Otitis media is a pathological condition common to mammalian species, and most common to children. During episodes of otitis media, fluid accumulates in the middle ear or, as it is also known, the tympanic cavity.
Acute otitis media is a condition in which fluid accumulation in the middle ear is accompanied by signs or symptoms of ear infection (including both viral and bacterial etiologies). Such pathology may exhibit a bulging eardrum accompanied by pain or, in some instances, perforation of the tympanic membrane. Such perforations may also be accompanied by drainage of purulent material. In contrast, otitis media with effusion is typified by fluid accumulation within the tympanic cavity without signs of infection.
Both acute otitis media and otitis media with effusion may cause substantial pain as pressure increases, positively or negatively, within the confines of the tympanic chamber. Antibiotics, steroids, and antibiotics in combination with steroids have been utilized to treat otitis media. Antihistamine/decongestants have also been utilized in the treatment of otitis media with effusion.
The anatomical features of the middle ear define what can be described as a sealed chamber. On its lateral border, the middle ear is effectively isolated from the external auditory meatus (in the absence of a punctured ear drum), by the tympanic membrane. Medially, the middle ear is effectively sealed from the inner ear by a bony wall. The posterior wall of the tympanic cavity communicates with a large, but effectively sealed mastoid antrum. Only the anterior wall of the middle ear contains a passageway for effective communication outside of the tympanic cavity. There, a natural pathway provided by the auditory or, as it is also known, the eustachian tube, provides communication with the nasopharynx.
As stated above, during episodes of acute otitis media, the painful increased middle ear pressure may naturally resolve through a resultant perforation of, and drainage through, the tympanic membrane. However, the increased fluid pressure associated with otitis media with effusion does not resolve via this mechanism. In fact, for those patients suffering otitis media for prolonged periods of time, and especially for those evidencing significant associated hearing loss, myringotomy with the placement of a tympanostomy tube may be indicated as a means of equalizing middle ear pressure and in order to restore normal hearing. Recently, laser surgery has also been utilized to provide an aperture through the tympanic membrane through which the fluid trapped within the middle ear may drain. Besides the perforations of the eardrum provided by infection (acute otitis media), myringotomy and laser surgery, the eustachian tube, a natural middle ear drainage path described above, is provided by mammalian anatomy. Unfortunately, during episodes of otitis media with effusion (OME), a time when the natural pathway and pressure relief functions of the eustachian tube would be most useful, the increase pressure required to open the lumen (as described in more detail above and below), effectively eliminates this means of relieving middle ear pressurization. Reduced patency of the eustachian tube is believed to be one of the primary causes of OME in pediatric patients. In fact, it is known that OME elevates eustachian tube opening pressure independent of other pathological conditions effecting this conduit. The term "opening pressure" as it is utilized throughout this disclosure and within the claims, refers to the pressure, typically measured in millimeters of mercury, necessary to cause the lumen of the auditory tube to open and provide a patent pathway between the nasopharynx and tympanic cavity.
Treatment of otitis media by means of administration of anti-inflammatory agents, antibiotics, decongestants and/or anti-histamines, or combinations thereof, is limited in effectiveness as, in the absence of perforation, there is presently no method for direct application of such drugs directly to target tissues of the eustachian tube and/or middle ear. Systemic applications of drugs via parenteral or oral routes, while eventually reaching the eustachian tube and middle ear, may have adverse systemic effects and, more importantly, are not especially effective at delivering a concentrated dose of the applicable drugs where they are truly needed, directly to the target tissues. Simply put, the sealed chamber anatomy of the middle ear has, up until the present time, constituted a barrier to direct drug application.
Although the central lumen of the eustachian tube does provide a pathway to the tympanic cavity, it is, as described below, ordinarily closed and resistant to fluid passage due to its inherent anatomical configuration. During episodes of otitis media, the relatively high surface tensions present at the air/liquid interface located upon the epithelial lining of the tube lumen further increase the opening pressure required to open this channel. Although direct application of therapeutically active agents, effective in the treatment of otitis media, to the lumen of the eustachian tube, and via the lumen to the middle ear, would be highly advantageous in treating otitis media, no method or composition has yet been disclosed capable of overcoming the surface tension within the tube lumen so as to facilitate opening of the tube and transport of such drugs throughout the lumen and on to the tissues of the middle ear. What is needed is a composition and method of applying same, especially formulated and adapted to decrease the surface tension of the auditory tube so as to decrease the opening pressure thereof thereby providing a patent conduit for therapeutic agents, effective in the treatment of otitis media, to travel through said tube to effectively treat said condition.
Pathological conditions can arise from, and can cause changes in surface tension values of air/liquid interfaces in other 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 a recent review: Surfactants and the Lining of the Lung, The Johns Hopkins 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. 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. 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) as well as and virtually any other phospholipid, as well as any of the lysophospholipids; any of the plasmalogens, dialklylphospholipids, phosphonolipids, carbohydrates; and proteins, such as, for example, albumin, pulmonary surfactant proteins A, B, C and D. The naturally occurring surfactant system is further described in U.S. Pat. No. 5,306,483.
DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure. For this purpose, 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.
It has also heretofore been disclosed to utilize therapeutic agents, in combination with surfactant/spreading agents to effectively administer drug therapy uniformly throughout the epithelial lining of the lung. U.S. Pat. No. 5,306,483 (the "483 patent") 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. More specifically, 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. The '483 patent teaches the combination of dipalmitoyl phosphatidylcholine (DPPC) or any of the other fully saturated Acyl chain phospholipids, 80.0 to 99.5% by weight, and 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 no 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 10% by weight, compounds in lipid-crystalline structures in fluorocarbon (both chloro- and hydrofluorocarbon) propellants in which therapeutically active agents, drugs and other materials can be carried into the lungs after release from and through metered dose nebulizer. 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. In addition, 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).
