DE1594102A1 - Thickening of alpha cyanoacrylates - Google Patents

Description

159A102

21 150

American Gyanamid Company "Wayne, New Jersey, V. St. A,

Calibration of alpha-cyanoacrylates

The invention relates to improved adhesives and an improved process for their production and in particular to an adhesive which is composed of at least one monomeric ester of alpha-cyanoacrylic acid and at least one partially polymerized ester of alpha-cyanaerylic acid. The invention also relates to a process for the production of this adhesive, in which the alpha-cyanoacrylic acid "when used as an adhesive is exposed to the conditions of polymerization in the presence of free radicals *

The excellent adhesives that are produced according to the invention Yerfahren can be used to cool different To connect substances to each other, The substances to each other

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to be connected are referred to as "AdhSrenden" * The adherend may be the same or different materials and include for example substances such as animal-like meat, bones, skin, muscle and nerve tissue, and the tissue of organs, such _o as the rush of easing, Liver and blood vessels, adhesives according to the invention can also be used to connect porous and non-porous materials, e.g. B ₉ of HoIa ₅ metal glass,

Leather and rubber are mixed with materials of the same or different types

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be turned »

The use of esters of alpha cyanoic acid (hereinafter sometimes referred to as "cyanoacrylates") as adhesives is known. The rapidity with which these substances form tough bonds makes them excellent for most common bonding purposes, as well as for many unusual ones · suitable on bemerkenswertesten is probably the usefulness of these adhesives in the medical field, where, as you found ha · can * ") usual sutures as Hittel for closing the incisions made in surgical Sing reefs replace. the obvious benefits that come with this spare make this class of adhesives extremely valuable.

The ease of use of cyanoacrylate adhesives also contributes to the fact that they are easy to use. Kan cleans the surface to be bonded-Lehen carries Ofcstoff to one or both surfaces and the surfaces are in adhesive contact, Bine difficulty, however AEIE

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occurs during this connection process, the low Vis viscosity inherent in monomeric cyanoacrylates, and thus the tendency of the material to spread to undesired areas before it solidifies.

To solve this problem, attempts have already been made to produce cyanoacrylate preparations with such a viscosity that the material can be applied in a controlled manner from a conventional release device, for example a pipe or a squeeze bottle. Two such methods are described in US Pat. No. 3,178,379 described. The first method uses a small amount of polymer! _Ö cyanoacrylate in the monomeric material aufgelöst- Such compositions are simply prepared by mixing the monomeric cyanoacrylate having the desired polymeric viscosity modifiers and other ingredients as are customarily used in such adhesives ₉ Zobe a polymerization inhibitor, and then stirring the mixture prepared to form a solution Although certain successes have been achieved with such mixtures, they have certain disadvantages with regard to clarity, stability and activity. Each of these properties is somewhat worsened in the mixture compared to the pure monomeric oyanacrylate

In the second kethoc'e, which is described in the patent mentioned ρ, a polymeric viscosity modifying agent

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tel (for which many different polymers are used can) dissolved in a solvent that is compatible with the monomeric cyanoacrylate «The solution of the polymer is then mixed with the monomer, whereupon the solvent is removed from the mixture in vacuo * According to the information In the patent mentioned, this method for the production of a thickened cyanoacrylate adhesive has a favorable effect on the clarity “Stability in mass and adhesive activity of the Composition from. Even then, however, it is evident ^ that it is rather unfavorable to form a solution combine them with another material, stir the mixture and then remove the solution = product to treat agents in a vacuum. In addition, trace amounts of moisture or other impurities are brought in with the added material, which affects the stability and effectiveness of the adhesive especially for surgical purposes can adversely affect. Furthermore, both the recovery as well as the loss of the solvent is costly. Finally, it is likely that some solvent is in the product remains as an impurity, which is responsible for the use of the Adhesive is undesirable for medical purposes »

The invention is therefore mainly intended for cyanoacrylate adhesives, the beneficial properties of pure cyanoacrylates have and at the same time have such a viscosity that they

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can be easily handled during use. Furthermore, the invention mainly has a thickened cyanoacrylate adhesive aura goal, which consists only of a cyanoacrylate and polymerized derivatives thereof, as well as necessary stabilizers to the exclusion of other foreign matter.

