Adhesive composition for wound closure

Abstract

Stabilized monomer and polymer adhesive compositions useful in the formulation of biomedical adhesives and sealants for application to living tissue are provided.

Claims

1. A stable biocompatible adhesive composition comprising: a 2-octyl cyanoacrylate monomer capable of polymerization and having a purity of at least 98%, wherein a weight % of the 2-octyl cyanoacrylate monomer is between about 83% to about 89%; a first viscosity modifier comprising polymethyl methacrylate (PMMA), wherein the first viscosity modifier comprises a molecular weight from about 400,000 Da to about 500,000 Da; a second viscosity modifier comprising the PMMA, wherein the second viscosity modifier comprises the molecular weight from about 100,000 Da to about 130,000 Da, and wherein each of the first viscosity modifier and the second viscosity modifier comprises the weight % between about 2% to about 5%; a plasticizer comprising tributyl O-acetylcitrate (TBOAC), wherein the weight % of the TBOAC is between about 3% to about 6%; a solvent having the weight % between about 3% to about 7%; a first stabilizer in an amount of about 5,000 parts per million (ppm) to about 15,000 ppm; a second stabilizer in the amount of about 100 ppm to about 300 ppm; a polymerization initiator comprising benzalkonium chloride (BZC), wherein the weight % of the BZC is between about 0.1% to about 0.3%; and a polymerization accelerator comprising hexamethylenetetramine (HMTA), wherein the weight % of the HMTA is between about 0.1% to about 0.3%.

2. The composition of claim 1, wherein said 2-octyl cyanoacrylate monomer has a purity of 99% by weight or greater.

3. The composition of claim 1, wherein said solvent is acetone.

4. The composition of claim 1, wherein said first stabilizer is butylated hydroxyanisole (BHA).

5. The composition of claim 1, wherein said second stabilizer is sulfur dioxide (SO.sub.2).

6. The composition of claim 1, wherein said solvent is acetone, said first stabilizer is butylated hydroxyanisole, and said second stabilizer is sulfur dioxide.

7. The composition of claim 1, wherein: the weight % of each of said first viscosity modifier and said second viscosity modifier is from about 3% to about 5%; the weight % of said TBOAC is from about 4% to about 6%; and the weight % of said solvent is from about 4% to about 6%.

8. The composition of claim 1, wherein said BZC is dissolved in another solvent and applied to an applicator, and wherein said other solvent substantially evaporates before said stable biocompatible adhesive composition comes into contact with said applicator, thereby initiating a polymerization reaction and producing a solid, biocompatible wound sealant.

9. An adhesive composition comprising: between about 83 weight % and about 89 weight % of a 2-octyl cyanoacrylate monomer having a purity of at least 98%; between about 2 weight % and about 5 weight % of a first polymethyl methacrylate (PMMA) viscosity modifier having a molecular weight from about 400,000 Da to about 500,000 Da; between about 2 weight % and about 5 weight % of a second PMMA viscosity modifier having the molecular weight from about 100,000 Da to 130,000 Da; between about 3 weight % to about 6 weight % tributyl O-acetylcitrate (TBOAC); between about 3 weight % and 7 weight % acetone; between about 5,000 parts per million (ppm) and about 15,000 ppm of butylated hydroxyanisole; between about 100 ppm and about 300 ppm of sulfur dioxide; between about 0.1 weight % and 0.3 weight % of a polymerization initiator, the polymerization initiator comprising benzalkonium chloride (BZC); and between about 0.1 weight % and 0.3 weight % of a polymerization accelerator, the Polymerization accelerator comprising hexamethylenetetramine (HMTA).

10. The composition of claim 9, wherein said butylated hydroxyanisole is about 10,000 ppm, and wherein said sulfur dioxide is about 150 ppm.

