Oxygen Carriers (“Blood Substitutes”)Raison d'Etre, Chemistry, and Some Physiology Blut ist ein ganz besondrer Saft1

Fluorocarbons and fluorinated amphiphiles in drug delivery and biomedical research

Solid, water-insoluble lipospheres formed of a solid hydrophobic core having a layer of a phospholipid embedded on the surface of the core, containing biologically active agent in the core, in the phospholipid, adhered to the phospholipid, or a combination thereof, are disclosed for use in providing extended release of active agent, including drugs such as vaccines and anesthetics, insect control agents such as insecticides and repellents, and agricultural compounds such as fertilizers, fungicides, pesticides, and herbicides. Lipospheres can be prepared by a melt technique or a solvent technique, summarized as: (1) forming a liquid solution or suspension of the agent by either melting the agent, or dissolving or dispersing the agent in a liquid vehicle, to form a mixture of liquid agent that solidifies at room temperature or greater; (2) adding phospholipid and an aqueous solution to the liquid agent to form a suspension; (3) mixing the suspension at a temperature above the melting temperature until a homogeneous fine dispersion is obtained; and then (4) rapidly cooling the dispersion to below the melting temperature of the liquid mixture containing the agent. Agent can also be added to the phospholipid or mixed with the resulting lipospheres. The agent containing lipospheres have several advantages over other delivery systems, including emulsions, vesicles and liposomes, including stability, low cost of reagents, ease of manufacture, high dispersibility in an aqueous medium, a release rate for the entrapped substance that is controlled by the phospholipid coating and the carrier. Examples demonstrate the effective administration of anesthetics, antigens, and insect repellent (DEET).

Lipospheres for controlled delivery of substances

Fluorous micro- and nanophases with a biomedical perspective

The present invention is in the area of administration forms and delivery systems for drugs, vaccines and other biologically active agents. More specifically the invention is related to the preparation of suspensions of colloidal solid lipid particles (SLPs) of predominantly anisometrical shape with the lipid matrix being in a stable polymorphic modification and of suspensions of micron and submicron particles of bioactive agent (PBAs); as well as to the use of such suspensions or the lyophilizates thereof as delivery systems primarily for the parenteral administration of preferably poorly water-soluble bioactive substances, particularly drugs, and to their use in cosmetic, food and agricultural products. The emulsification process includes melting of the agent (a lipid and for bioactive agent) and mixing with an aqueous phase (heated to melt temperature). The emulsification is completed by a high-pressure homogenization.

Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof

50-95 Parts by weight of a perfluorocarbon compound such as perfluorodecalin, perfluoromethyldecalin, perfluoro alkylcyclohexanes having 3 to 5 carbon atoms in the alkyl, perfluoro alkyltetrahydrofurans having 5 to 7 carbon atoms in the alkyl, perfluoro alkyltetrahydropyrans having 4 to 6 carbon atoms in the alkyl, perfluoroalkanes having 9 to 11 carbon atoms, and 50-5 parts by weight of a perfluoro tert.-amine such as perfluoro tert.-alkylamines having 9-11 carbon atoms, perfluoro N-alkylpiperidines having 4 to 6 carbon atoms in the alkyl, and perfluoro N-alkylmorpholines having 5 to 7 carbon atoms in the alkyl are emulsified in an aqueous medium by the aid of a high-molecular-weight nonionic surfactant have a molecular weight of about 2,000 to 20,000, and phospholipids as emulsifying agent, and fatty acids having 8 to 22 carbon atoms or salts or monoglycerides thereof as emulsifying adjuvant. The resulting oxygen-transferable emulsion having a particle size of 0.05 to 0.25μ is very stable for a long period of time, can be mixed with plasma extenders, and retains for long time in the blood stream of animals when it is used as an artificial blood substitute while being excreted very rapidly.

