Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-12-04
2003-11-11
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C514S958000, C514S975000, C128S200230
Reexamination Certificate
active
06645467
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the field of pharmacological compositions and methods of utilizing such compositions in order to improve air flow throughout the upper respiratory system. More specifically, the present invention discloses compositions having powerful surfactant effect upon the air/liquid interface resident upon the epithelial lining of the upper respiratory system—and the use of such compounds—in order to open air spaces and air ways which have become partially or completely obstructed by proximal epithelial wall edema, constriction, adhesion and/or collapse caused by the presence and effect of highly viscous mucous exudate—generated as a product of inflammatory response—secreted thereupon.
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: 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 lipid surfactants and one or more spreading agents, in powder form, a therapeutically active substance and one or more fluorocarbon propellants, said lipids, spreading agents and therapeutically active substances being insoluble in the propellants and said lipid surfactants and spreading agents being selected from cholesteryl esters, phospholipids, carbohydrates and proteins; 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 a 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 mammalian upper respiratory system is comprised of various conduits and chambers especially adapted for conduction of air to and away from the lungs. Besides forming a simple conduit, the upper respiratory system is responsible for warming, moisturizing, and removal, by means of entrapment and filtration, the various impurities found in inspired air so as to protect the lower respiratory system from disease and irritation, while simultaneously conditioning inspired air for maximum gas exchange. Generally, the upper respiratory system can be said to be comprised of the nose, nasal cavity, nasopharynx, paranasal sinuses, oropharynx and laryngopharynx.
As ambient air is inspired through the nose, it first passes through the external nares where relatively large hairs filter and remove larger particles from the air stream. From the external nares, the air is then drawn through the nasal cavity for further filtration. Within the nasal cavity, small boney protuberances known as the nasal conchae line the lateral walls of the chamber. The conchae, also known as turbinate bones, create great turbulence within the inspired air. The conchae thereby increase the collision and contact of smaller particulate matter with the adherent mucous coating of the epithelial surfaces lining the nasal cavity. Thus, such particles that avoid filtration by nasal hairs may become trapped within the nasal cavity. Mucous producing goblet cells which create the mucous coating of the upper respiratory system, assisted by the movement of cilia located on the free border of the epithelial cells, acts to continually flush such particulate matter, and any organisms which they may carry, towards the pharynx where they are swallowed and any such organisms destroyed in the acidic environment of the stomach. In addition, mucous production may also flush such matter out of the system through the external nares.
The paranasal sinuses also act as a filtration system in that the mucous membranes lining the sinuses also tend to trap impurities entering these
Jagoe Donna
Krass Frederick
Scientific Development and Research, Inc.
Strauss, Esq. Richard L.
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