Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2001-07-05
2002-07-09
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S089000, C558S090000, C558S156000, C558S157000
Reexamination Certificate
active
06417383
ABSTRACT:
This application is a 371 of PCT/KR00/00043 Jan. 20, 2000.
BACKGROUND OF THE INVENTION
The present invention relates to a temperature-sensitive cyclotriphosphazene derivatives and a preparation method thereof. More particularly, the present invention relates to cyclotriphosphazene derivatives represented by Formula 1 that have thermosensitivity and a stereo-specific chemical structure, and preparation method thereof.
(wherein HNA is an amino acid group selected from glycine (—NHCH
2
COO
−
), aminomalonic acid (—NHCH(COO
−
)
2
), aspartic acid (—NHCH(CH
2
COO
−
)COO
−
) and glutamic acid (—NHCH(CH
2
CH
2
COO
−
)COO
−
), R is either ethyl or benzyl, m is a repeating unit of poly(alkoxyethyleneglycol) selected from 2, 7, 12 and 16, and n is an integer representing the number of alkyl carbons selected from 0, 1, and 3).
The present inventors have found that the cyclotriphosphazene compounds, obtained by substituting the chlorine atoms in hexachlorocyclotriphosphazene (N
3
P
3
Cl
6
) with a low- or high-molecular weight poly(alkoxyethyleneglycol) and amino acid ester, show a diverse thermosensitivity in an aqueous environment depending on their chemical structures.
Thermosensitivity in the present invention refers to the reversible phenomenon wherein a material is dissolved in water at a low temperature but precipitated as a result of the lowered solubility above at a critical temperature, and re-dissolved in water by lowering the temperature. This phenomenon is contradictory to the general phenomenon that solubility increases at higher temperatures. Thermosensitivity is often observed for water-soluble polymers that are dissolved below and precipitated above the so-called lower critical solution temperatures (LCST). Below the LCST, interaction between polymer and water molecules by hydrogen bonding is greater than the intermolecular hydrophobic interaction between polymer molecules, which results in dissolution of the polymer in water. As the temperature of the aqueous solution increases, however, the hydrogen bonding of the polymer-water molecules weakens whereas the hydrophobic interaction between the polymer molecules increases. As, the temperature of the aqueous solution reaches the LCST, the hydrophobic interaction becomes greater than the hydrogen bonding interaction between the polymer and water molecules resulting in the precipitation of the polymer in aqueous solution.
Thermosensitivity is found mainly among the hydrophilic polymers and non-ionic surfactant oligomers. The hydrophilic polymers exhibiting thermosensitivity are categorized as poly(ethyleneglycol) and organic polymers is wherein the hydrophobic and hydrophilic groups are bound together. The LCST of the hydrophilic poly(ethyleneglycol) depends on the molecular weight. Below the molecular weight of 200,000, the LCST is not observed (Bailey, F. E. et. al.,
Poly
(
ethyleneoxide
), Academic Press, New York, 1976). Above the molecular weight of 200,000, the LCST decreases as the molecular weight of the polymer increases. The LCST of the hydrophilic organic polymers changes depending on the ratio between the hydrophobic and hydrophilic groups. Generally, as the content of the hydrophilic group increases, the phase transition temperature increases. On the other hand, as the content of the hydrophobic group increases, the phase transition temperature decreases. The thermosensitivity of the non-ionic surfactant follows the same rule as the hydrophilic organic polymers.
