Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2002-04-16
2003-04-29
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C523S114000
Reexamination Certificate
active
06555123
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to injectable liquid forms or microdispersions of polymers suitable for use in soft tissue repair, augmentation, and as viscosupplements.
A variety of different materials have been used to repair or augment soft tissue defects or to contour abnormalities caused by facial defects, acne, surgical scarring, trauma or aging. Unfortunately, none of these materials is considered to be ideal owing to short-comings in effectiveness or efficacy. For example, liquid silicone was often used to correct soft tissue defects. However, this material was subsequently banned by the FDA when it was discovered that it could migrate to distant parts of the body and cause physiological and clinical problems. Another material, bovine collagen, became available in the 1970's and appeared to be an effective material for treating soft tissue defects. Over time, however, it was discovered that this material was fairly rapidly absorbed. The rapid resorption was partially solved by crosslinking the collagen to extend its lifetime to six months; however, frequent injections of the material are still required. Furthermore, allergic reactions due to bovine proteins present in the collagen persist in the cross-linked material.
A number of newer materials for soft tissue or augmentation have been described. Ceramic particles of calcium phosphate mixed with an aqueous gel carrier in a viscous polymer have been described in U.S. Pat. No. 5,204,382 to Wallace et al. However, there appear to be risks associated with the use of these nonabsorbable particulate materials relating to their migration in vivo. Polymers in combination with solvents and a thermosetting material with a curing agent have both been proposed by Dunn in U.S. Pat. Nos. 4,938,763; 5,278,201; and 5,278,202, but the solvents necessary to dissolve the polymers appear to be less than acceptable, and the materials have limited utility in filling soft tissue defects because they solidify. Furthermore, these materials and other similar commercial materials have ultimate yield stresses close to 10,000 psi compared to between 500 and 2,000 psi for human skin, raising pulpability concerns and making them too hard for repair of soft tissue and especially for dermal augmentation or repair. Other polymer blends based on lactic acid polymers also have been suggested in U.S. Pat. No. 4,235,312 to Buchholz.
Other materials for injection, which solidify to serve as bulking agents or as matrices for tissue ingrowth, are described in U.S. Pat. No. 5,709,854 to Vacanti, et al., and PCT/U.S.96/09065 by Reprogenesis. Exemplary materials in the '854 patent include alginate solutions which are mixed with calcium ions to induce crosslinking after injection. The PCT application discloses alternative crosslinkable synthetic polymers which have similar properties upon exposure to light or multivalent ions.
In this case, however, the polymers are considered to be too viscous to be injected through a needle, which significantly limits their utility. Furthermore, the oligomers also may be slightly soluble in body fluids, facilitating a rapid diffusion out of the site of implantation. To address these concerns, U.S. Pat. Nos. 5,728,752 and 5,824,333 to Scopelianos et al., disclose polymers derived from &egr;-caprolactone, trimethylene carbonate, and/or ether lactones with glycolide, lactide and p-dioxanone units, for use in the repair of soft tissues and augmentation which have lower viscosities and do not harden after implantation. While these compositions appear to have such desirable properties, these materials are fairly rapidly degraded and therefore would need to be re-injected at frequent intervals. Moreover, some of these polymers break-down to monomers well known to cause undesirable inflammatory responses in vivo.
It is therefore an object of the present invention to provide polymeric materials for soft tissue repair and augmentation that are safe, injectable, long lasting, bioabsorbable, and biocompatible.
It is a further object of this invention to provide methods for preparing and using such materials.
SUMMARY OF THE INVENTION
Polyhydroxyalkanoate materials are provided which are suitable for repair of soft tissue, augmentation, and as viscosupplements in animals, particularly humans. The materials comprise liquid polyhydroxyalkanoate polymer compositions or polyhydroxyalkanoate microdispersions. Devices also are provided for storage and delivery of the polyhydroxyalkanoate compositions in vivo.
Methods are provided for repairing or augmenting soft tissue in animals using the materials. In a preferred embodiment, the method include the steps of (a) selecting the animal soft tissue to be repaired or augmented; and (b) placing an injectable, liquid polyhydroxyalkanoate polymer or a polyhydroxyalkanoate microdispersion into the animal soft tissue, preferably using a minimally-invasive method such as injection. In another embodiment, the liquid polyhydroxyalkanoate polymer compositions or polyhydroxyalkanoate microdispersions are used as viscosupplements.
DETAILED DESCRIPTION OF THE INVENTION
It was discovered that polyhydroxyalkanoate polymers can be selected and/or rendered are suitable for use in soft tissue repair, augmentation, and as viscosupplements. In preferred embodiments, these polyhydroxyalkanoate polymer compositions have low viscosities which enable them to be injected into soft tissue or the knee joint with a syringe and needle. These polymers preferably do not harden after implantation. Degradation rates can be controlled so that certain compositions are slow to bioabsorb, thereby decreasing considerably the frequency with which the composition must be re-injected.
I. The Polyhydroxyalkanoate Compositions
The composition comprises a fluid material which comprises a polyhydroxyalkanoate. The polyhydroxyalkanoate is either in the form of a liquid or a microdispersion, and optionally may further include agents to increase the safety and efficacy of the composition. The PHA must be a fluid at body temperature or must be in the form of a microdispersions in a fluid carrier.
As used herein, the term “body temperature” refers to the approximate average normal, internal temperature of the animal into which the composition is to be introduced, for example, about 37° C. in humans.
Physical properties of the compositions which make them useful for the augmentation of soft tissue are that they can be easily delivered, preferably by injection, to the desired tissue and that the composition is biocompatible and slowly bioabsorbed.
As used herein, the term “biocompatible” refers to compositions that are well tolerated by the body and which do not cause a prolonged adverse inflammatory reaction that would affect their function or performance.
As used herein, the term “bioabsorbable” refers to compositions which decomposes under normal in vivo physiological conditions into components which can be metabolized or excreted. “Slow bioabsorption” means that the composition performs the intended repair, augmentation, or viscosupplementation function for the appropriate time period, preferably longer than 1 month. In contrast, a material that is too quickly bioabsorbed requires frequent re-injection.
As used herein, the term “microdispersion” refers to a suspension of particles. The particles form a separate, phase from that of the continuous phase. The particles may be in an amorphous or crystalline state. The particle size and concentration is chosen to provide the appropriate properties of the mixture. Typically, the particle size is on the order of 1 nm to 500 &mgr;m.
The compositions preferably can be easily injected using conventional techniques, that is, they can be injected manually, such as with a syringe and needle, preferably one having a 16 gauge diameter, more preferably having a 22 or larger gauge (i.e. smaller diameter needle).
In one embodiment, the PHA is a wax at room temperature (e.g., between 20 and 25° C.) which can be heated to body temperature or greater so that the compositi
Martin David P.
Williams Simon F.
Azpuru Carlos
Holland & Knight LLP
Tepha, Inc.
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