Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-20
1999-03-09
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514922, 514937, 514943, A61K 31535
Patent
active
058801235
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/02936, filed Dec. 15, 1995.
This invention relates to the novel use of a non-ionic surface-active agent (otherwise known as a surfactant or wetting agent) or an emulsion for the reduction of the hemolytic effects of an amphiphilic compound.
Hemolysis of red blood cells (erythrocytes) is observed when such cells are suspended in a solution which has a lower osmotic pressure than that of the fluid in the red blood cells--i.e. when the solution is hypotonic. This has the effect of causing the red blood cells to swell and burst due to diffusion of water into the cells. Conversely, if red blood cells are suspended in a hypertonic solution--i.e. where the osmotic pressure is greater than that of the fluid in the cells--they may lose water and shrink (crenation).
This classical view of hemolysis has resulted in the development of "isotonic solutions" which exert the same osmotic pressure as blood plasma. In isotonic solution (e.g. 0.9% sodium chloride) red blood cells maintain their "tone" and the solution is said to be isotonic with human erythrocytes.
Hemolysis following parenteral administration of a pharmaceutical formulation may cause localised tissue damage, irritation, anaemia and in extreme cases may lead to organ damage, particularly damage to the kidneys.
It is now apparent, however, that hemolysis is not only caused by the administration of a hypotonic parenteral formulation. It has been observed that amphiphilic compounds will also exhibit hemolytic effects on red blood cells, even when administered in an isotonic solution.
Surprisingly, it has now been found that a non-ionic surface-active agent or emulsion can be used to dramatically reduce the hemolytic effects of an amphiphilic compound.
There is therefore provided in a first aspect of the present invention, the use of a non-ionic surface-active agent or an emulsion for the reduction of the hemolytic effects of an amphiphilic compound.
In an alternative aspect of the present invention, there is provided a method for reducing the hemolytic effects of an amphiphilic compound which comprises formulating said compound with a non-ionic surface-active agent or in the form of an emulsion.
Surface-active agents, otherwise known as surfactants or wetting agents are generally molecules which comprise a hydrophobic portion (e.g. an alkyl chain) and a hydrophilic portion (e.g. a polar or ionic group).
Surface-active agents may be divided into a number of classes including anionic agents, cationic agents, amphoteric agents and non-ionic agents, of which the non-ionic agents are particularly useful in the present invention.
Non-ionic agents include fatty alcohols; glyceryl esters such as the naturally occurring mono-, di- and triglycerides; fatty acid esters of fatty, and other, alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose and cholesterol; polyoxyethylene sorbitan fatty acid esters; and polyoxyethylene ethers.
Particularly preferred non-ionic surface-active agents are the polyoxyethylene sorbitan fatty acid esters which are commercially available under the trade-name Tween.TM., for example, the monooleate ester (Tween 80.TM.).
The precise choice of non-ionic surface-active agent and the concentration used will depend largely upon the physical properties of the chosen agent. It is believed that the masking of the hemolytic nature of an amphiphilic compound in accordance with the present invention is effected by the formation of micelles by the surface-active agent. Micelle formation occurs over a range of concentration of the surface-active agent known as the critical micellization concentration (cmc). It is therefore desirable to use in the present invention a concentration of the non-ionic surface-active agent which falls within the cmc range for the chosen agent. Micelles are formed by surface-active agents due to the lack of affinity of the hydrophobic regions of the surfactant molecules for their aqueous environment. An aggregate is therefore formed by strong hydrophobic chain-chain interact
REFERENCES:
CA 116:11227, Kaneki et al., May 1991.
Friess, et al., Pharmazie, vol. 49, No. 2-3, pp. 197-201 (Feb.-Mar., 1994).
Sajadi Tabassi, et al., J. Pharm. Pharmacol., vol. 46, No. Suppl., 4 p. 1060 (1994, Dec.).
Biesendorfer, et al., Biochemical Pharmacology, vol. 30, No. 16, pp. 2287-2292 (Aug. 1981).
Bock, et al., Congr. Int. Technol. Pharm., 6th, vol. 4, pp. 380-387 (1992).
Hagerstrand, et al., Biochimica Biophysica Acta, vol. 1109, pp. 117-126 (1992).
Jordan Kimberly
Merck Sharp & Dohme Limited
Rose David L.
Thies J. Eric
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