined walls of the external auditory canal, to adhere to each other.
- a major lipid component utilized in practicing a preferred embodiment of the present invention may advantageously be selected to be phospholipid 1 ,2 dipalmitoyl, phosphatidlycholine (DPPC).
- DPPC is the most surface active of the phospholipids or any of the subclass of fully saturated acyl chain phospholipids. That is to say that DPPC, in combination with any spreading agent(s) disclosed herein, has a maximum effect in reducing surface tension at an air/liquid interface.
- Another, minor lipid component that also acts as a spreading agent for the major component is advantageously selected to be diacylphosphatidylglycerol (PG).
- PG diacylphosphatidylglycerol
- DPPC and PG can be synthesized. However, since DPPC and PG are the main phospholipid constituents of cells, they are also readily extractable from such cells by non-polar solvents, i.e., chloroform, ether, acetone. DPPC's structural formula is: 0
- Phospholipids such as DPPC and CP may be obtained commercially, in a highly purified form from Fluka Chemical Co. of Ronkonkoma, N.Y.; Sigma Chemical CO. of
- DPPC and PG are preferred component(s) which may be advantageously utilized in the present inventions methods for administering therapeutically active agents to the external auditory canal.
- these lipids increase the patency of the auditory canal by direct action of their surfactant qualities.
- the constituents may be selected to be present in the composition over a fairly wide range of from 99.99 to about 30 weight percent DPPC and from about 70 to about 0.01 PG based upon total weight of the mixture. Increased effectiveness is provided by a preferred mixture comprised of from about 99.99 to about 50 weight percent DPPC and from about 50 to about 0.01 weight percent PG, both based on total weight of the mixture. However, it is still further preferred that weight percentages of from about 80% to about 99.5% DPPC and 20% to 0.5% PG be selected.
- the resistance referred to results from: reduction of the volume, partial obstruction, or complete occlusion of the external auditory canal due to swelling of the epithelial walls thereof as the result of inflammation; reduction of the volume, partial obstruction or complete obstruction of said air ways and air spaces due to the accumulation of increased amounts of cerumen secreted thereupon; and reduction of the volume, partial obstruction or complete obstruction of said outer air canal due to the collection of fluids therewithin -including fluids containing the waste products of the immune response or exogenous water-.
- the aerosolized mixture of lipid crystals does not include, or act as a carrier for, a therapeutically active agent(s)
- the above-described reduction in obstruction of the external auditory canal is brought about by the separation of proximal and or opposing epithelial surfaces lining the canal and collection of fluids there between by means of decreasing the surface tension thereupon.
- proximal epithelial surfaces lining the external auditory canal and “proximal epithelial surfaces lining the external auditory canal” and “opposing epithelial walls” as utilized throughout this specification and throughout the claims, refers to portions of the epithelial surface lining the outer auditory canal that, due to close proximity and/or opposition to each other, may come into contact as the result of, for example, epithelial or sub-epithelial edema, excess surface secretion of cerumen, inflammatory waste products or a combination thereof; high surface tension or any combination thereof.
- proximal walls of epithelial lining of the outer ear canal that are adherent to each other are separated and opened by means of both lipid crystal mediated reduction of surface tension and, upon action of said anti- inflammatory, reduction of edema, reduction of cerumen, and decrease in the viscous nature thereof.
- Another lipid that can be utilized in practicing the methods of the present invention is cholesteryl palmitate( CP), which also serves as a spreading agent.
- This cholesteryl ester is a neutral lipid which belongs to a class of organic compounds that are also cell constituents and are extractable by non-polar solvents such as chloroform, methanol, ether, etc.
- the structural formula of CP is:
- CP may be obtained commercially in a highly purified form from Fluka Chemical Co. and Sigma Chemical Co and Primedica.
- the CP component constitutes a minor portion of the composition.
- CP is selected to be present in a weight percentage sufficient so as to enable effective spread and distribution of the lipid upon the mucosal surfaces.
- the constituents may be selected to be present in the composition over a fairly wide range of from 99.99 to about 30 weight percent DPPC and from about 70 to about 0.01 CP based upon total weight of the mixture.
- Increased effectiveness is provided by a preferred mixture comprised of from about 99.99 to about 50 weight percent DPPC and from about 50 to about 0.01 weight percent CP, both based on total weight of the mixture.