11. A system for treating living tissue comprising: an applicator comprising: a first reservoir disposed in a non-contact relationship with a second reservoir, wherein the first reservoir comprises: between about 83 weight % and about 89 weight % of a 2 octyl cyanoacrylate monomer; between about 3 weight % and about 5 weight % of a first viscosity modifier comprising polymethyl methacrylate (PMMA), wherein the first viscosity modifier comprises a molecular weight from about 400,000 Da to about 500,000 Da; between about 3 weight % and about 5 weight % of a second viscosity modifier comprising the PMMA, wherein the second viscosity modifier comprises the molecular weight from about 100,000 Da to about 130,000 Da; between about 3 weight % and about 6 weight % of tributyl 0-acetylcitrate (TBOAC); between about 3 weight % and about 7 weight % of acetone; between about 5000 parts per million (ppm) and about 15000 ppm of butylated hydroxyanisole; and between about 100 ppm and about 300 ppm of sulfur dioxide, and the second reservoir comprising: a polymerization initiator, wherein the polymerization initiator comprises benzalkonium chloride (BZC) having a weight % between about 0.1% to about 0.3%; and a polymerization accelerator, wherein the polymerization initiator comprises hexamethylenetetramine (HMTA) having the weight % between about 0.1% to about 0.3%; and an applicator tip capable of combining contents of the first reservoir with contents of the second reservoir to form an adhesive composition and then applying said adhesive composition to a living tissue.

12. A composition comprising: about 88.35% by weight of 2-octyl cyanoacrylate having a purity of more than about 99% by weight; from about 100 parts per million (ppm) to about 300 ppm of sulfur dioxide (SO.sub.2) as a first polymerization inhibitor; about 7337 ppm of butylated hydroxyanisole (BHA) as a second polymerization inhibitor; about 5.06% by weight of a biocompatible plasticizer comprising tributyl O-acetylcitrate (TBOAC); about 3.27% by weight of a viscosity modifier comprising polymethyl methacrylate (PMMA); about 2.59% by weight of acetone; and about 11.44% by weight of cured cyanoacrylate measured using HNMR at 50 degrees C. at 78 days after exposure to 10 kGy of electron beam radiation.

13. The composition of claim 12, said composition having an initial viscosity, wherein said initial viscosity increases less than about 10% after 90 days at 30 degrees C.

14. The composition of claim 13, wherein said initial viscosity increases less than about 10% after exposure to the 10 kGy of electron beam radiation.

15. The composition of claim 12, wherein said 2-octyl cyanoacrylate has a cured weight % of less than about 5% after 60 days at 30 degrees C.

16. The composition of claim 12, wherein said 2-octyl cyanoacrylate has a cured weight % of less than about 5% after 60 days at 50 degrees C.

17. A stable biocompatible wound closure adhesive composition comprising: from about 83 percent to about 89 percent by weight of 2-octyl cyanoacrylate having a purity of more than about 99% by weight; from about 100 parts per million (ppm) to about 300 ppm of sulfur dioxide (SO.sub.2) as a first polymerization inhibitor; from about 5000 ppm to 15000 ppm of butylated hydroxyanisole (BHA) as a second polymerization inhibitor; from about 4 percent to about 6 percent by weight of a biocompatible plasticizer comprising tributyl O-acetylcitrate (TBOAC); from about 3 percent to about 5 percent by weight of a first viscosity modifier comprising polymethyl methacrylate (PMMA), wherein the first viscosity modifier comprises a molecular weight from about 400,000 Da to about 500,000 Da; from about 3 percent to about 5 percent by weight of a second viscosity modifier comprising the PMMA, wherein the second viscosity modifier comprises the molecular weight from about 100,000 Da to about 130,000 Da; and from about 4 percent to about 6 percent by weight of acetone, wherein a setting time of the stable biocompatible wound closure adhesive composition is between about 60 and about 120 seconds, wherein a butt joint strength of the stable biocompatible wound closure adhesive composition is between about 5 and about 15 lbf, and wherein a peak reaction temperature of the stable biocompatible wound closure adhesive composition is less than about 40 degrees C.

18. The composition of claim 17, wherein the stable biocompatible wound closure adhesive composition has an initial viscosity, and wherein said initial viscosity increases less than about 10% after 90 days at 30 degrees C.

19. The composition of claim 18, wherein said initial viscosity increases less than about 10% after exposure to 10 kGy of electron beam radiation.

20. The composition of claim 17, wherein said 2-octyl cyanoacrylate has a cured weight % of less than about 5% after 60 days at 30 degrees C.

21. The composition of claim 17, wherein said 2-octyl cyanoacrylate has a cured weight % of less than about 5% after 60 days at 50 degrees C.

Description

DESCRIPTION

(1) This invention relates to specific alkyl cyanoacrylate compositions that are particularly well suited for topical application to human skin.

(2) As used herein, the following terms have the following meanings:

(3) The term “cyanoacrylate” refers to an adhesive compound or mixture of compounds based on cyanoacrylate monomers. Partial polymers (i.e., oligomers) of such cyanoacrylates are also encompassed within this definition. A preferred cyanoacrylate for use in this invention is octyl-2-cyanoacrylate (2-OCA).

