Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2000-04-11
2001-11-20
Nutter, Nathan M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
active
06319984
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel biodegradable polyphosphazene represented by Formula 1 that undergoes phase transition as the temperature changes and the preparation method thereof. More particularly, the present invention relates to a novel biodegradable polyphosphazene that undergoes a sol-gel or sol-solid phase transition as the temperature changes and the preparation method thereof.
(wherein X is O or NH, NHR is a depsipeptide selected from ethyl-2-(O-glycyl)glycolate (NHCH
2
COOCH
2
COOC
2
H
5
) or ethyl-2-(O-glycyl)lactate (NHCH
2
COOCH(CH
3
)COOC
2
H
5
), NHR′ is an amino acid ethyl ester selected from glutamic acid diethy ester (NHCH(CH
2
CH
2
COOC
2
H
5
)COOC
2
H
5
), phenylalanine ethyl ester (NHCH(C
7
H
7
)COOC
2
H
5
), valine ethyl ester (NHCH(CH(CH
3
)
2
)COOC
2
H
5
), or leucine ethyl ester (NHCH(CH
2
CH(CH
3
)
2
)COOC
2
H
5
), NHR″ is glycine ethyl ester (NHCH
2
COOC
2
H
5
) or alanine ethyl ester (NHCH(CH
3
)COOC
2
H
5
) and a, b, c, d, e and f are mole fractions of each copolymer that have values between 0~1.0 with a relationship a+b+c+d+e+f=1.0. Also n is a degree of polymerization of polyphosphazene and is between 100~1000.)
A temperature-sensitive polymer refers to a polymer that undergoes a liquid to solid or liquid to gel phase transition, due to the large difference in solubility, as the temperature of the aqueous solution changes. The phase transition is reversible. At low temperatures, water molecules are bound to the hydrophilic moiety of the polymers by hydrogen bonding. As the temperature increases, the hydrogen bonding weakens resulting in a release of the water molecules, and the hydrophobic interaction becomes stronger during the process resulting in precipitation of the polymer. This type of phase transition temperature is called the lower critical solution temperature (LCST). Therefore, the phase transition temperature of the temperature-sensitive polymer increases as the content of the hydrophilic moiety in the polymer increases, and decreases as the content of the hydrophobic moiety increases. Studies for application using such thermosensitive polymers are actively underway in the fields of biomedical materials including drug delivery systems, environmental sciences, biological sciences, and cosmetics.
Thermosensitivity is reported for poly(N-isopropyl acrylamide) or polyethylene oxide copolymer, hydroxy group polymers and a number of polyphosphazenes (K. Park Eds, Controlled Drug Delivery, 485 (1997)). Most thermosensitive polymers, however are not degradable, and therefore are not suitable as a material for drug delivery (B. Jeong et. al.,
Nature,
388, 860 (1997)).
The present inventors have reported that poly(organophosphazenes), which can be obtained by substitution of polydichlorophosphazene with methoxy-poly(ethylene glycol) and amino acid ester, dissolve in water at low temperatures but precipitate out as a solid above the LCST and slowly hydrolyze in an aqueous environment (S. C. Song et. al.,
Macromolecules,
32, 2188 (1999)).
However, these synthetic polymers were found to be unsuitable as biomaterials since the LCST of most of these polymers are above the body temperature and their hydrolysis rate is too slow. Therefore, it was necessary to synthesize polymers having a desired hydrolysis rate and the LCST. Thus, the present inventors have found that polymers can be designed and synthesized to have the phase transition temperature and hydrolysis rate suitable as biomaterials by introducing a depsipeptide as a third side group and more hydrophobic amino acid ester in the polymer backbone. The LCST of thus synthesized polymers is in the vicinity of the body temperature, and the hydrolysis rate increases as the depsipeptide content increases.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel polyphosphazenes that are temperature-sensitive and whose biodegradation rate can be controlled.
More particularly, the object of the present invention is to provide polyphosphazenes whose temperature-sensitivity and biodegradability can be controlled as desired by substituting polydichlorophosphazene with methoxy-poly(ethylene glycol) and amino acid ester and a preparation method thereof.