Oxygen-transferable fluorocarbon emulsion

A stable fat emulsion having low side effects, which is suitable as nutritive infusion fluid for intravenous injection, is provided. The emulsion contains 5-50 (W/V) % of soybean oil, yolk phospholipids in a weight ratio to the soybean oil of 1/4-1/25, 0.01-0.30 (W/V) % of a fatty acid or salt thereof having 12-20 carbon atoms and the balance of water.

Fat emulsion for intravenous injection

Quantitative structure-activity relationships of a series of perfluorochemicals (PFCs) for use as oxygen transporters were investigated in terms of their in vivo half-lives (t1/2). The logt1/2 values can be correlated by a linear combination of lipophilic (e.g., critical solution temperature (CST)), physicochemical (e.g., molecular weight and vapor pressure (Pv)) and topological (e.g., number of fluorines (NOF)) parameters on regression analyses. The most important excretion-rate-determining factor was the CST. The Pv alone of PFCs did not correlate well with logt1/2. However, a combination of CST and Pv produced the most meaningful and important correlation, indicating that Pv plays a pivotal role in the excretion and can be considered a kind of correction factor to the CST. The t1/2 can thus be predicted from the combination of CST and Pv. It can also be predicted from structural information : the smaller the NOF, the shorter the t1/2. The incorporation of hetero atom (s) such as nitrogen and oxygen in the PFC molecule, which has been considered to produce better emulsion stability but results in persistence in the body, had relatively little effect in terms of t1/2. These results suggested that, taking the emulsifiability of hetero atom-containing PFCs into consideration, a cyclic F-ether and F-tertiary amine with fused ring (s), containing fewer fluorines than acyclic analogues, might be a good candidate compound as an oxygen transporter.

Quantitative structure-in vivo half-life relationships of perfluorochemicals for use as oxygen transporters.

It has been assumed that a mononuclear phagocyte system is related to the excretion of PFC emulsions: PFC particles are phagocytized by blood monocytes to be expelled through the lung alveoli. This monocyte-related mechanism may well explain excretion at an early stage when PFC particles are abundant in the blood stream. It does not, however, fully explain the manner by which PFC cells are released from the RES cells into the blood stream and into the adipose tissue. To explain this, the following mechanism has been proposed and discussed based on some experimental results. PFC emulsion particles taken up by the RES organs, are stripped at their surfactant layers in the cells and move across the cell membranes to the blood vessels and into other tissues such as adipose, at a rate that depends on the lipophilicity of the PFC's. In the blood stream, PFCs are delivered by lipoproteins to the lung and excreted into the expired air. Pharmacokinetical analysis with a compartmental model for the excretion also s...

Discussion and considerations for the excretion mechanism of perfluorochemical emulsion.

PURPOSE: The titled ultrafine particulate pharmaceutical, containing a specific brominated pefluorocarbon, an emulsifying agent, e.g. egg yolk phospholipid, and a specific emulsifying adjuvant, having low toxicity without the accumulation in the living body, and capable of adjusting the osmotic pressure to a physiological isotonicity. CONSTITUTION: An ultrafine particulate contrast medium for blood vessels, containing an 8W12C brominated perfluorocarbon (PFC) having at least one or two bromine atoms in the molecule, an emulsifying agent selected from an egg yolk phospholipd or soybean phospholipid or/and a high polymeric nonionic surfactant, e.g. polyoxyethylene-polyoxypropylene copolymer, having a molecular weight of about 2,000W20,000, and an 8W22C fatty acid or salt thereof or a fatty acid monoglyceride as an emulsifying adjuvant, having a particle diameter of 0.05W0.4μ, and storable for a long term with high safety. The contents of the components are as follows: 5W50W/V% brominated PFC, 2W6W/V% emulsifying agent and 0.001W0.1W/V% emulsifying adjuvant. COPYRIGHT: (C)1983,JPO&Japio

Yoshio Tsuda

Papers

Oxygen-transferable fluorocarbon emulsion

Fat emulsion for intravenous injection

Quantitative structure-in vivo half-life relationships of perfluorochemicals for use as oxygen transporters.

Discussion and considerations for the excretion mechanism of perfluorochemical emulsion.

Contrast medium for blood vessel