- the CP component be selected to be present in an amount ranging from about 0.5% to 20% by weight and DPPC be selected to be present from about 99.5% to about 80%, based upon the total weight of the mixture.
- otitis externa refers to those drugs effective in direct treatment of the above-described inflammatory response,' as well as those drugs effective in the treatment of the underlying or precipitating cause of such inflammation.
- a therapeutically active agent may be selected for its particular effectiveness against viral, protozoic, bacterial, fungal and/or parasitic organisms.
- such therapeutic effective agents may be selected for direct effect upon inflammation as there is no precipitating organism responsible for said condition.
- the present invention contemplates embodiments which include as a therapeutic agent, singly or in combination: drugs effective in the direct treatment of inflammation such as, for example, corticosteroids including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, betamethasone, betamethasone dipropionate and betamethasone valerate as well as all other effective formulations.
- drugs effective in the direct treatment of inflammation such as, for example, corticosteroids including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, betamethasone, betamethasone dipropionate and betamethasone valerate as well as all other effective formulations.
- embodiments of the present invention include, as a therapeutically active agent, anti-viral agents such as, for example zovirax; antibiotics including, for example, neomycin sulfate, colistin sulfate, polymyxin b, and anti-mycotic preparations such as nystatin and clotrimazole. It is further contemplated that certain embodiments of the present invention include combinations of anti-inflammatory agents and anti-microbial agents, the inclusion of a single or multiple antibiotic being determined by the sensitivity of an identified a causative underlying micro organism, as determined by culture and sensitivity studies.
- anti-viral agents such as, for example zovirax
- antibiotics including, for example, neomycin sulfate, colistin sulfate, polymyxin b, and anti-mycotic preparations such as nystatin and clotrimazole.
- anti-viral agents such as, for example zovirax
- antibiotics including, for example,
- therapeutically active agent also refers to gene therapy agents.
- gene therapy agents refers to a biochemical substance -as well as vectors thereof- selected from the group including, but not limited to, proteins, peptides or amino acids; nucleic acids such as DNA, including full length genes or fragments thereof derived from genomic, cDNA, or artificial coding sequences, gene regulatory elements, RNA including mRNA, tRNA, ribosomal RNA, ribozymes and anitsense RNA, oligonucleotides, oligoribonucleotides, deoxyribonucleotides and ribonucleotides as such agents may exist as isolated and purified compounds or in unpurified mixtures, such as tissue, cell or cell lysate.
- agents may be naturally occurring, synthetic, or a mixture thereof.
- effective formulations refers to those specific species of a particular therapeutic agent effective in the treatment of the above-described inflammation and/or underlying causative agent.
- carrier when said combination is mixed with a therapeutically active agent so as to act as a carrier therefore.
- carrier when practicing the method of the present invention wherein therapeutically active agents are administered directly to the epithelial lining of the external auditory canal, it is preferred that carrier, the mixture of one or more lipids and one or more spreading agents, be comprised of a mixture of DPPC and CP in a. 200:1 ratio (by weight). However, it has been found that a ratio range of from 5:1 to 300:1 (DPPC/CP) will also produce an effective carrier for this particular embodiment.
- the weight ratio of betamethasone to carrier is advantageously selected to be 1 microgram betamethasone to 5 milligrams carrier.
- a weight ratio range of 0.5 to 1000 micrograms betamethasone/5 milligrams carrier yields an effective and functional mixture.
- the therapeutically active agent may also act as the spreading agent component.
- the therapeutically active agent is selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins.
- the surfactant component/therapeutically active agent are selected to be present in the same respective weight ratio ranges as discussed above in regards to surfactant/spreading agent.
- the therapeutically active agent is selected to be hydrocortisone acetate it is preferred to select the weight ratio of hydrocortisone to carrier to be 1.0 milligram/4.0 milligrams. However, it has also been found that a weight ratio range of from 0.005 to 1.5 milligrams (hydrocortisone) : 4.995 to 3.5 milligrams carrier, respectively, forms an effective mixture and functional mixture.
- the ratio of neomycin to carrier may be advantageously selected to be 0.4 mg antibiotic to 4.6 mg carrier (DPPC/CP) by weight.
- DPPC/CP antibiotic to 4.6 mg carrier
- Fluorocarbon propellants are utilized in practicing the method of the present invention, namely: trichlorodifluoromethane, dichlorodifluoromethane, and tetrafluoromethane or mixtures thereof, which are commercially available from Union Carbide Corp., Danbury, Conn, and Armstrong Laboratories, West Roxbury Mass. are advantageously selected for formation of the lipid crystalline figures of the present invention.
