Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Skin cosmetic coating
Reexamination Certificate
2002-03-20
2003-12-23
Wilson, Donald R. (Department: 1713)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Skin cosmetic coating
C424S443000, C427S002310, C523S118000, C528S482000, C528S492000, C606S214000
Reexamination Certificate
active
06667031
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates broadly to a method of treating stabilized cyanoacrylate adhesives prior to their application to a substrate, particularly with reference to medical procedures using such adhesives.
2. Description of the Prior Art
Medical interest in cyanoacrylate polymers has been apparent since at least the mid-nineteen sixties as evidenced by numerous reports on its use as a tissue bonding agent. Collins et al. reported on the effectiveness of homologous chain cyanoacrylates for bonding of biological substrates. J. A. Collins, et al., ARCH. SURG. Vol. 93, 428 September 1966; F. Leonard et al., J.A.P.S. Vol. 10: 1617, 1966. Both articles report the observation of high rates of polymerization with longer chain esters than with the methyl or ethyl monomers. There appeared to be more biocompatability with the longer chains as noted by the ease of spreading monomer films on bio-substrates. This contrasted with in vitro polymerizations where the lower homologues reacted much faster. There was particular interest in the degradation of these polymers as they related to possible harmful effects that would preclude their use in surgery.
Woodward et al. reported histotoxicity of these monomers in rat tissue. S. C. Woodward, et al., ANN. SURG. Vol. 162, July 1965. The study involved in situ polymerization of three cyanoacrylate monomers: methyl, hexyl, decyl. It was reported that histotoxic effects were greatest with methyl and decreased with the other two monomers.
The same group reported on the use of radioactive methyl cyanoacrylate for monitoring routes for the loss of the polymer. J. J. Cameron et al., SURGERY, Vol. 58, August 1965; C. H. McKeever, U.S. Pat. No. 2,912,454, Nov. 10, 1950. Results indicated that the polymer was degraded and excreted principally through the urine and feces. Analysis of the animal's organs revealed no signs of radioactivity. This implied no degradation products were incorporated into any of the animal's metabolic pathways. By analogy to polyvinylidene cyanide, they noted that the cyanoacrylate polymer degraded in the presence of water and more so in the presence of bases. The first observed degradation product turned out to be one of the starting materials, i.e., formaldehyde. In vitro studies have shown that the polymers degrade via hydrolytic scission in homogeneous as well as heterogeneous conditions. F. Leonard et al., J.A.P.S., Vol. 10: 259, 1966. These degradation products were confirmed to be formaldehyde and the corresponding cyanoacetate. The conditions of solution degradation affected the consequent rates, namely, under neutral conditions rates decreased as the homologous series was ascended while alkaline conditions increased all rates.
The same study reported that the hydroxyl group was evident in the polymer as the initiating species. This was concluded from infrared spectral data that displayed hydroxyl group absorption at 3600 cm(−1). Further support for this is the noted suppression of the OH as water is replaced with methanol and the observed methoxy absorption at 1100 cm (−1). Preferential initiation was shown to occur with NH2 containing substances such as pyridine, cysteine, alanine, and glycine in aqueous solutions. This suggested that in vivo adhesion was more than a mechanical interlocking of the solid polymer with the tissue. This appears to be the case as it was noted that typical polymer solvents were not effective in solvating tissue-bound polymer.
From this it appears that in vivo studies of degradation do not necessarily correspond to in-vitro conditions. Part of the degradation mechanism relies on the conditions of the polymer for hydrolytic scission. The chemical bonding of the polymer excludes this surface from hydrolytic activity. A mechanism of degradation was proposed that suggests an action similar to unzipping in acrylics, however, the difference being that the monomer is not regenerated. The proposed mechanism necessitates the presence of the hydroxyl as well as the presence of water.
An unusual effect was reported regarding the aqueous degradation of isobutyl cyanoacrylate. R. H. Lehman et al., ARCH SURG. Vol. 93: 441, 1966. Of the monomers tested(methyl, propyl, butyl, isobutyl, heptyl, octyl), it was the only one that degraded more rapidly than any of the unbranched homologues, with the exception of the methyl monomer. as a tissue adhesive in surgical applications. The presumed superiority of these products was attributable to the rapid hydrolytic decay and concurrent low degree of histotoxicity. Since no data is presented regarding formaldehyde evolution, it is presumed that the hydrolysis mechanism does not scission the polymer to generate it.
A second study reported that in vivo experimentation gives credence to the chain scission mechanism by hydrolysis. M. Yonezawa et al., YUKI GOSEI KAGAKU KYOKAISHI, Vol. 25, 1967. When beta-(14) carbon tagged cyanoacrylate is implanted in rats, radioactive urea is isolated from urine. This suggest that tagged fromaldehyde is released, converted to carbon dioxide and in turn reacts with ammonia to produce urea. F. Leonar, ADHES. BIOL. SYS. 1970.
Rates of degradation on ethyl, butyl and hexyl cyanoacrylates were evaluated with regards to molecular weights, concentrations, and side chain structures. W. R. Vezin et al.,J. PHARM. PHARMACOL., Vol. 30,1978, suppl.. The method employed buffered systems of pH ranges from 5.97 to 7.88. As expected, the rates increased with increasing pH Scanning electron microscopy of the degraded polymer indicated that reaction occurs at the surfaces and not internally through diffusion. It was postluated that the greater the length of the -alkyl side chain, the more protection provided to the labile hydroxyl end of the polymer chain. This is turn would provide greater resistance to degradation of the polymer. Degradation for hexyl, butyl, and ethyl were, respectively, 1.0, 1.36, 9.55.
The same group reported on a study whereby degradation rates were retarded by increasing the chain length of the polymer. W. R. Vezin et al., J. BIOMED. MAT. RES., Vol. 93,1980. Very small quantities of impurities in the monomers had a significant impact on the final outcome of the degree of polymerization. Further to this study, within the ethoxyethyl system, loneger chain length enhanced the degradation resistance of the resultant polymer.
A comparative study of ethyl cyanoacrylate and polyurethane in-situ generated adhesives and coatings was reported in U.S. Pat. No. 4,057,535 to Lipatova et al. The study claimed the superiority of the polyurethane structure due to high flexibilty and compatibility with the treated tissues. The single comparison was made with incised tissue and consequent application between the wound edges. Inferiority of this application for the cyanoacrylate was readily evident, but true topical applications were not compared. eleven examples given, four were of a topical method, yet no data was presented as no application of the ethyl or any other homologue was done conjunctively for comparative efficacy. A further deficiency of this patent is the practicality of use. No indication is given for a device to properly apply the two part system and appears to indicate an at-site preparation.
Another patent, U.S. Pat. No. 5,192,536 to Robinson overcomes the issue of the apparent difficulties associated with invention disclosed in U.S. Pat. No. 4,057,535 by taking preformed polyurethane and issolving it in a rapidly evaporating solvent such as tetrahydrofuran. The composition is designed to form a “membrane-like cover over the wound” and “assists in maintaining closure of the wound”. Again no compartative studies were reported.
U.S. Pat. No. 3,995,641 to Kronenthal et al. discusses the novelty of modified cyanoacrylates, namely, carbalkoxyalkyl cyanoacrylates. The patent disclose their usefulness as a tissue adhesive in surgical applications. The presumed superiority of these products was attributable to the rapid hydrolytic decay and concurrent low degree of histot
Spartan Products Inc.
Welsh & Flaxman LLC
Wilson Donald R.
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