Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-02-02
2004-03-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S491000, C424S493000, C424S497000, C424S422000, C424S423000, C424S426000
Reexamination Certificate
active
06703047
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to hydrogels used as sealants for tissue fluid leaks, as adherent drug delivery depots, as means for augmenting and/or supporting tissue, and as means for serving a useful medical or surgical purpose. More particularly, the present invention relates to compositions and methods for forming tissue adherent hydrogels using substantially dry precursors.
BACKGROUND OF THE INVENTION
In situ therapy has primarily focused on transformation of precursor solutions into solids within a patient's body. Transformations have been achieved by a variety of means, including precipitation, polymerization, crosslinking, and desolvation. Precursor materials may be natural or synthetic, or a combination thereof. Examples of solution-based in situ therapy techniques include U.S. Pat. Nos. 4,804,691; 5,122,614; 5,410,16; 4,268,495; 5,527,856; 5,614,204; 5,733,950; and 5,874,500.
Significant limitations exist when using solutions for in situ therapy. Solutions of low viscosity may flow away and be cleared from an application site before transformation and solidification occurs. Furthermore, formulation of the solutions may be complex, as preparation of precursor solutions typically requires reconstitution of the precursors, or, when the solutions are stored frozen, thawing.
Polymerizable powdered mixtures have been combined with liquid initiators to form settable pastes for use as bone cements, as discussed in U.S. Pat. Nos. 4,456,711; 5,468,811; and 4,490,497. However, all these compositions and related methods for making medically-useful products from such compositions are limited by use of a non-aqueous solvent or initiator. Polymerizations are not activated by the presence of aqueous physiological surroundings.
A variety of applications exist for in situ therapy. During surgery, for example, tissues and organs may be damaged or traumatized, and may thereby develop leaks. Furthermore, the organs may be too fragile to manipulate and repair using conventional surgical means, such as suturing. In situations where leaks appear or where conventional surgical management is difficult, surgical adhesives and sealants may be useful.
Several tissue sealants are known in the art. The most commonly used biologically-based sealant is fibrin glue or fibrin sealant. This sealant typically comprises aqueous solutions of purified fibrinogen and thrombin. A coagulum is formed by mixing these two solutions together, and the coagulum may serve as a sealant or tissue adhesive. However, adhesion strength is limited, and setup time may be long. Furthermore, a wound leaking fluids is likely to wash the sealant away from an application site prior to solidification of the coagulum, thereby limiting the efficacy of fibrin glue. Likewise, the efficacy of all liquid sealants is limited by adherence of liquid sealants to tissue surfaces that present liquid interfaces. It therefore becomes important to have substantially dry surfaces prior to application of liquid tissue sealants. However, creation of dry application sites in situ is often unfeasible during surgery.
A product under the brand name Tachocomb (Behringwerke, Germany) has recently been introduced, which uses dry components to form a hemostatic patch of the fibrin sealant. The patch has been formed using horse collagen, bovine thrombin, and human fibrinogen. Since the component materials are procured from animal sources, allergic responses and disease transmission may result. The materials are also expensive to manufacture. Furthermore, the efficacy of fibrin-based sealants may be adversely affected by anticoagulants routinely administered as part of surgical and interventional procedures.
More recently, synthetic alternatives to fibrin sealants have been developed. One such material comprises photoactivated poly(ethylene glycol) (“PEG”), which is marketed as FocalSeal™ (Focal, Inc., Lexington, Mass.). Focal, Inc., claims that FocalSeal™ provides superior strength characteristics over fibrin sealants and glues. However, use of light to initiate polymerization limits applicability in surgical environments where bleeding is not effectively controlled, since blood impedes light transmission. Other surgical sealants, including synthetic sealants such as Co-Seal™, are marketed by Cohesion Technologies (Palo Alto, Calif.). However, these sealants, as well as FocalSeal™, require a dry surface for application.
In view of the drawbacks associated with previously-known methods and apparatus for in situ therapy, it would be desirable to provide methods and apparatus that overcome these drawbacks.
It further would be desirable to provide methods and apparatus that use dry materials procured from sources other than non-human animals.
It still further would be desirable to provide methods and apparatus for in situ therapy that are activated solely by the presence of aqueous physiological surroundings.
It further would be desirable to provide methods and apparatus that do not require complex formulation prior to use.
It would also be desirable to provide methods and apparatus that remain effective in the presence of anticoagulants.
It would be desirable to provide methods and apparatus for in situ therapy that are inexpensive to manufacture and are highly effective in clinical practice.
SUMMARY OF THE INVENTION
In view of the foregoing, it is an object of the present invention to provide methods and apparatus for in situ therapy that overcome drawbacks associated with previously-known methods and apparatus.
It is also an object of the present invention to provide methods and apparatus that use dry materials procured from sources other than non-human animals.
It is another object to provide methods and apparatus for in situ therapy that are activated solely by the presence of aqueous physiological surroundings.
It is yet another object to provide methods and apparatus that do not require complex formulation prior to use.
It still further is an object of the present invention to provide methods and apparatus that remain effective in the presence of anticoagulants.
It is an object of the present invention to provide methods and apparatus for in situ therapy that are inexpensive to manufacture and are highly effective in clinical practice or field use, such as a battle field where rapid medical attention may be needed.
These and other objects of the present invention are accomplished by providing compositions and methods for forming tissue-adherent hydrogels using substantially dry precursors. The dehydrated hydrogel precursors are premixed prior to in situ therapy and utilize naturally-occurring body fluids as an aqueous environment that initiates transformation. The precursors do not form an insoluble, crosslinked solid until such time as they are exposed to the aqueous physiological setting. Upon exposure to the aqueous setting, dissolution and nearly simultaneous crosslinking of the dehydrated precursors occurs, thus forming an insoluble hydrogel implant. The implant is preferably bioabsorbable.
The dehydrated precursor-based hydrogels of the present invention may be used for a variety of medical applications, including use as sealants for fluid leaks from tissue, as adherent drug delivery depots, and as means for augmenting and/or supporting tissue. The hydrogels are typically a mixture of two or more individual dry precursors. The precursors may be selected for specific therapeutic uses, for example, adherence, coagulation of blood, dessication, etc. The precursors may be administered directly to an open wound site or may be dispensed using a means of application. The means of application may include, for example, a non-adhesive backing material, an absorbable backing material, a syringe applicator, a powder atomization or aerosolization system, or a needle-less injector.
When used as a sealant and applied to a wound site, rapid uptake of blood or other tissue fluid occurs, thereby facilitating crosslinking of the dehydrated precursor components and providing adherence of the resulting coagulum to underlying tissue. Additionally
Edelman Peter G.
Sawhney Amarpreet S.
Di Nola-Baron Liliana
Incept LLC
Page Thurman K.
Patterson Thuente Skaar & Christensen P.A.
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