- the fluorocarbon propellants may be advantageously selected to be present over a range of 2 to 30 times the amount, by weight, of lipid, but components of lipid and propellants both are needed in order to obtain the required lipid crystalline figures.
- DPPC is advantageously selected as the major lipid component since the amphoteric nature of this phospholipid allows the molecule to act as a carrier for any drug or therapeutic agent.
- a charge on other lipid components a negative charge on PG, for example
- Example 1 Because of the highly amphoteric nature of the carrier utilized herein, the use of any presently known and available, as well as anti-viral, antibiotic or gene therapy agent developed in the future capable of providing effective treatment of infections of the external auditory canal and tympanic membrane are contemplated and fully functional with the methods and compositions herein.
- Example 1 Because of the highly amphoteric nature of the carrier utilized herein, the use of any presently known and available, as well as anti-viral, antibiotic or gene therapy agent developed in the future capable of providing effective treatment of infections of the external auditory canal and tympanic membrane are contemplated and fully functional with the methods and compositions herein.
- Example 1 Example 1
- the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC and CP. Both materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses. Specifically, the DPPC and CP were purchased from Sigma Chem., St Louis, Mo. All purchased materials were checked for purity by standard chromatographic analysis. The hydrocortisone acetate utilized in this example was also purchased from Sigma Chemical. The DPPC and CP were then mixed in the dry powder form in a weight ratio of 200:1 (DPPC:CP). To 4 milligrams of the resultant carrier, 1 milligram of hydrocortisone acetate was added in order to yield a weight ratio of 4:1 (carrier: hydrocortisone acetate).
- a pellicle forms on top of the propellants but is easily re-suspended by gentle shaking.
- the size of the metering valve can be varied to deliver from 1 mg up to 5.4 mg of the DPPC:CP: hydrocortisone acetate aerosolized mixture.
- metered dose valves having a greater dosing range are also contemplated and can be utilized in other embodiments of the present invention.
- the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC and CP. Both materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses. Specifically, the DPPC and CP were purchased from Sigma Chem., St Louis, Mo. The neomycin sulphate utilized in this example can be purchased from Parke-Davis division of Warner Lambert, Morris Plains, New Jersey. All purchased materials were checked for purity by standard chromatographic analysis. The DPPC and CP were then mixed in the dry powder form in a weight ratio of 200:1 (DPPC:CP).
- the filled bottles were then gently shaken to disperse the solids that are insoluble in the propellants.
- the bottles were immersed in a water bath to test for leaks and then fitted with an administration adapter.
- the suspension was homogenous. After standing at room temperature for about three days, a pellicle forms on top of the propellants but is easily re-suspended by gentle shaking.
- the size of the metering valve can be varied to deliver from 1 mg up to 5.4 mg of the DPPC:CP: neomycin sulphate aerosolized mixture.
- metered dose valves having a greater dosing range are also contemplated and can be advantageously utilized in practicing the methods of the present invention.
- DPPC and CP Chromatographically pure DPPC and CP (99% pure) were obtained from Avanti Polar Lipids Co. of Birmingham, Ala. and Sigma Chemical Co. of St. Louis, MO.
- DPPC and CP were mixed in a weight ratio of 200:1 (DPPC:CP) . Then 5 grams of this mixture was suspended in 55 grams of the first propellant, trichloromonofluoromethane (P11) and subdivided into 30 ml. Wheaton plastic- coated glass bottles with a 20 mm neck finish. Valois metering valves were crimped onto each bottle through which 40 gms of the second propellant, dichlorodifluoromethane (P12), was passed.
- the filled bottles were then gently shaken to disperse the solids that are insoluble in the propellants.
- the bottles were thereafter immersed in a water bath to test for leaks and then fitted with an otic adapter.
- the suspension was homogenous. After standing at room temperature for about three days, a pellicle forms on top of the propellants but was easily re- suspended by gentle shaking.
- the size of the metering valve can be varied to deliver from 1 mg up to 5.4 mg of the DPPC:CP aerosolized mixture.
- Each of the afore-mentioned Examples "I” and “II” are administered by releasing a metered dose of the mixtures, by means of an otic administration adaptor, directly to and throughout the external auditory meatus.