Surprisingly, it has now been found that polymeric cyanoacrylate can be densified to any desired degree without losing its adhesiveness by subjecting the monomer (which is free of appreciable amounts of inhibitors to free radical polymerization) to the conditions of a subjecting free radical induced polymerization to form in situ a partial polymerization to cause "The material obtained is a mixture of monomeric" and polymeric cyanoacrylate _o This mixture is then preferably with an inhibitor of polymerization caused by free radicals (e.g., "B. hydroquinone , butylated hydroxytoluene (2,6-di-tert-butyl-pcresol) or the like) are added to prevent thickening beyond the desired point. Adhesive purpose is used. Conditions applied under which an anionic polymerization is initiated. The invention is al so essentially that it is far more expedient to use cyanoacrylate, since it has previously been partially polymerized by radical initiation.

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apply as impolymerized oyanacrylate. The practical application of the invention results in a composition which, after complete polymerization, has been polymerized both radically as well as anionically in the order given. The advantage of the process according to the invention for the preparation of suitably applicable cyanoacrylates is that there is no need to mix another polymer or a thickener into the cyanoacrylate monomer. The cyanoacrylate can be thickened to any desired viscosity without any mixing and without the use of solvents. If the adhesive is to be used for surgical purposes, this is a particularly important advantage. For purposes other than surgical purposes, the purity of the material is not of such critical importance and it may be advisable to modify the properties of the adhesive by using compatible additives. If necessary, a further polymerizable monomer or a low molecular weight polymer thereof can be mixed with the cyanoacrylate before it is subjected to a polymerization proceeding via free radicals. Such monomers are monomers of the vinyl type including, for example, styrene, vinyl acetate, methyl methacrylate, acrylonitrile, thylacrylate, vinylidenecyanide and vinyl chloride

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In the practical application of the invention, monomeric cyanoacrylate, which is free from all weakly basic impurities, for example water or alkanols and practically free from inhibitors for polymerization caused by free radicals, is, however, with a small amount of a Lewis acid, g _o B »SO ₂ . BP ₃ or HF, stabilized against anionic polymerization iat _P by initiation by means of free.Kadikaie partially polymerized to a material with a viscosity of about 50 to 50 _x 10 ⁵ ßP / 25 ° C. The polymerization caused by free radicals can "by conventional measures For example, a conventional initiator, for example a peroxide such as benzyl peroxide or an azo compound such as azobisisobutyronitrile, and the mixture obtained can be added to the monomer, which is practically free of an inhibitor for free radicals, in the usual way up to the desired viscosity polymerize "is preferably not added to an initiator, but the free radical polymerization is _m;. initiated it by thermal energy and / or radiation of various types, the thermal energy that is required ·, to initiate the formation of free radicals may conveniently prepared by Heat the ITonomer sample to a temperature above about 45 ° C become T. The radical polymerization can also be achieved by irradiating the monomer with UV light, X-ray

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rays, gamma rays or electron radiation can be initiated. One puts feat that an artificial Radiation source is particularly well suited to the desired polymerization within a reasonable period of time achieve.

It is a particular advantage of the invention that it enables a one-step process for simultaneous thickening and sterilization of the cyanoacrylate material and its packaging . B _{e is made of} polyethylene. The filled syringe can be wrapped in one or two wrappers of the type used to hold common sutures. The packaging can then be irradiated in the manner described above, so that the desired partial polymerization and sterilization are achieved at the same time the dispensing syringe or _hrise _t containing the cyanoacrylate be tiber coated inside with einem.Material which for each applied type of radiation partially or completely impermeable. In this ^ Veise is possible 'that the Ä'ussere the distributor a higher amount of radiation to. For sterilization purposes, the inside of the manifold would receive a lower amount of free radical initiation.

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For the purposes of the invention, it is not critical which ester of alpha-cyanoacrylic acid is used in each case. The most common are the methyl and ethyl esters, you can but also use other esters and mixtures thereof »Such other esters are, for example, alkyl» or alkenyl esters where the esterifying group has 3 to 18 carbon atoms (e.g. Allyl, Oyclopentyl, Cyclohexyl, n-Pentyl, Octyl, Dodecyl and octadecyl), aryl esters (e.g. phenyl and tolyl) and Aralkyl esters (e.g. benzyl and phenethyl) «,.

