Synthesis Of Oxygen Carrying, Turbulence Resistant, High Density Submicron Particulates

Abstract

An artificial oxygen carrier (AOC) for use in the body. A first gas permeable first shell encloses an oxygen carrying agent. The first shell has a second oxygen carrying agent surrounding it, and there is a second gas permeable shell enclosing the second agent. The concentric shells are not subject to turbulent breakup, or chemical decomposition, do not release the agents.

Description

[0001]This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61 / 236,810, filed on Aug. 25, 2009.FIELD OF THE INVENTION[0002]The present invention relates to encapsulated active substances, such as perfluorocarbon and polyhemoglobin, that are used as retrievable artificial oxygen carriers and / or retrievable carriers of therapeutic and diagnostic reagents in the blood or other liquids.BACKGROUND OF THE INVENTION[0003]In the prior art there are a range of particulate carriers intended for the controlled delivery of biologically active substances within the body. Their sizes range from micron to submicron, and their compositions range from organic (e.g. polymers, lipids, surfactants, proteins) to inorganic (calcium phosphate, silicate, CdSe, CdS, ZnSe, gold and others). Each of these particulate carriers are designed to carry a chemically or biochemically reactive substance, and either release it over time, or at a specific location, or both.[0004]Me...

AI Technical Summary

Benefits of technology

[0018]The needs in the prior art described in the previous paragraph are satisfied by the present invention. To satisfy the above listed needs of the prior art the unique features of the present invention are: (1) a particulate artificial oxygen carrier (AOC) made from a unique combination of organic and inorganic components whose physical and chemical properties permit functioning as an AOC while being retrievable from whole blood using density-gradient continuous flow centrifugation, (2) an AOC whose synthesis may be carried out by either a batch method or continuous method, and (3) a specialized centrifugal rotor based on density gradient separation to accomplish the task of removal from blood or other biofluids. In addition, the AOC is retrieved from a patients system as soon as its medical purpose is accomplished in order to alleviate the physiological stress on already compromised patients.

[0019]The particulate artificial oxygen carrier is designed to be continually circulated in a closed loop fluid circulation system, is not subject to turbulent breakup, chemical decomposition, or accumulation of debris, and does not release its payload but is capable of exchange of small ions and gases, and which can be retrieved at any time desired using continuous flow separation employing density-gradient centrifugation, which may be supplemented with magnetic fields, affinity filtration or other methods, without suffering damage, or inflicting damage on other materials that may already be present in the flowing fluid.

Problems solved by technology

However, the function of real blood is complicated, and the development of artificial blood has generally focussed on meeting only a specific function, gas exchange—oxygen and carbon dioxide.

Artificial blood mixable with autologous blood can support patients during surgery and support transfusion services in emerging countries with limited healthcare, blood donations and storage facilities, or high risk of exposure to disease since screening procedures are too expensive.

However, the disposal of particulate carriers with natural metabolism of the patients is extremely difficult.

Despite significant advances in donated blood screening and storage, concerns about the supply, cost and safety of donated stored blood remain.

When testing blood for dangerous pathogens therein there is currently no practical way to test for emerging diseases such as Cruetzfeld-Jacob disease, smallpox and SARS.

While these two types of AOCs each have some advantages, none are yet approved for clinical use in the U.S. Some perfluorocarbon (PFC) based AOCs are Oxygent (Alliance Pharmaceutical Corporation, San Diego, Calif.

In contrast to the above described promising features for perfluorocarbon (PFC) based AOCs, use of such PFC-based AOCs has resulted in flu-like symptoms, a need for higher than normal oxygen pressure, problems such as emulsifier toxicity, formation of oxygen free radicals, long term retention of the AOCs in the tissue, damage to lung tissues, a decrease in platelet count, and problems related to loss of nitrous oxide (NO) from circulation in the blood.

The loss of NO is also a problem with hemoglobin based AOCs.

In addition, recent phase III trials for Oxygent (Alliance Pharmaceutical Corporation, San Diego, Calif.) which uses a stable perfluorooctyl bromide / perfluorodecyl bromide egg yolk phospholipid emulsion and has 4-5 times greater oxygen carrying capacity than Fluosol-DA-20 (Green Cross, Japan) have shown an increased incidence of stroke in treated patients compared to controls, and so trials of Oxygent have been halted.

These emulsifiers interact with proteins and emulsifiers found in blood leading to instability.

As a result, large quantities of PFC in circulation cannot be tolerated.

However, there is a potential to transmit diseases from the animals from which the hemoglobin was obtained and purified, and high production costs have slowed advances.

Polymeric hemoglobins (pHb) bind O2 and CO2, with a binding mechanism much like that of red blood cells (RBC), but even a small quantity of unpolymerized Hb left in the circulation can become very toxic.

Premature breakdown can increase the risk of toxicity, and such a large amount can overtax the body's natural removal processes.

Polymerized Hb remains costly.

Animal sources of Hb run the risk of transferring, among other things prion-based diseases.

It requires high quality separation and purification procedures, that add to the cost.

While both polymeric hemoglobins (Hb) and perfluorocarbons (PFC) based AOC products deliver oxygen in significant quantities to cells and tissue, their side effects, such as nitric oxide related vasoconstriction, stroke, cardiac arrest, flu-like symptoms and long term chemical toxicity, have forced the termination of all the clinical trials in the U.S. An all out effort to reduce the toxicity of relatively large quantity of AOC injected into a body by metabolic decompositions has failed.

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