- the aerosolized mixture, propelled by the above-described propellants, is then effectively deposited upon the air/liquid interface resident upon the epithelial lining of the external auditory canal.
- an amorphous spread film layer forms upon the air/liquid interface resident thereupon.
- said mixture of lipid crystals by means of the afore- mentioned surfactant properties, lowers the surface tension of said air/liquid interface so as to allow the afore-mentioned opening of the external auditory canal and elimination of pooled liquid obstructions which may be present thereon.
- Example "I" wherein the therapeutically active agent is the anti-inflammatory hydrocortisone acetate, the agent acts directly upon the inflammatory process occurring within the epithelium of the external auditory canal, reducing the production of the afore-mentioned excess cerumen and viscous inflammatory secretions while also decreasing tissue edema. Both excess secretions and edema act to partially obstruct, or, in some instances, totally occlude the outer ear canal.
- therapeutic agents of anti-inflammatory activity increase auditory canal patency by increasing conduit volume.
- the DPPC and/or DPPC/PG lipids of the present invention act independently of selected therapeutic agent(s) in promoting the opening of the external auditory canal by reduction of the surface tension of the epithelial lining thereof-by reducing the intermolecular and surface charges found at the air/interface of the viscous secretion covered lumen-
- DPPC and/or DPPC/PG lipids of the present invention are able to increase the patency of the external auditory canal independent of the action of any therapeutic agent carried thereby.
- the present invention also contemplates the use of antibiotics such as, for example, neomycin sulphate (Example "II"), nystatin b and colistin sulphate as well as any other antibiotic agent effective in the treatment of the underlying bacterial infection.
- antibiotics such as, for example, neomycin sulphate (Example "II"), nystatin b and colistin sulphate
- both anti-mycotic and anti-viral agents are advantageously employed for treatment of those instances of infective otits externa wherein a fungal or viral infection is the causative factor.
- the DPPC and/or DPPC/PG act to introduce such drugs into the external auditory epithelium in the same manner as described immediately above in regards to anti- inflammatory agents.
- Such anti-biotic, anti-viral and anti mycotic agents act indirectly upon the inflammatory process provoked by the presence of antigenic microbial proteins by acting to reduce or eliminate the presence thereof.
- antigenic challenge of such microbes is reduced by the action of such therapeutic agents, the degree and intensity of inflammation -edema and excess cerumen - is reduced.
- DPPC and DPPC/PG aerosolized mixtures act as carriers for such drugs, they also continue to provide the independent and more expeditiously effect auditory canal patency discussed above by effecting a decrease in surface tension of the air/liquid interface resident thereupon -on contact--.
- Example "III" preparation of an aerosolized mixture of lipid crystals for use in practicing the method of the present invention is disclosed that is advantageously formulated for forming a barrier against exogenous water contacting the epithelial lining of the external ear duct as well as increasing the patency thereof without the use of a therapeutically active agent.
- the aerosolized mixture propelled by the above-described propellants, is deposited upon the air/liquid interface resident upon the epithelial lining of the outer ear canal.
- an amorphous spread film layer is formed thereupon, effectively spreading throughout the eternal auditory canal.
- the increased surface tensions thereof -associated with inflammation and resultant increased cerumen and exudate discussed in great detail above- is substantially reduced.
- the reduction of said surface tension effects an opening of the outer ear canal by releasing adherent or partially adherent proximal and/or opposing epithelial surfaces, lining said conduit- from adhesion, one to another, as well as reducing pooled fluids blocking or partially blocking said outer ear canal.
- no therapeutically active agent is included in the aerosolized mixture or contemplated in this embodiment. Increased patency and release of fluids is provided by means of interaction of the surfactant/spreading agent combination alone.
- embodiments of the present invention not incorporating therapeutically active agents may be preferred so as to control the effects of such inflammation while minimizing systemic effects inherent in the use of many of such agents.
- Particle Size and Gross Configuration Particle size of the aerosolized crystals produced and utilized in practicing the present invention is, as discussed below, important to effective administration.
- the size (diameter) of the lipid crystals were therefore determined utilizing in a cascade impactor. Flow through the impactor was adjusted to be substantially identical to the flow from a nebulizer utilized in practicing the disclosed method. All of the lipid crystals were found to have a diameter equal to or less than 16 microns. The diameter of about 95 percent of the particles were found to be equal to or less than 4 microns in diameter. Of the particles found to be 4 microns or less, half were, in fact, 1 micron in diameter.