The following examples illustrate the invention without representing it restrict.

example 1 Irradiation of methyl ^ alpha-cvanacryl with UV light

4 ml of methyl alpha cyanoacrylate was exposed to UV light under a GoEoBH-6 lamp at a distance of approximately 10 cm (4 inches). After one hour, the monomeric material was polymerized to a viscosity with the desired value (2.5 ^{10 5} cP.). Then about 0.05 # hydroquinone was added to prevent further radical polymerization «

The partially polymerized methyl alpha cyanoacrylate obtained in this way was checked as follows * A few drops were on one

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Brought rubber stopper that had previously been cleaned. was " The surface of the plug that had the adhesive on was then against the surface of another Pressed rubber stopper, which had also been cleaned beforehand. After the stoppers had been held together for a short time, they were so tightly connected that they could not be removed except by tearing the rubber. could be separated. It should be noted that the connection of the two rubber pots by anionic polymerization which occurred as a result of trace amounts of moisture in the atmosphere and on the rubber stoppers * Moisture is a very effective initiator for an anionic Polymerization.

Example 2

Irradiation of n ^ P r o p yl ^ alpha-cyanoacrylate with UV light

> According to the procedure described in Example 1, n-propyl-alpha-cyanoacrylate was irradiated until the material as a result radical polymerization had the desired viscosity. The alpha cyanoacrylate was partially polymerizing Hydroquinone added in the Henge given in Example ^ 1 as an inhibitor for radical polymerization. It it was found that the partially polymerized material had the adhesive properties observed in Example 1.

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159A102

Example 3

5 g of ethyl alpha cyanoacrylate in a 28 g (1 oz.) Polyethylene bottle with screw cap was exposed to radiation from a 25OKVP X-ray device that was equipped with 30 BiA was operated »The bottle was with the longitudinal axis horizontally and in the middle under a beryllium window X-ray tube placed at a distance of 5 cm. After 5 minutes at room temperature the viscosity was desired achieved. 0.005 g of hydroquinone was added to stop the free radical polymerization reaction.

It was found that the material obtained in this way had the adhesive properties of ethyl-alpha-cyanoacrylate _o

Example 4 _; Irradiation of n ^ octyl ^ alpha ^ cyanoacrylate with UV radiation

Following the procedure of Example 1, n = octyl-alpha-cyanoacrylate * ⁿ 7 sturden was thickened to the desired viscosity value by exposing a sample of n-octyl-alpha-cyanoacrylate, which was free from inhibitors for radical polymerizations. After seven hours the irradiation was stopped and butylated hydroxytoluene (some crystals) became

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added to stop the radical polymerization. It was found that the material obtained had the desired adhesive properties when it met the conditions has been subjected to anionic polymerization

Example 5

Irradiation of a mixture of methyl *; and iyOctyl-alpha cyanoacrylate with UV light

Following the procedure of Example 1, a mixture of methyl and n-octsl-alpha-cyanoacrylate in a ratio of 25 yes: 75 # 3 hours exposed to UV light under a G.E.BH-6 lamp. then the mixture obtained was treated with butylated hydroxytoluene as an inhibitor for radical polymerization / The material shows excellent adhesive properties when it is ani < is exposed to anic polymerization conditions.

Following the procedure of Example 5, additional alpha-cyanoacrylates were made subjected to radical polymerization. Underneath were n-pentyl, η-butyl, cyclopentyl · and η Decyl-alphy-cyanoacrylate. The desired viscosity was in Hours, 2 hours, 3 hours or 1/3 Sturide reached. After this the desired viscosity

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the desired viscosity was reached, the mixture of monomeric and polymeric / cyanoacrylate with a trace = amount of butylated hydroxytoluene added to stop another radical polymerization.

Example 6

Her position r a sterile pack of partially polymarisiertem

alpha-cyanoacrylate

5 g of n-octyl-alpha ^ cyanaerylate was poured into a 14 g (0.5 oz.) Polyethylene screw bottle with a cap made of polyethylene filled. The top of the cap was covered with a removable plastic protective cap. This system was about 5 hours with a G.E. BH-6 W light sources irradiated to achieve the desired viscosity. Then were 0.005 g of butylated hydroxytoluene added to prevent further free radical polymerization, It was found that the composition had the expected adhesive properties and was suitable for surgical use.

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Example ^

of glue

Use of Aa.abJjnAjaoJLu; fc, yronitrii (AIBH) as.

Several crystals "'-AIBN were added to 1 ml of n-propyl-älpha-oyanaerylat. After 2 1/2 hours at 42.5 ° ^u , the nl?

Alpha-cyanaeiylate bia polynierized to the desired viscosity There were some crystals of butylated hydroxytoluene added to stop another free radical polymerization.

