Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-01-12
2001-05-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S423000, C424S484000, C424S487000
Reexamination Certificate
active
06238688
ABSTRACT:
BACKGROUND OF THE INVENTION
Recently, polymer gels, especially those stimuli-responsive “intelligent” gels, have attracted much attention for their potential biological and medical applications, i.e., as special adsorbents, as actuators, and in drug delivery devices. Y. Osada & S. B. Ross-Murphy,
Sci. Amer.
268(5):82 (1993); B
IOLOGICAL AND
S
YNTHETIC
P
OLYMER
N
ETWORKS
(O. Kramer ed., Elsevier, London 1988); M. Shibayama & T. Tanaka,
Adv. Polym. Sci.
109:1 (1993); T. Tanaka, I. Nishio, S. Sun, & S. Ueno-Nishio,
Science
218:467 (1982); A. S. Hoffman, J. Controlled Release 6:297 (1987). A gel is a three-dimensional cross-linked polymer network swollen by a large quantity of solvent, whose properties fall between those of a liquid and those of a solid. For this reason, polymer gels are sometimes classified as wetware in order to distinguish them from software and hardware.
Despite a variety of interesting physical and chemical properties, synthetic gels are still used mainly in only a few applications, such as in foods, as water adsorbents, and in soft contact lenses. Two main obstacles—namely, the gel shrinking/swelling speed and strength—have limited many of the potential applications of gels. Much effort has been applied in the last two decades to overcome these two obstacles. For example, it has been reported that the slow shrinking rate can be attributed to the formation of a hard skin layer at very initial stage of the gel shrinking, which prevents further diffusion and outflow of solvent molecules, such as water molecules, from inside the gel. A. Gutowska et al., J. Controlled Release 22:95 (1992); T. G. Park & A. S. Hoffman,
Enzy. Microb. Technol.
15:476 (1993); K. Sekimoto,
Phys. Rev. Lett.
70:4154 (1993); H. Yu & D. W. Grainger,
J. Appl. Polym. Sci.
49:1553 (1993); R. Yoshida et al.,
J. Biomat. Sci.
-
Polym. Ed.
6:585 (1994); Y. H. Kim et al.,
J. Controlled Release
28:143 (1994). Using another hydrophobic polymer to modify thermal sensitive polymer gels via an interpenetrating polymer network (“IPN”) structure has also been reported. A. Gutowska et al.,
Macromolecules
27:4167 (1994); R. Yoshida et al.,
Nature
374:240 (1995). This leads to a stronger gel, and in some cases, a moderately improved shrinking rate. Most of the applications of these IPNs are in drug delivery. Recently, Yoshida et al. reported that grafting a hydrogel can increase its shrinking rate. R. Yoshida et al.,
Nature
374:240 (1995). However, preparation of such a comb-type grafted hydrogel is not a simple task.
It would therefore be desirable to provide an easily producible polymer gel composition which has improved shrinking rate and strength characteristics. The present invention meets these and other needs.
SUMMARY OF THE INVENTION
The present invention generally relates to polymer compositions that have enhanced temperature-dependent shrinking rates, increased strength, and improved pliability over previously known polymer compositions. In particular, the present invention provides thermally responsive polymer gel compositions comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within the hydrophobic polymer matrix, wherein the polymer gel composition has enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone. This combination results in polymer gel compositions having improved properties, including increase shrinking rates, increased gel breaking strength, and other advantageous properties, such as described above. The compositions of the invention find particular use in surgical applications for the repair and reinforcement of damaged tissues, such as, for example, blood vessels, neurons, nerves, and the like, especially in warm-blooded animals. In addition, the compositions of the invention are particularly useful in in vivo and ex vivo surgical applications for sealing leaking or ruptured blood vessels and for joining two blood vessel segments or two nerve segments, and the like, especially in warm-blooded animals. In a particular aspect, the hydrophobic polymer matrix comprises poly(n-isopropylacrylamide) (PNIPAAM) and the interpenetrating hydrophilic polymer network comprises an amount of protein, typically gelatin, disposed within the PNIPAAM.
In another aspect, the invention provides a composition of matter which comprises a polymer gel comprising a thermally sensitive polymer matrix and a hydrophilic polymer network interpenetrating said the thermally sensitive polymer matrix. The polymer gel is capable of shrinking at a greater rate in response to a change in temperature as compared to the thermally sensitive polymer matrix alone.
The invention also provides a thermally responsive biocompatible polymer gel composition, comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within said hydrophobic polymer matrix, wherein the polymer gel composition has a shrinking rate that is greater than a shrinking rate of the hydrophobic polymer matrix.
In still another aspect, the invention provides an interpenetrating polymer network gel composition comprising a thermosensitive polymer, and a hydrophilic polymer interpenetrating the thermosensitive polymer. The thermosensitive polymer and the hydrophilic polymer are arranged with respect to each other so that at least one type of interaction develops between the thermosensitive polymer and the hydrophilic polymer. Such interaction is sufficient to cause the composition to shrink at a greater rate than the thermosensitive polymer alone at a temperature above a shrinking temperature of the composition.
The invention also provides thermally responsive polymer gel compositions formed into sheets or tubes. Such sheets and tubes find useful in various applications of the invention, including in methods for sealing severed or ruptured blood vessels and as prosthetic blood vessels for medical and surgical applications.
In another aspect, the invention provides a thermally responsive polymer gel composition comprising PNIPAAM and gelatin, and further comprising a chemical incorporated into the gel composition, said chemical capable of being released from the composition in response to an increase in the temperature of the gel composition to a temperature above a shrinking temperature of the composition.
In yet another aspect of the invention, methods for sealing a blood vessel system in vivo are provided. Such methods comprise providing a tube comprising a thermally responsive biocompatible polymer gel composition of the present invention, the tube having a first end and a second end, and an internal lumen therebetween, and the tube being maintained at a temperature of no more than about 32° C., and providing a severed blood vessel comprising a first end and a second end, the vessel being within a warm-blooded animal having a minimal internal ambient temperature of from about 25° C. to about 40° C., and more preferably, at least about 35° C. The first severed end of the blood vessel is inserted into the first end of the tube, and the second severed end of the blood vessel is inserted into the second end of the tube. The tube is allowed the tube to achieve the ambient temperature and to shrink around the first and second ends of the blood vessel, thereby sealing the blood vessel. For such methods, a preferred thermally responsive biocompatiable polymer gel composition comprises PNIPAAM and gelatin in relative amounts described herein below.
In yet another aspect, the invention provides an in vivo method for repairing a blood vessel system in a warm-blooded animal. The method comprises the steps of providing a tube comprising a thermally responsive polymer gel composition of the present invention, said tube having a first end, a second end, and an internal lumen therebetween, said tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood v
Jiang Suhong
Wu Chi
Allen Kenneth R.
Fubara Blessing
Page Thurman K.
The Chinese University of Hong Kong
Townsend and Townsend / and Crew LLP
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