- the mean diameter demonstrated by the lipid crystals utilized in the method of the present invention was 1.75+/- .25 microns. Micronization may be advantageously utilized in order to insure reduced particle size. Therefore, the methods of the present invention also contemplate the use of a micronization mill such as, for example, the "DYNO" mill, type KDL, manufactured by Glen Mills Inc., of New Jersey in the preparation of the aerosolized mixture. For example, approximately 13.33 grams of CP and 83 grams of DPPC powder were weighed and transferred to a bead mill within the milling chamber of a DYNO mill (having about 480 cc of glass beads). The chamber was then sealed.
- a micronization mill such as, for example, the "DYNO" mill, type KDL, manufactured by Glen Mills Inc., of New Jersey in the preparation of the aerosolized mixture. For example, approximately 13.33 grams of CP and 83 grams of DPPC powder were weighed and transferred to a bead mill within the milling chamber of a
- HFC-134a 1 liter was added and the system chilled to about -10° C at a pressure of approximately 65 psi. Milling was achieved in about 1 hour. Thereafter, the resultant slurry was utilized to fill15 mil epoxy phenolic lined aluminum cans (Safet Embamet, St. Florantine, France), fitted with Valois metering valves (DFI/ACT/kematal, Valois, Le Neuborg, France with Micron-4 acuators (also Valois). A laser particle sizer, model 2600c, Malvern Instruments, Inc., was thereafter utilized to size the resultant particles as shown in Table "1", below. This data indicates that approximately 90% of the particles emitted fro the valve and actuator system are under 7 ⁇ m or less in diameter.
- the mean diameter is approximately 5 ⁇ m and the mass median aerodynamic diameter (MMAD) is about 3.4 ⁇ m with a geometric standard deviation (GSD) of about 0.5. Particle size results in physically unstable dispersions should change dramatically over a few days of undisturbed storage.
- Structural characteristics of the mixture of lipid crystals utilized in practicing the present invention were further assessed by capturing the aerosolized particles on standard scanning electron microscopic grids fixed to glass slides at 22° C, (dry).
- the lipids deposited on glass both as dry particles and as coalesced droplets. The latter evaporated immediately leaving dry lipid.
- the dry lipids were fixed in osmium vapor (O s 0 4 ), coated and viewed with a scanning electron microscope. Crystalline figures about 100 angstroms thick, were grouped in clumps on the dry surface. This is a unique configuration.
- the mixture of one or more lipids, one or more spreading and one or more propellants disclosed in the present invention is especially formulated and combined to form a unique crystalline structure with physical dimensions highly advantageous to all embodiments.
- the propellants must be selected so that the surfactant and spreading agents are not soluble therein.
- the crystalline structure results in, as discussed above, a mean particle size of 1.75 microns.
- the minute physical dimensions of the individual nebulized particles enables the propellant utilized in practicing the present invention to easily and effectively transfer the disclosed mixture to and throughout the desired target tissue.
- a larger physical configurations such as, for example, a liposome, would not enable such diminutive particle size within and effective physical transport by the propellant.
- the aerosolized mixture of the present invention is crystalline.
- the crystalline nature of the mixture imparts increased efficiency of particle dispersion within the aerosol mist applied by means of a metered-dose nebulizer.
- the fluorocarbon medium either chlorofluorocarbon or hydrofluorocarbon
- vaporizes rapidly and the DPPC/CP, DPPC/CP drug, DPPC/PG drug or DPPC/PG/CP drug dispersion deposits on an aqueous surface at 37°C, initially in the crystalline form, and then, instantaneously, spreads over the surface as an amorphous surface film.
- the drug likewise is effectively spread upon the aqueous surface.
- the surfactant/spreading agent functions and characteristics of the method and composition of the present invention were tested as follows. Aerosolized crystalline figures of the present invention were impacted upon a liquid surface (normal saline solution, NSS) at 37' C, 100% humidity in a surface balance resulted in a rapid .spreading of a principally amorphous film that covered the entire surface (18.1 cm 2 ). Surface tension of the film was measured during expansion and compression at 37° C, 100% humidity. Film expansion to 110.4 cm 2 produced a surface tension of 72 dynes/cm and compression to 18.1 cm 2 lowered surface tension to less than 1 dyne/cm.