(4) The term “biocompatible plasticizer” refers to any material which is soluble or dispersible in alkyl cyanoacrylate, which increases the flexibility of the resulting polymer coating on the skin surface, and which is compatible with the skin as measured by the lack of skin irritation. Specific stabilizers can include, by way of example only, tributyl O-acetylcitrate, butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctylphthalate, n-butyryl tri-n-hexyl citrate, benzoate esters of di- and poly-hydroxy branched aliphatic compounds, tri(p-cresyl) phosphate, and the like.

(5) The particular plasticizer employed can be critical and must not produce skin irritation as measured by well-known assays such as primary skin-irritation. The plasticizer must not cause the adhesive to be weak or polymerize prematurely. A particularly preferred plasticizer is tributyl O-acetylcitrate.

(6) Compositions contain a sufficient amount of a viscosity modifier or combination of modifiers to provide for a viscosity of from about 20 to 500 centipoise at 20° C. The thickening agent employed is a biocompatible material which increases the viscosity of the cyanoacrylate composition and includes, by way of example, a partial polymer of the cyanoacrylate, polymethyl methacrylate (PMMA) or polymers soluble in the alkyl cyanoacrylate. Thickening agents are deemed to be biocompatible if they are both soluble in the alkyl cyanoacrylate composition and are compatible with the skin as measured by the lack of skin irritation. The lack of skin irritation can be measured by conventional procedures such as primary skin irritation. Thickening agents must not cause the adhesive to be weak or polymerize prematurely.

(7) At the amounts employed, the stabilizer, for example, sulfur dioxide, and the plasticizer are soluble in the cyanoacrylate and, accordingly, after mixing a uniform solution is produced. The solution can be optionally filtered to remove insoluables.

(8) Some compositions can be prepared generally mixing the requisite amounts of the liquid components until a homogeneous mixture is obtained. When utilized, SO2 gas can be bubbled through the mixture. The mixing procedure cab be conventional and is typically conducted under anhydrous conditions to ensure against water contamination of the composition.

(9) The specific viscosity employed for the cyanoacrylate composition depends, in part, on the intended application of the composition. For example, relatively low viscosities are often preferred where application is to be made to a large surface area. This preference results from the fact that those forms are less viscous and, accordingly, will permit easy application to large surface areas of a thin application. Contrarily, where application is to be made to a specific position on the skin, higher viscosity materials are preferred to prevent “running” of the material to unintended locations.

(10) The particular thickening agent employed to enhance the viscosity of the composition can be critical. Preferred thickening agents include polymethyl methacrylate (PMMA) monomer, oligomer, or blends thereof.

(11) Upon contact with skin moisture and tissue protein, the alkyl cyanoacrylate will polymerize or, in the case of partially polymerized alkyl cyanoacrylate, will further polymerize, at ambient conditions (skin temperature) over about 30 seconds to 120 seconds to provide a solid layer which forms over and strongly adheres to the surface of the skin.

(12) The compositions may additionally contain one or more optional additives such as colorants (e.g. D&C violet), perfumes, anti-diffusion agents, rubber extenders, modifying agents, etc. Optional additives should be both miscible and compatible with the cyanoacrylate adhesive. Compatible additives are those that do not prevent the use of the cyanoacrylate adhesives in the manner described herein.

(13) In general, colorants are added so that the polymerized film will contain a discrete and discernable color. Perfumes are added to provide a pleasant smell to the formulation. Rubber extenders are added to further enhance the flexibility of the resulting polymer coating. The amount of each of these optional additives employed in the cyanoacrylate adhesive composition is an amount necessary to achieve the desired effect.

(14) The resulting composition is generally stored in an applicator for use in a single dose application such as a sealed frangible vile or for use in repeated applications. Single dose applicators include those having a breakable or removable seal that prevents moisture, including atmospheric moisture, from contacting the formulation and potentially causing unwanted polymerization.

(15) The viscosity of an adhesive composition must be controlled in order to prevent undue escape of the adhesive from any given area to which it is applied as well as to allow sufficient time for the monomeric material to polymerize and thus to bring about the desired bonding action, such as wound sealing or closure.

