Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1997-12-19
2002-08-27
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S423000, C424S424000, C424S425000, C424S426000, C424S443000, C514S021800, C514S054000
Reexamination Certificate
active
06440427
ABSTRACT:
The present invention relates to a tissue treatment composition, especially a tissue adhesive having improved properties and to the use of such compositions as anti-adherence or would healing compositions, as slow-release drug formulations, for coating tissues or prosthetic materials, and as carriers for cell transplants.
The use of blood coagulating substances for stopping bleedings and for sealing wounds has been known for a long time. Thus, the hemostatic effect of fibrin powder was reported about 80 years ago, and attempts were made to employ fibrin or fibrin patches to stop bleeding in brain and general surgery.
Today such use of fibrin as a biologic adhesive has been widely accepted and found application in many fields of surgery. Generally fibrin sealants are based upon the two components fibrinogen and thrombin. As these components mix a fibrin coagulum is formed in that the fibrinogen molecule is cleaved through the action of thrombin to form fibrin monomers which spontaneously will polymerize to form a three-dimensional network of fibrin, largely kept together by hydrogen bonding. This corresponds to the last phase of the natural blood clotting cascade, the coagulation rate being dependent on the concentration of thrombin used.
In order to improve the tensile strength, covalent crosslinking between the fibrin chains is provided for by including Factor XIII in the sealant composition. The strength of the fibrin clot is further improved by the addition of fibronectin to the composition, the fibronectin being crosslinked and bound to the fibrin network formed.
To prevent a too early degradation of the fibrin clot by fibrinolys, the fibrin sealant composition may comprise a plasminogen activator inhibitor or a plasmin inhibitor, such as aprotinin. Such an inhibitor will also reduce the fibrinolytic activity resulting from any residual plasminogen in the fibrinogen composition.
Similarly, compositions according to the invention which include hyaluronic acid (or other polysaccharides), may also comprise a hyaluronidase inhibitor such as one or more flavonoids (or corresponding inhibitors for other polysaccharides) in order to prevent premature degradation (i.e. to prolong the duration) of the hyaluronic acid component by hyaluronidase which is always present in the surrounding tissues. The hyaluronic acid may, as mentioned above, be crosslinked, a commercially available example being Hylan® (trademark, available from Biomatrix, Ritchfield, N.Y., USA). The hyaluronic acid compositions may e.g. have the form of gels, solutions, etc.
The results obtainable by fibrin sealants are basically:
(i) Hemostasis. The fibrin clot acts as a hemostatic barrier and reduces the risk of serum, lymph and liquor leakage. The hemostatic effect may be enhanced if the fibrin sealant is combined with a biocompatible solid flat material such as collagen.
(ii) Glueing. Due to its adhesive properties the fibrin sealant atraumatically connects tissues by forming a strong joint between them and adapts uneven wound surfaces. This glueing effect is increased by fibronectin being bound to exposed collagen.
(iii) Wound healing. The fibrin sealant promotes the ingrowth of fibroblasts which in combination with efficient hemostasis and adhesion between the wound surfaces provides for an improved healing process. Wound healing promoted by fibrin sealants results in strong scar formation and does not prevent the formation of adhesions. The use of the compositions according to the invention as an anti-adherence/wound healing composition does, however, result in a normal (regenerative) tissue rather than scar tissue, i.e. optimal wound heaing. Furthermore, such compositions also reduce the inflammatory response as appears from the test results reported in Table 4 below.
Fields of application include among others: ear, nose and throat surgery, general surgery, dentistry, neurosurgery, plastic surgery, thorax and vascular surgery, abdominal surgery, orthopaedics, accident surgery, gynaecology, urology, and opthalmology. Fibrin sealants have also been used for local application of drugs, such as antibiotics, growth factors and cytostatics.
Commercial fibrin glues (prepared from human plasma) are available under the trade names Tissucol, Tisseel and Fibrin-Kleber Humano Immuno (Immuno AG, Vienna, Austria) as well as Beriplast (Behringwerke AG, Marburg, Germany) (these trade names being registered trademarks in several countries). Tisseel™ is a two-component kit containing a fluid thrombin component including calcium chloride and a somewhat more viscous fibrinogen component including factor XIII, fibronectin, aprotinin and plasminogen. The two components are delivered deep frozen in two separate syringes, or as two lyphilized powders with corresponding aprotinin and calcium solutions as solvents. As explained above the fibrin sealant consolidates when the two components are combined due to fibrin monomer aggregation. The setting rate is dependent on the thrombin concentration and varies from a few seconds (high thrombin concentration) to a couple of minutes (low thrombin concentration).
However, an important and well known disadvantage of the known preparations resides in the water-like fluidity of the components when applied, which leads to considerable handling difficulties of the glue. Efforts have been made to overcome this problem and facilitate the mixing of the components by the development of particular application modes such as a double-syringe applicator (e.g. that supplied under the trade name Duploject®, Immuno AG, Vienna, Austria, and which is disclosed in e.g. U.S. Pat. No. 4,359,049, or a special spray system as disclosed in e.g. EP-A-156 098). The basic problem with a low viscosity glue still remains, however. Firstly, a non-viscous or low viscosity glue is unsuitable for use on non-horizontal surfaces since it will run off before setting. Secondly, there is a definite risk of a non-viscous or low vicosity glue running off to sites where it is unwanted and where it might cause complications. This is particularly the case in vascular surgery since the fluid glue may reach inside the vessels before it sets and thereby cause thromboembolic complications. An instantantaneously setting fibrin glue (containing a high concentration of thrombin), on the other hand, cannot be used where the parts to be sealed require subsequent adaptation.
A different approach has been disclosed by i.a. Bass et al in J. Vasc. Surg. May 11, 1990 (5):718-25, which is incorporated herein by reference. This paper discloses a technique called laser tissue soldering (or welding), wherein a laser energy absorbing dye (chromophore) and fibrinogen are soldered by means of a laser to produce a strong anastomosis which is said to be i.a. faster healing than a conventional sutured anastomosis. Similar coagulation and/or bonding effects can be achieved with other proteins and energy sources.
It is an object of the present invention to provide an improved fibrin glue which is devoid of the above low viscosity problem, and which promotes wound healing without scar formation or development of adhesions. This object is achieved by including in a fibrin glue composition of the above mentioned type a viscosity increasing amount of a biodegradable and biocompatible polymer capable of forming a viscsous aqueous solution. In accordance with the present invention it has thus been found that by the addition of such a viscosity enhancing polymer, the glue composition will obtain a viscosity adequat to facilitate and improve the handling and application thereof, while not negatively affecting the favourable properties of the fibrin glue. For wound healing and anti-adherence purposes the adhesive properties may, however, be less pronounced, or even missing.
Accordingly, the present invention relates to a tissue treatment composition comprising (i) fibrin or fibrinogen and (ii) a biodegradable and biocompatible polymer capable of forming a viscous aqueous solution, optionally also other proteins.
One use form of the present tissue adhesive composition
Biovitrum AB
Fish & Richardson P.C.
Kishore Gollamudi S.
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