Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-08-16
2003-02-18
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C514S951000, C514S956000, C514S958000, C128S200230
Reexamination Certificate
active
06521213
ABSTRACT:
FIELD OF INVENTION
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 uniformly distributing and delivering therapeutically active agents, effective in the treatment of otitis externa, to the entire epithelial lining of said canal.
BACKGROUND OF THE INVENTION
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 a recent review: 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. 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) 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. 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 in order to restore deficient or low levels of natural surfactant. 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, yielding 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).
The outer ear canal, or, as it is also known, the external auditory canal, is lined by 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. Strains of Staphylococcus, Streptococcus and Psuedomonas species often capitalize on such alkaline conditions leading to infection and the resultant inflammatory response characteristic of infective otitis externa—immune mediated swelling, redness, heat and pain, often associated with a discharge which contains white blood cells—. Discomfort caused by this condition ranges from a slight itch to severe pain. Temporary deafness may also result as swelling and discharge physically closes off the ear canal and prevents conduction of ambient sound to the ear drum. In addition to bacteria, fungal and viral organisms are also causative of infective otitis externa. Non-microbial antigenic material is causative of another form otitis externa specifically allergic otitis externa.
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. In addition, 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 response waste resulting from the lysis, phagocytosis and necrosis of antigenic material. In addition, cerumen producti
Jagoe Donna
Krass Frederick
Scientific Development and Research, Inc.
Strauss, Esq. Richard L.
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