(16) The problem been generally recognized by workers in this field and a rather wide variety of viscosity modifiers for alpha-cyanoacrylate adhesives have been suggested in patents and the literature. The present invention relates to among other aspects, a viscosity modifier system for use as a component of this type of adhesive and having solubility in alpha-cyanoacrylates and a high order of heat stability. These properties render such modifiers particularly advantageous when used as components of surgical adhesives which can be subjected to heat, filtration, or electron beam sterilization procedures in order to provide that the resulting compositions are sterile and safe for their intended uses.

(17) Another requirement of alpha-cyanoacrylate adhesive compositions which are to be employed for surgical uses is that both the adhesive component and the viscosity modifier must be relatively non-toxic and each component must be biodegradable, that is, each must be susceptible of biochemical transformation or degradation which will result in harmless products which can be readily absorbed into and carried away from the point of application by the body fluids and thus ultimately eliminated from the system.

(18) This invention has as an object to provide alpha-cyanoacrylate adhesive compositions having viscosity and other characteristics which render them particularly useful as wound closure adhesives or sealants.

(19) One object is to provide alpha-cyanoacrylate adhesive compositions having viscosity and other characteristics which render them particularly useful for surgical applications.

(20) A further object is to provide alpha-cyanoacrylate adhesive compositions particularly adapted for use in the surgical field and characterized by the fact that both the adhesive and the viscosity modifying components are biocompatible.

(21) A further object is to provide alpha-cyanoacrylate adhesive compositions for both general and surgical uses containing a viscosity modifier which is soluble in cyanoacrylate monomers and has a high degree of stability under sterilization conditions and during storage.

(22) Another object is to provide alpha-cyanoacrylate adhesive compositions containing a biocompatible viscosity modifier and stabilized against polymerization by the presence of one or more polymerization inhibitors.

(23) In order to stabilize the compositions of the present invention against unwanted rapid polymerization, and also to provide a satisfactory shelf life, one or more polymerization inhibitors may be employed. The inhibiting material may be an acidic stabilizer or a free radical scavenger or both. A free radical scavenger may be defined as a material which has the ability to react with an unpaired electron to produce a substance which does not initiate further polymerization.

(24) Among the free radical scavengers which may be employed as stabilizers in the adhesive compositions of the invention may include: hydroquinone, monomethyl ether of hydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, and t-butyl hydroquinone. BHA is a preferred stabilizer.

(25) The PMMA component(s) employed as the viscosity modifier in accordance with the invention may be one or more PMMA viscosities.

(26) In formulating adhesive compositions in accordance with the invention, the concentration of PMMA in the monomeric alpha-cyanoacrylate may, the range of 2-6 percent by weight of the total composition. The formulations and adhesive compositions of the instant invention were studied in order to optimize various properties such as viscosity and adhesive strength. For example, different viscosity blends of PMMA monomer or oligomer may be combined or optimize the viscosity and strength characteristics of the cured and uncured compositions.

(27) As used herein, the term ppm (parts per million) refers to the amount of stabilizer (m.sub.stabilizer) in relation to the mass of the original adhesive composition (m.sub.f) by the formula: m.sub.stabilizer/(m.sub.stabilizer+m.sub.f)×1,000,000.

(28) Numerous viscosity modifiers were screened for development of tissue adhesives. PMI and PMMA were among the thickeners evaluated in nine different adhesive compositions. Based on the test results, PMMA or blends thereof, was selected as the most desirable viscosity modifier.

(29) Relative viscosity, butt joint strength, peel strength, tensile strength, maximum reaction temperature, setting or cure time, and enthalpy of reaction were measured to select optimum parameters for desirable embodiments of the invention.

(30) Formulations developed herein exhibited increased strength, equivalent adhesive properties, and lower peak temperature exothermic reactions than known target materials while producing flexible compliant adhesive barriers.

(31) Testing was performed to optimize and validate various initiator or accelerator formulations. Enhanced setting time of less than about 120 seconds and butt joint strength of about 10 lbs. were goals for some of the development tests.

(32) Several levels of butylated hydroxyanisole (BHA) (e.g. 5,000 and 15,000 ppm) were tested for stability under simulated e-beam sterilization conditions at various radiation levels.

(33) Additional testing was performed with BHA at 20,000, 30,000 and 50,000 ppm with various initiators to develop a stabilized adhesive composition having optimum setting time, reaction temperature, and strength. BZC was selected as a preferred initiator at levels between about 5000 and about 20000 ppm.

(34) Adhesive composition with BHA levels of 20, 30, and 50K ppm at 10, 15, and 20 kGy radiation levels were characterized. Control adhesives formulated without stabilizer increased viscosity at all exposure levels.