- NSS normal saline solution
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Abstract
Description
Claims
Priority Applications (2)
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EP02791351.6A EP1460967B1 (en) | 2001-12-11 | 2002-11-29 | Composition and method for treatment of otitis externa |
ES02791351.6T ES2624447T3 (en) | 2001-12-11 | 2002-11-29 | Composition and method for the treatment of otitis externa |
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US10/011,626 US7064132B2 (en) | 1999-11-28 | 2001-12-11 | Composition and method for treatment of otitis external |
US10/011,626 | 2001-12-11 |
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EP (1) | EP1460967B1 (en) |
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US6676930B2 (en) * | 1999-11-28 | 2004-01-13 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
US20050009931A1 (en) * | 2003-03-20 | 2005-01-13 | Britten Nancy Jean | Dispersible pharmaceutical composition for treatment of mastitis and otic disorders |
US20040214753A1 (en) * | 2003-03-20 | 2004-10-28 | Britten Nancy Jean | Dispersible pharmaceutical composition for treatment of mastitis and otic disorders |
RU2325189C2 (en) * | 2003-03-20 | 2008-05-27 | Фармация Корпорейшн | Method and pharmaceutical composition for antiphlogistic agent delivery |
US20050004098A1 (en) * | 2003-03-20 | 2005-01-06 | Britten Nancy Jean | Dispersible formulation of an anti-inflammatory agent |
US7981104B2 (en) * | 2005-01-25 | 2011-07-19 | Patrick Slater | Method for treating otitis externa |
US8337481B2 (en) | 2005-01-25 | 2012-12-25 | Patrick Slater | Method for treating otitis externa |
US20070173463A1 (en) * | 2006-01-20 | 2007-07-26 | Brechtelsbauer Paul B | Method and composition for treating otitis media |
US8758836B2 (en) * | 2011-09-09 | 2014-06-24 | Nina S. YOSHPE | Method and formulation for treating dry ear inflammation with cortisone |
JP2017529313A (en) * | 2014-08-08 | 2017-10-05 | シンセン ハイタイド バイオファーマシューティカル リミテッド | Liquid pharmaceutical compositions, drug delivery devices, and methods of their preparation and use |
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US5141674A (en) | 1984-03-08 | 1992-08-25 | Phares Pharmaceutical Research N.V. | Methods of preparing pro-liposome dispersions and aerosols |
JPH01258620A (en) | 1988-04-08 | 1989-10-16 | Dai Ichi Seiyaku Co Ltd | Local pharmaceutical for otopathy |
US5174988A (en) * | 1989-07-27 | 1992-12-29 | Scientific Development & Research, Inc. | Phospholipid delivery system |
US5888505A (en) | 1991-02-21 | 1999-03-30 | Eoe, Inc. | Method for selectively inhibiting the growth of microbes using a haloperoxidase-halide-peroxide system |
ES2079994B1 (en) | 1992-10-07 | 1996-08-01 | Cusi Lab | PHARMACEUTICAL FORMULATION BASED ON POLYMIXINE-TRIMETOPRIM AND AN ANTI-INFLAMMATORY AGENT FOR ITS TOPICAL OPHTHALMIC AND ETHICAL USE. |
WO1996039146A1 (en) | 1995-06-06 | 1996-12-12 | Bayer Corporation | Non-irritation, non-sensitizing, non-ototoxic otic antibacterial compositions |
US5843930A (en) | 1995-06-06 | 1998-12-01 | Bayer Corporation | Method of treating otitis with ciprofloxacin-hydrocortisone suspension |
WO1997029738A1 (en) | 1996-02-16 | 1997-08-21 | The Administrators Of The Tulane Educational Fund | Methods and compositions for treating eustachian tube dysfunction by inhalation |
US5954682A (en) | 1996-09-25 | 1999-09-21 | Advanced Medical Instruments | Therapeutic applicator apparatus and method |
JP3892085B2 (en) * | 1996-10-04 | 2007-03-14 | 東興薬品工業株式会社 | Animal ear cream |
US6040463A (en) | 1996-10-07 | 2000-03-21 | Merck & Co., Inc. | Sordarin derivatives |
US6093417A (en) | 1999-01-11 | 2000-07-25 | Advanced Medical Instruments | Composition to treat ear disorders |
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EP1460967A2 (en) | 2004-09-29 |
US7064132B2 (en) | 2006-06-20 |
EP1460967B1 (en) | 2017-02-15 |
US20020076383A1 (en) | 2002-06-20 |
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WO2003055410A3 (en) | 2003-10-16 |
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