These temperature-sensitive polymers and surfactants are widely applied in many fields, including drug delivery systems, medical biomaterials, thin films, separation of biochemical reactions, cosmetics and optics. One of the important features of the temperature-sensitive materials is that an organic solvent is not needed to load the drugs. Most of the biologically active materials lose their activity when exposed to organic solvents or high temperatures. By using the temperature-sensitive materials, however, drugs can be loaded at a lower temperature in an aqueous environment. Subsequently, the temperature can be increased to above the LCST to induce precipitation for drug loading. The most widely studied drug delivery systems using thermosensitive polymer is poly(N-isopropyl acrylamide) whose LCST is 33.2° C. Examples include studies on heparin, an anti-coagulant, release from thermosensitive polymer coatings (Gutowska, A. et. al.,
J. Biomedical materials Research
, 29, 811(1995)) and on catalytic activity changes across the LCST of the enzymes loaded in a thermosensitive gel (Chang, L. et. al.,
J. Controlled Release
, 4, 223(1986)). In a study regarding membrane permeability of a drug using temperature-sensitive polymers was observed the membrane permeability of insulin through temperature-sensitive polymers (Bae, Y. H. et. al.,
J. Controlled Release
, 9, 271(1989)). There are other reports on the poly(ethyleneglycol) co-polymer, hydroxy polymers and inorganic polyphosphazenes (Tanigami, T. et. al.,
Macromolecules
, 22, 1397 (1989), Allock, H. R. et. al.,
Macromolecules
, 25, 5573(1992), Allock, H. R. et. al.,
Macromolecules
, 29, 1313(1996)).
Most of these existing techniques are related to non-degradable polymers, and thus have limitations in practical application to drug delivery systems. This is because non-degradable polymers can be toxic since they may be accumulated or generate toxic side-products in, human body. Also the high molecular weight of these polymers makes them bio-incompatible, and limits their application to drug delivery systems. Especially, these existing thermosensitive polymers could not be designed to have a desirable LCST for a particular purpose, since the ratio between the hydrophilic and hydrophobic moieties can not be modified easily. Therefore, there has been a need to develop an oligomeric drug delivery system which is biodegradable and whose thermosensitivity can be controlled accurately. Recently, the present inventors have discovered polyphosphazenes that have thermosensitivity (Song, S.-C. et. al., Macromolecules, 32, 2188 (1999)) and bio-degradability (Lee, S.B. et. al., Macromolecules, in press (1999)) simultaneously. Up to date, the temperature-sensitive oligomeric materials have been the non-ionic surfactant. This non-ionic surfactant, however, can not be applied to a drug delivery system, since they contain non-degradable hydrophobic alkyl chains. Moreover, thermosensitive oligomeric cyclotriphosphazenes are yet to be reported. In the present invention, thermosensitive oligomeric cyclotriphosphazenes have been developed for the first time whose LCST can be accurately controlled.
SUMMARY OF THE INVENTION
Therefore, an object of the present invention is to provide novel oligomeric cyclotriphosphazenes whose thermosensitivity can be accurately controlled.
Another object of the present invention is to provide a method of preparing the thermosensitive oligomeric cyclotriphosphazenes by substitution of the chloride atoms of hexachlorocyclotriphosphazene with a poly(alkoxyethyleneglycol) and an amino acid ester to have a stereo-specific chemical structure and to control their LCST accurately.
To achieve the above-mentioned objects, the present inventors have found that various temperature-sensitive cyclotriphosphazenes can be synthesized by reacting a hexachlorocyclotriphosphazene with hydrophilic poly(alkoxyethyleneglycols) having different molecular weights and successively with a variety of hydrophobic amino acid esters. Especially, it has been found that the LCST of the resultant cyclotriphosphazene derivatives can be controlled according to the desired purposes, since the LCST of the cyclotriphosphazene depends on the composition of poly(alkoxyethyleneglycol) and amino acid ester and on the lengths of the poly(alkoxyethyleneglycol) and terminal hydrophobic alkyl chains.
DETAILED DESCRIPTION OF THE INVENTION
The preparation method of cyclotriphosphazene derivatives represented by Formula 1 and which have stereo-specific chemical structure are explained in more detail as
Lee Sang Beom
Sohn Youn Soo
Song Soo-Chang
Higel Floyd D.
Korea Institute of Science and Technology
Morrison & Foerster / LLP
Shameem Golam M. M.
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