Although the '483 patent does disclose a process for preparing a drug delivery system especially adapted for uniformly applying a therapeutic agent to the epithelial lining of the lung, heretofore, no method or composition has been disclosed in the past that is particularly adapted, configured and formulated for the delivery of therapeutic agents to target tissues of the eustachian tube, or, via the eustachian tube, the middle ear.
Otitis media can, due to fluid accumulation, cause significant pressure, both positive and negative, in the afore-mentioned confines of the middle ear. Pressure differentials between the middle ear and the surrounding atmosphere, whether due to the addition of such fluids, or due to the relative decrease or increases of ambient atmospheric pressure, can cause great pain and discomfort. Such pressure conditions subject the tympanic membrane, and the associated pain receptors, to bulging and stretching. In addition, the accumulation of fluids, and the resulting static tension applied to the tympanic membrane, can greatly reduce hearing.
As mentioned above, the eustachian tube is specifically adapted to provide communication between the middle ear (a sealed chamber), and ambient atmospheric pressure, by providing a pathway between the tympanic cavity and the nasopharynx. Thus the auditory tube serves as a pressure equalization means for the middle ear. However, in order to provide this equalization function, and, at the same time, allow proper middle ear sound conduction, the eustachian tube, and the pathway it provides between the middle ear and the nasopharynx, are ordinarily closed. The lumen of the tube, as discussed below, is ordinarily open only during the act of swallowing and other movements that cause contraction of the attached musculature.
In humans, the eustachian tube is, on the average, 3.5 cm in length. The posterior one third of the tube is comprised of a bony wall with the anterior two thirds of the tubular structure being cartilaginous in composition. The auditory tube provides, by means of a central lumen, a fluid passage way between the nasopharynx and middle ear. However, the somewhat flattened medial and lateral walls of the tube are ordinarily in direct contact occluding and effectively limiting passage of liquids and gasses therethrough and allowing optimal sound conduction function of the middle ear which requires a sealed chamber. During swallowing, the tensor veli palatini muscle, which inserts into the lateral surface of the cartilaginous portion of the tube, contracts and pulls the wall of the tube laterally opening the central lumen thereby providing the communicating pathway needed for fluid flow between the middle ear and the nasopharynx. The action of the muscle upon the tube is needed to overcome the surface tension attracting the flattened medial and lateral walls of the central lumen together as well as the elastic recoil of the tube cartilage which also tends to close the lumen. The surface tension is due to the sero-mucous secretions found on the epithelial lining of the lumen.
In normal physiologic function, the sero-mucous secretions of the auditory tube, and the relatively low surface tensions they produce at the lateral and medial walls of the lumen, do not interfere with the normal opening and related pressure equalization functions of the auditory tube. However, middle ear, tube and upper respiratory infections and/or inflammatory conditions, such as allergies, can greatly effect the nature and increase the amount of the secretions found upon the lumen surface. Generally, such pathologic conditions greatly increase the surface tension of the lumen walls by increasing the relative amount of mucoid secretions, effectively interfering with, or completely preventing the opening of the tube. In addition, the tissues of the eustachian tube may become inflamed and engorged with fluids and cause further increases in opening pressures.
The above-described alterations in the nature and amount of secretions as well as inflammation of tube tissues are common during episodes of otitis media. Therefore, at a time when eustachian tube drainage of the middle ear would be highly desirable, this normally effective physiologic means of eliminating painful pressure often associated with such pathology is either hindered or completely eliminated. The common cold, flu, hay fever and other allergies can also result in eustachian tube failure for the same reason. However, inflammatory changes in tube tissues and lumen secretions are not the exclusive cause of such auditory tube failures.
Rapid changes in ambient pressure may also inhibit or completely prevent normal equalization functions of the auditory tube. If ambient pressure changes too quickly, the pressure gradient between the atmosphere and tympanic cavity may be too great to allow lumen opening. For example, the pressure within the tympanic cavity of a diver who, for example, ascends from a relatively deep dive without effectively and continuously equilibrating his or her middle ear through action of the eustachian tube (by swallowing, wiggling the jaw or utilizing other means to contract the attached musculature) can experience terrific pain know as a "squeeze" which may be very difficult to overcome. Such situations are more likely in such instances when, for example, a diver engages in such activity, wisely or unwisely, while he is or she is suffering from an allergy or cold (for the above-described reasons). By rising in depth without frequent and effective eustachian tube function, the relatively low ambient pressure surrounding the diver effectively seals off the eustachian tubes communication with the relatively highly pressurized middle ear. A diver, under such circumstances, may simply descend back a few feet to a depth where the pressure gradient is non-existent or minimal, and thereby lower the opening pressure of the auditory tube allowing it to open and equalize the tympanic cavity. However, a passenger on a plane is in no position to change altitudes to obtain a "second chance" to equilibrate. If such a passenger is unable to frequently and effectively equilibrate the middle ear during altitude changes due to, for example, increased secretions within the tube resulting from a cold, he or she is forced to bear significant pain.
Although, as described below, surfactant compositions, both natural and artificial, have been heretofore known, formulated and utilized to decrease surface tension within the lung, no such compositions, or methods for administering said compositions, have been heretofore suggested, taught or disclosed in regards to decreasing the surface tension within the lumen of the eustachian tube. Likewise, no method has heretofore been known which provides an effective decrease in opening resistance of the eustachian tube while simultaneously enhancing the pressure equilibration functions thereof.