To achieve these objects, polydichlorophosphazene was reacted with methoxy-poly(ethylene glycol), and then successive substitution reactions, were carried out using a variety of amino acid esters and depsipeptides. The present inventors have found that the polyphosphazene derivatives can be designed and synthesized to have desirable phase transition temperatures near the body temperature and the appropriate rates of hydrolysis therefof. More particularly, it has been found that the phase transition temperature and degradation rate of these polyphosphazenes can be controlled depending on the composition of methoxy-poly(ethylene glycol) and amino acid ester, the kinds of amino acid ester used, and the content of depsipeptide.
DETAILED DESCRIPTION OF THE INVENTION
The preparation method of polyphosphazene represented by Formula 1 can be explained in more detail as follows. Vacuum or nitrogen lines are used to avoid moisture in all of the preparation processes. Water was removed sufficiently for all of the solvents used in the process. Low molecular weight (Mw=10
4
~10
5
) polydichlorophosphazene linear polymer, (N=PCl
2
)
n
, is obtained by thermal polymerization of cyclotriphosphazene, (N=PCl
2
)
3
according to the literature (Y. S. Sohn, et. al.,
Macromolecules,
28, 7566(1995)).
That is, 2.0 g(17.26 mmol) of hexachlorocyclotriphosphazene of Formula 2 which has been purified by sublimation and 3~10% AlCl
3
with respect to the hexachlorocyclotriphosphazene are mixed in a glass tube reactor and sealed. The glass reactor is rotated at 1 revolution per minute (rpm) and reacted for 5 hours at 230-250° C. to obtain polydichlorophosphazene of Formula 3.
(wherein X is O or NH, NHR is a depsipeptide selected from ethyl-2-(O-glycyl)glycolate (NHCH
2
COOCH
2
COOC
2
H
5
) or ethyl-2-(O-glycyl)lactate (NHCH
2
COOCH(CH
3
)COOC
2
H
5
), NHR′ is an amino acid ethyl ester selected from glutamic acid diethyl ester (NHCH(CH
2
CH
2
COOC
2
H
5
)COOC
2
H
5
), phenyl alanine ethyl ester (NHCH(C
7
H
7
)COOC
2
H
5
), valine ethyl ester (NHCH(CH(CH
3
)
2
)COOC
2
H
5
) or leucine ethyl ester (NHCH(CH
2
CH(CH
3
)
2
)COOC
2
H
5
), NHR″ is glycine ethyl ester (NHCH
2
COOC
2
H
5
) or alanine ethyl ester (NHCH(CH
3
)COOC
2
H
5
) and a, b, c, d, e and f are mole fractions of each copolymer that have values between 0~1.0 with a relationship a+b+c+d+e+f=1.0. Also n is a degree of polymerization of polyphosphazene and is between 100~1000.)
To 200 g of methoxy-poly(ethylene glycol) is added 200 ml of benzene, and the solution mixture is distilled azeotropically at 70~80° C. to remove excess water, followed by vacuum-dry at 80~90° C. in oil bath for 3 days. To this, sufficient amount of 3 Å molecular sieve is added and dry nitrogen is filled to keep drying condition until next step reaction. For reactions with polydichlorophosphazene of Formula 3, the hydroxy group of methoxy-poly(ethylene glycol) is converted to alkoxide form of Formula 4 or to amino group to make &agr;-amino-&ohgr;-methoxy-poly(ethylene glycol) of Formula 5. The process of converting the hydroxy group to amino group is as follows. One equivalent weight of methoxy-poly(ethylene glycol), two equivalent weights of 4-toluenesulfonylchloride and 4 equivalent weights of triethylamine is mixed and stirred for 12 hours in dried chloroform, and further reacted with two equivalent weights of sodium azide in dimethylformamide for additional 12 hours at 80° C. Methoxy-poly(ethylene glycol) azide is further reacted with 10% palladium/charcoal catalysts under 3.4 atmospheric hydrogen gas for 48 hours to produce &agr;-amino-&ohgr;-methoxy-poly(ethylene glycol) of Formula 5.
(wherein M represents sodium or potassium)
Polydichlorophosphazene of Formula 3,
Lee Bae Hoon
Lee Sang Beom
Sohn Youn Soo
Song Soo-Chang
Korea Institute of Science and Technology
Morrison & Foerster / LLP
Nutter Nathan M.
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