The test of the adhesive produced in this way showed that the partially polymerized material for alpha-gyanacrylates expected adhesive properties'

Example ^ 8

When using monomeric n = Peniyl · -alpha-eyanacrylat for the Procedure of Example 1 is partially polymerized thickened it obtained n-pentyl-alpha-cyanoacrylate, which can be used as an adhesive. ^

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Example l, .9,
Application for surgical, jewelery

Ao A white New Zealand rabbit weighing between 2.0 and 2.3 kg (4.5 to 5 lbs ") was anesthetized with sodium pentobarbital." The abdominal hair was removed with scissors and the skin was removed with a 1: 1000 solution of zephiran brushed in water. With a scalpel, two longitudinal wounds, each about 14 cm (5 1/2 inches) in length, were made through the skin on each side of the midline to the upper surface of the panniculus carnosus. The bleeding was fought with sponges. The skin of one wound was brought back together by hand and 3 drops (about 0.05 ml per drop) of a solution of monomer, n-pentyl = alpha-cyanoacrylate thickened by radical polymerization were applied at equal intervals to the cutting line. The adhesive was spread into a thin film about 1.13 cm (1/2 inch) wide across the incision and the skin laxed through for about 30 seconds

Pinger pressure held together. During this time, the monomer n-pentyl-alpha-cyanoacrylate had polymerized to form a tough, flexible, firmly adhering, translucent material of uniform thickness and sufficient strength to keep the wound closed. The other skin wound was made in the usual surgical procedure with surgical sutures made of ^Ο βϊβ &

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closed.

After the operation, the Sier was returned to its cage and 7 was kept on an S-standard diet. Wake up The sutures were removed from the sutured wound on the fourth day. On the seventh day, the two wounds were examined. With Adhesive-sealed wound showed only a hair-thin scar; the wound closed with suture material, on the other hand, showed one slightly clearer scar, which together with the needle punctures made a more noticeable impression «

The animal was sacrificed and the skin was cut out strips of skin about 1.3 cm wide were im Cut out at right angles to the incisions and the strips containing both wounds were separated. the Strips were placed in a tensile strength test and the force required to tear the skin at the cut line was, was determined. There was no difference in force required to tear between that with the adhesive closed wound and the wound closed with threads established.

B. Another animal was made in the manner described above In this case, a wound was thickened with n-pentylalpha-cyanaorylate and the other with the same monomer that had not been subjected to radical polymerization.

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schloseen «In each case, an incorrect approximation of the skin was brought about by sliding the edges of the skin over one another immediately before the adhesive was applied. After the adhesive had spread, an attempt was made to correct the incorrect position at each incision. In the pail of the wound closed with the non-thickened monomer, the polymerization had taken place so rapidly that correction was impossible. There was enough time in the pail of the wound closed with the thickened monomer to correct the defect before the polymerization had progressed so far that correction was no longer possible. The thickened adhesive produced a film with a uniform surface of the same type as described above. In contrast, the unthickened monomer produced a film of uneven thickness with localized opaque areas. After seven days, the wound closed with the thickened adhesive showed the hairline scar described above . The wound closed with the non-thickened adhesive showed a gaping gap where the incorrect approach had taken place, and also a wider, less uniform scar along the rest of the incision "

Example 10 .

The thickened polymers of the present invention are excellent suitable for use as coatings for living tissue of animals or humans, which as a result of traumatic damage or surgical procedure has bleeding surfaces. For example

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was it common in cases of lung damage or lung cancer remove all of the lung to create a cut line that can be successfully occluded. It was it has now been found that the damaged part can be removed and the polymer according to the invention thickened to coat the cut surface with the formation of a new area that gradually heals through natural processes and meanwhile ao is effectively protected against loss of liquid or gas leakage that only the damaged part has to be cut out while the remainder can be sealed by using these thickened polymers as a seal.

In the same way, in the case of internal injuries, if, for example, the liver or spleen are torn, for example in an automobile accident or for some other reason or if a part with a cyst or for other reasons has to be removed, the remaining area with the thickened polymer according to the invention plated and with success a new surface was werden.Bisher get to bring ee generally require the other parts by sewing together what due to the drastic Wirkun _o of jflähttm in such soft tissue further injury ν ..mrsachtt by using d ^ s invention * Thickened polymers can be sealed in any desired form and a high percentage of functional i. · '. .em

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Tissue can be preserved. In the case of abrasions, for example on the body of an accident victim, considerable Abandoned surfaces through contact with road surfaces * After the usual wound cleansing and quitting of the bleeding can the remaining tissue by the invention Adhesive completed and thus the truthfulness infection.