(35) Compositions having BHA levels between about 10K, 20K ppm, 30K ppm, and 50K ppm and BZC levels between about 7.5 mg, 10 mg, and 15 mg respectively were characterized.

(36) Viscosity, setting time, reaction temperature, and butt joint strength were evaluated. Setting time of about 60-120 seconds, butt joint strength of about 10 lbs., and reaction temperature below about 32 C were achieved for some optimized adhesive compositions.

(37) The following examples illustrates certain embodiments of the invention but is not meant to limit the scope of the claims in any way.

EXAMPLES

(38) Example 1 summarizes a study related to one non-limiting example of an embodiment of the present invention. In the study to determine stability under exposure to electron beam radiation, the wt % of cured cyanoacrylate of several samples was measured using HNMR. The results are shown in Table I below.

(39) TABLE-US-00001 TABLE I Total Cured Sample PMMA TBOCA Acetone BHA Cyanoacrylate CA 30 2- 3.82% 4.83% 3.11% 5151 87.73%    0% Control ppm (30° C.) Day 68 2 2-EB- 3.68% 4.93% 3.04% 4074 87.95%  3.42% 5 ppm (30° C.) Day 68 2-EB-5 4.00% 5.09% 2.74% 4729 87.70%  5.01% 50° C. ppm Day 44 Sample 2 30 2- 4.11% 5.06% 3.08% 4447 87.30%  4.99% Control ppm (50° C.) Day 71 2-EB-5 4.09% 5.13% 3.04% 4350 87.31%  8.41% (50° C.) ppm Day 71 6-EB-10 3.50% 5.07% 2.72% 8457 87.86%  1.32% (30° C.) ppm Day 78 6-EB-10 3.27% 5.06% 2.59% 7337 88.35% 11.44% (50° C.) ppm Day 78

(40) For example, a formulation control composition showed 0% cured material after 68 days at 30 degrees C. Exposure to e-beam radiation increased the cured weight % at 30 and 50 degrees respectively. The composition was optimized for maximum stability under time at temperature or radiation conditions. Sample 6-EB-10 demonstrated surprising stability after exposure to 10 kGy after 78 days, that is, less than 2% cured cyanoacrylate was detected by HNMR.

Example 2

(41) In another non limiting example, mechanical properties were studied on a formulation comprising about 3.75% PMMA and 10,000 ppm BHA.

(42) TABLE-US-00002 TABLE II Sample 27D 28D 29D 1 402.79 536.38 507.44 2 432.88 634.60 388.77 3 358.67 442.22 429.29 4 632.67 497.16 498.98 5 434.45 630.88 449.95 6 439.25 588.56 669.64 7 609.58 504.70 604.02 8 567.72 584.71 635.87 9 555.05 535.81 470.97 10 629.50 559.40 496.91 Average 506.26 551.44 515.18 StDev 103.02 60.83 92.22

(43) As shown in Table II, all values are listed in Newtons (N). Testing was performed according to ASTM F2255-05 (Reapproved 2010) Standard Test Method for Strength Properties of Tissue Adhesives in Lap-Shear by Tension Loading.

(44) Setting time of 30-120 seconds was achieved for some compositions studied. Butt-joint strength was at or near 10 lbs. and reaction temperature was below 32° C.

(45) This study demonstrated a variety of stable compositions with adequate workability, strength, and heat of reaction.

Example 3

(46) In one illustrative non-limiting study, as shown in table III below, viscosity measurements were taken on various embodiments of the invention.

(47) TABLE-US-00003 TABLE III CON- Sample 2E35 6E35 10E35 2E310 6E310 10EB10 TROL Rep 1 60.1 59.4 57.8 52.9 54.1 46.9 50.8 Rep 2 54.6 59.5 60.1 52.0 52.5 50.8 50.5 Rep 3 57.0 60.9 57.9 52.9 52.3 51.2 51.4 Avg 57.2 59.9 58.6 52.6 53.0 49.6 50.9 Viscosity (cP) Std Dev. 2.8 0.8 1.3 0.5 1.0 2.4 0.5

(48) Sample compositions were stored at 30 degrees C. for 91 days. Nominal changes in viscosity and standard deviation were reported, thus demonstrating desirable shelf life and stability for at least 3 months. Samples coded EB5 and EB10 were exposed to 5 kGy and 10 kGy respectively. Control samples were not exposed to radiation.

(49) From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims.