Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1985-11-21
1987-06-23
Rosen, Sam
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
424101, 514 75, 514 76, 514 78, A61K 3714, A61K 31685
Patent
active
046753109
DESCRIPTION:
BRIEF SUMMARY
THIS INVENTION relates to gas transportation and more particularly to stable carriers for oxygen and other gases, for use both in vivo and in vitro, in which a gas ligand is protected by a stable, permeant and biocompatible barrier of polymeric phospholipid(s).
Efforts directed toward the development of oxygen carriers as replacements for red blood cells have extended over several decades. The need for blood substitutes stems from the numerous problems associated with homologous blood transfusions which include donor availability, requirement for cross-matching, transmission of hepatitis, transfusion reactions, poor storage stability and others. The required characteristics for red cell substitutes include chemical and physical stability, increased biological half-life, low immunogenicity, biological inertness (no pathogenic potential), thromboresistance and adequate oxygen affinity.
Blood is a complex tissue, made up of a large number of components, which interact to sustain homeostasis. The most frequent indicator for transfusion or blood replacement is to restore or maintain oxygen-carrying ability. Normally, there is a significant reserve in arterial oxygen content in the form of excess haemoglobin. Very large (but isovolemic) decreases (greater than 50%) in haemoglobin concentration can be tolerated; the resultant decrease in oxygen content is compensated by an increase in cardiac output. Nonetheless, there is a great demand for homologous blood replacement; in the United States in 1975, 11.5.times.10.sup.6 units of blood and blood products were transfused.
The systems which have been investigated as possible red blood cell substitutes include haemoglobin solutions, oxygen-absorbant organic liquids and artificial cells. The initial difficulties associated with the infusion of free haemoglobin involved a toxicity which derived from contamination of the solution with stromal lipids. These problems have been lessened by better preparatory methods. However, persistant difficulties have restricted the use of haemoglobin solutions for transfusion. In plasma, haemoglobin tetramers dissociate to dimers and are rapidly cleared from the circulation (half-life of several hours). Free haemoglobins are vasoactive, and present the risk of hypertension and bradycardia. Additionally, haemoglobin in plasma lacks the acidic environment and phosphate content of red blood cells, resulting in a higher affinity for oxygen and a lower capcity to off-load oxygen to the tissues. The use of liquid fluorocarbons as substitutes for red cells has received much attention since the middle 1960's. Some patients have been infused successfully with these solutions, but the potential for widespread use is doubtful. The major restrictions in the use of fluorocarbons are its short half-life (approximately 11 hours), poor miscibility with blood and variable blood compatibility.
Investigations which lead to the development of "artificial cells" began in the early 1950's. By this time it was well known that biological membranes consist of a lipid bilayer with associated proteins. Synthetic bilayers of phosphatidylcholine, prepared by dispersing small amounts of of the dry lipid in salt solutions, were first employed as models of cellular membranes in 1958 (Bangham, Pethica and Seaman, 1958). That phospholipid dispersions could behave as osmometers, that is, form sealed containers, was first demonstrated in 1965 (Bangham, Standish and Watkins, 1965). Semi-permeable membranes of a non-biological nature, such as nylon, were first used to encapsulate cytoplasmic constituents in 1964 (Chang, 1964), but the capsules are too large and sufficiently "foreign" to be placed in the circulation.
Dispersions of the neutral phospholipid, phosphatidylcholine, have been extensively studied as models of cellular membranes (Chapman, 1982). The capacity to form "sealed" containers has focused much attention on the potential of liposomes as pharmacological capsules. This utility of liposomes has been hampered by their leakage rates and propensity toward aggrega
REFERENCES:
patent: 4348329 (1982-09-01), Chapman
patent: 4397870 (1983-08-01), Sloviter
patent: 4532130 (1985-07-01), Djordjevich et al.
Chapman Dennis
Hayward James A.
Biocompatibles Limited
Rosen Sam
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