Monomeric compositions effective as wound closure devices

Details Monomeric compositions effective as wound closure devices Monomeric compositions effective as wound closure devices

1997-08-12

2003-05-20

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Topical body preparation containing solid synthetic organic...

Skin burn or open wound treatment

C424S078350, C424S078020, C424S078050, C424S078070, C424S078270, C424S407000

Reexamination Certificate

active

06565840

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to monomer and polymer compositions useful to form biomedical adhesives and sealants, and methods of applying them. More particularly, this invention relates to wound closure monomer and polymer compositions and their use for medical, surgical and other in vivo applications.
BACKGROUND
Products in primary use for wound closure are surgical sutures and staples. Sutures are recognized to provide adequate wound support. However, sutures cause additional trauma to the wound site (by reason of the need for the needle and suture to pass through tissue and the need to anesthetize the wound area via needle application) and are time-consuming to place, and, at skin level, can cause unattractive wound closure marks. Surgical staples have been developed to speed wound apposition and provide improved cosmetic results. However, surgical staples also impose additional wound trauma and require the use of ancillary and often expensive devices for positioning and applying the staples. Both sutures and staples are especially problematic in pediatric cases where the patient may have a strong fear response and refuse to cooperate with their placement, and in geriatric cases where the skin tissue is weaker and prone to tearing.
Alternatively, adhesives have been proposed as wound closure devices. One group of such adhesives is the monomeric forms of alpha-cyanoacrylates.
Reference is made, for example, to U.S. Pat. Nos. 5,328,687 to Leung et al; U.S. Pat. No. 3,527,841 to Wicker et al.; U.S. Pat. No. 3,722,599 to Robertson et al.; U.S. Pat. No. 3,995,641 to Kronenthal et al.; and U.S. Pat. No. 3,940,362 to Overhults, which disclose alpha-cyanoacrylates that are useful as surgical adhesives. All of the foregoing references are hereby incorporated by reference herein.
Typically, the cyanoacrylate surgical adhesive is applied to one or both surfaces of wounds or incisions, including the internal portions of the wound, with any excess adhesive being quickly removed from the bonding surfaces. Subsequently, the edges of the wound are held together until they adhere. See U.S. Pat. No. 3,559,652 to Coover, Jr. et al. Two coatings of adhesive may be applied to the wound surfaces. However, this method of application produces significant levels of histoxicity due to the surgical adhesive being trapped within the wound site.
An additional method of application of the cyanoacrylate surgical adhesive to wounds or incisions involves the formation of a bridge over the wound site. As described in U.S. Pat. No. 3,667,472 to Halpern, the incised tissues are held together and maintained in fixed relationship until a cyanoacrylate adhesive has been applied over the incision and allowed the necessary time to develop a bond. Excess adhesive is removed from the incision. However, the composition utilized in this process suffers from inadequate film strength and flexibility with high histotoxicity in wound sites.
These conventional methods of application of tissue adhesive generally do not specify a particular method that is preferable, nor is there any mention of placing more than minimal amounts of glue upon wounds. The conventional application techniques strive to reduce application of excessive amounts of tissue adhesive to the wound due to histoxicity.
A topical tissue adhesive commercially available is Histoacryl® available from B. Braun Melsungen AG of Germany. The manufacturer recommends use of this adhesive only for closure of minor skin wounds and not for internal use. Moreover the manufacturer recommends that the adhesive be used sparingly or in thin films because thick films do not increase the film strength and can lead to necrosis of surrounding tissue due to thermogenic reaction. Moreover, films formed from this adhesive are brittle, permitting severe dehiscence of wounds.
Plasticizers have been added to cyanoacrylate surgical adhesive compositions. See, for example, U.S. Pat. Nos. 3,759,264 to Coover, Jr. et al., U.S. Pat. No. 3,667,472 to Halpern, U.S. Pat. No. 3,559,652 to Banitt, the subject matter of which is incorporated herein by reference. However, the incorporation of plasticizers in such compositions has led to decreased film strength of the polymerized material. Accordingly, such compositions have been utilized only within the wound site and not over the wound site as a bridge.
Other additives have been employed in cyanoacrylate surgical adhesives for the purposes of modifying the cure rate and shelf life of the adhesives. For example, cyanoacrylate polymerization inhibitors or stabilizers including Lewis acids, such as sulfur dioxide, nitric oxide, boron trifluoride and other acidic substances, including hydroquinone monomethyl ether, hydroquinone, nitrohydroquinone, catechol and hydroquinone monoethyl ether. See, for example, U.S. Pat. No. 3,559,652 to Banitt, the subject matter of which is incorporated herein by reference. These compositions contain significant amounts of impurities and, thus, require substantial amounts of stabilizer to inhibit premature polymerization of the monomer.
Other adhesives include both plasticizers and stabilizing agents. For example, U.S. Pat. No. 5,480,935 to Greff et al. describes a tissue adhesive having a plasticizer and a polymerization inhibitor. However, the plasticizers disclosed therein (i.e., alkyl phthalates) are highly toxic and are not suitable for use in biocompatible medical adhesives.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that combining the monomers described hereinafter with a plasticizing agent and an acidic stabilizing agent provides a surgical adhesive composition that, after application to wounds or incisions, polymerizes to form a strong and flexible bond on the wound or incision site. Furthermore, the present invention provides a process for application of this surgical adhesive composition in a bridge structure that provides an unexpectedly improved bond strength over conventional application techniques of the polymerized composition on the wound or incision site, which increases the effectiveness of such monomers and polymers in in vivo applications.
The surgical adhesive forms a flexible and strong bond over wounds and incisions. Moreover, the method of applying a surgical adhesive to a wound or incision provides a strong and flexible biocompatible bond.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
One embodiment of the present invention provides a wound closure monomer composition, comprising:
A) at least one monomer, which forms a medically acceptable wound closure polymer:
B) at least one plasticizing agent; and
C) at least one acidic stabilizing agent.
In other embodiments, the present invention is directed to methods of using the above-described monomers, copolymers and polymers made therefrom for biomedical purposes.
In one such embodiment, the edges of a wound or incision are held together and an excessive amount of the above-described surgical adhesive composition is applied to the already pinched or abutted opposing wound edges, preferably utilizing more than one application stroke. This process forms a bridge over the abutted opposing wound edges that is flexible and possesses high tensile strength. The excessive amount of adhesive placed on the abutted opposing wound edges forms a thick film thereon and unexpectedly increases film strength.
For example, the present invention includes a method of forming a biocompatible film across abutted tissue surfaces, comprising; (a) holding together at least two tissue surfaces to form abutted tissue surfaces, (b) applying across said abutted tissue surfaces an adhesive biocompatible monomer composition, and (c) allowing said composition to polymerize and form a biocompatible film on said abutted tissue surfaces having an in vivo film strength of at least 70 mmHg of vacuum pressure required to induce wound failure, generally from 70 mmHg to 400 mmHg of vacuum pressure required to induce wound failure, preferably from 90 mmHg to 400 mmHg of vacuum pressure required to induce wound failure, and more preferably

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