A coating of the thickened adhesive according to the invention allows for the maintenance of tissue that would otherwise have to be sacrificed, prevents bleeding, reduces fluid loss, and generally increases surgical possibilities. The thickened polymer has such a viscosity that bleeding from small capillaries is immediately inhibited. For larger blood vessels, clamps are used first Hemostasis achieved. Then you put the thickened adhesive on the separation point and leave enough time for the Allow polymer to cure before removing hemostats *

In the case of even larger blood vessels, the polymer can be used to glue the vessel walls together and then separately coat and seal the remaining tissue. The viscosity of the polymer makes it possible to use it effectively, something that has not yet been achieved ”; be ^konnt.fi: rtc the m.ebßtof.-? be brought to the desired stems regardless of gravity

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can and in contact with an aqueous medium cures ₈ as the anionic polymerization initiator participated in water-thin cyanoacrylates the adhesive flows from surfaces is washed off or rapidly than that an effective seal could be ersielt zn of such surfaces. The thickened adhesive according to the invention has a viscosity which is sufficient to hold the polymer in the desired location until the adhesive has solidified * In this way a stable, liquid-tight surface is obtained »

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Claims (1)

Claims S _{0 A} process for the production of a connection swioohen awsi adherends, characterized in that (1) one "surface of an adherend is coated with a polymorisable composition of a particular alpha-olefin anylate which is partially produced by free cadic acidic polymerisation essentially in has been the absence of an inhibitor for radical polymerization until a viscosity in the range of about 50 bia 50 χ 10 ^ c3? "measured at room temperature _f poly ^ &riaiert" and (2) the au connecting surfaces to form an adhesive bond swiachen these surfaces in the presence of an anionic polymerization initiator brings into contact with each other * 2 «Method according to Anapruch 1 _e, characterized in that the free radical polymerization is initiated by thermal activation or by irradiation with UV light, electron beams, X-rays or gamma rays, 3 · Method according to Anapruch 1, characterized in that man ea on human or animal tissue ala adherent applied 909818/1022 159A102 - P.2 4. Container which can release controlled amounts of viokoaer substances and is made of a material which is free from impurities _f which can initiate an anionic polymerization, characterized in that the container (&} at least one alpha cyanaerylate _f in the absence of an inhibitor for a polymerization brought about by free radical © by radical initiation Ma to a Yiulzorjltät in Bs- 5
rich has been partially polymerized from about 50 to 50 10 χ, (b) a v / irksasie amount Ainet; Free radical polymerization inhibitor; and (c) an amount of an anionic polymerization inhibitor sufficient to prevent autoini-firing. 5 «A container according to claim 4 _t characterized in that it is made of a polyolefin material. 6. Container according to claim 4, characterized in that it has been subjected to thermal activation or irradiation with UV light ο 7. A process for preparing a alpha- Cy anacrylat adhesive s, characterized in that (a) at least one monomeric alpha-cyanoacrylate, daa in v & aen-fclicheii free of an inhibitor of free radical polymerization 909818/1022 bad original is subjected to the conditions of free radical polymerization and (b) an inhibitor for free radical polymerization is added when the viscosity of the partially polymerizing alpha-cyano ^ acrylate is 50 to 50 χ 10 cP, and an aX'jiia-cyanaorylate adhesive wins that under is inert to the conditions of free radical polymerization, but is an effective adhesive in the presence of an anionic polymerization initiator. Adhesive, characterized in that it consists of a monomeric and a polymeric alpha ^ cyanoacrylate, which has been obtained in situ by radical polymerization of at least one monomeric alpha-cyanoacrylate, and an inhibitor for radical polymerization and an anionic polymerization inhibitor in an amount which is sufficient to inhibit auto-polymerization, and a viscosity at 25 ° 0 of about 50 to about 50 χ 10 ^ oP _o 9 · Adhesive according to claim 8, characterized in that it is produced by radical polymerisation of a mixture different monomeric alpha-Cyariacrylatü has been obtained α BAD OFHGINAL 909818/1022 10. Fast-acting adhesive according to claim 8, characterized in that it consists essentially of (a) at least one monomeric alpha-cyanoacrylate, (b) a polymer of this alpha-cyanoacrylate, which has been generated by radical polymerization in situ and such a concentration in the adhesive has that the viscosity at 25 ⁰ C is in the range of 50 to 50 χ 10 cP, (c) a small but effective concentration of an inhibitor for radical polymerization and (d) a small but effective concentration of an anionic polymerization inhibitor and is storage stable in the absence of air and moisture and is surgically acceptable for the adhesive union of human and animal tissue. 909818/1022 ^BAD