Method for heat sterilization of tissue adhesives leading to improved shelf life and product uniformity

Abstract

A method for sterilization of tissue adhesive is provided, the method comprising heating a container containing a quantity of tissue adhesive to a maximum temperature between 180°C and 230°C such that the time-averaged sterilization temperature heat flow is up to 500000 C*min / mmol for the millimolar quantity of tissue adhesive. The container is cooled to sterilize the cyanoacrylate tissue adhesive. A composition of matter is obtained, comprising a container with an airtight seal. A quantity of sterilized tissue adhesive is provided in the container, having a storage stability of at least 36 months at standard temperature and pressure.

Description

[Technical field]

[0001] [Related Applications] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 372,012, filed February 7, 2022; the contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention relates generally to tissue adhesives, and specifically to methods for sterilization of tissue adhesives that lead to improved shelf life and product uniformity. [Background technology]

[0003] Medical glues, sealants, and adhesives (hereafter referred to as tissue adhesives) are most commonly used to facilitate rapid, cosmetic, and cost-effective closure of surgical and traumatic wounds. They are also used to strengthen or protect the skin, to treat varicose veins, or as an alternative to surgical drapes, etc. Topical tissue adhesives seal wounds to prevent infection, prevent fluid loss, control bleeding, or approximate wound edges. To address various medical needs and develop the clinical properties necessary to replace, repair, close, and protect biological tissues within a subject's body, the properties of tissue adhesives are carefully designed and optimized for specific applications.

[0004] Tissue adhesives must be sterile and generally non-toxic and must provide effective performance under a variety of varying or demanding conditions at the application site, such as moisture, bleeding, flexibility, and strength requirements. Tissue adhesives should also be easy to apply and fast drying. Tissue adhesives for skin closure may be used in conjunction with mesh, sutures, and staples, or alone, to hold tissues together and act as a barrier against the entry of infectious agents or loss of body fluids.

[0005] The literature and regulatory filings describe several methods used to provide sterile tissue adhesives for clinical use. Gamma irradiation was described by McDonnell in 5,530,037; heating by Kotzev in 5,874,044; electron beam irradiation by Hickey in 6,143,805 and by Greff in 6,248,800; and X-rays by Zhang in 8,652,510. The amount of sterilizing radiation or process exposure required by regulatory agencies to claim "sterility" is related to the amount of microbial contamination (usually measured in colony forming units (CFU)) in the device prior to sterilization. Some manufacturers may therefore go to great lengths to reduce contamination of the device so that the sterilization process is less harsh and therefore less damaging to the product. In extreme cases, some products are filtered using 0.2 micron filters intended to remove any microbial contamination and then packaged in pre-sterilized containers under aseptic conditions. One such product, Histoacryl, was approved by the FDA as a tissue adhesive by PMA P050013 on February 16, 2007. However, this processing method carries significant risks and costs, and it is one of the very few medical devices that is not "terminally sterilized."

[0006] A particular class of synthetic tissue adhesives are cyanoacrylate-derived adhesives that are commonly used for external tissue repair. Cyanoacrylate-derived adhesives act quickly, provide strong bonds, are typically waterproof, somewhat flexible, and do not require secondary dressings. While some lower homologue cyanoacrylate adhesives have the potential for toxicity and tissue irritation, longer chain derivatives such as butyl cyanoacrylate and 2-octyl cyanoacrylate are less toxic and are approved by the U.S. Food and Drug Administration (FDA). Cyanoacrylate adhesives dry quickly, effectively stop bleeding, keep out dirt and air, and typically stay in place until the injured site heals. However, cyanoacrylate adhesives themselves were not originally recommended for use on deep or jagged wounds, or in areas of high mobility and flexion such as joints, but are now used in conjunction with meshes in these indications. In addition to their indications as tissue adhesives, cyanoacrylate adhesives are also FDA-approved as a barrier against common bacterial organisms. Long-chain cyanoacrylate products are often used locally to reinforce tissue closure and are used for small lacerations. In addition, cyanoacrylate tissue adhesives are also approved for the treatment of varicose veins and as liquid embolization systems for brain "arteriovenous malformations" (AVMs), and are used in some countries to secure hernia meshes.

[0007] Another class of tissue adhesives approved by the FDA for topical use is the methylidene malonate series of reactive monomers.

[0008] The fast acting properties of both these classes of adhesives come from highly reactive monomer species that undergo polymerization both by free radicals and ions. Their high reactivity results in a limited shelf life that is further shortened by excessive exposure to moisture, heat, light, or other forms of energy. This complicates sterilization, as the majority of terminal sterilization methods use high energy, or moisture and heat, to kill microorganisms.

[0009] The challenge in sterilizing these reactive monomeric tissue adhesives is to ensure that the monomers survive the "energy shock" of sterilization and still have a commercially viable shelf life. Often, large amounts of potentially toxic stabilizers are added to prevent the monomers from polymerizing during sterilization, but even so, shelf life is limited. It has been observed that unsterilized samples of cyanoacrylate tissue adhesives can last for 20 years, while sterilized cyanoacrylate adhesives have been observed to have a shelf life of 2 years or less at room temperature. Polymerization inevitably manifests itself as an increase in viscosity, and sterilized cyanoacrylate adhesives will solidify before use or become too viscous to be released. Thus, viscosity is the aging parameter that typically limits the shelf life of tissue adhesives and is the parameter most commonly monitored for aging.

[0010] A further complication of current sterilization methods is the difficulty of providing a uniform exposure to all units being sterilized if some economies of scale must be maintained in batch processing. This inevitably leads to some units receiving more energy than others to ensure that all units receive the minimum required exposure. This immediately impacts the performance characteristics of the product and batch-to-batch variations are easily seen. In addition, units receiving more energy will "age" faster, which leads to even greater differences as the product ages. This leads to customers perceiving performance variations between units of the product, leading to product complaints and even delayed product adoption due to performance variations.

[0011] Most commercial tissue adhesives are batch sterilized in two stages. First, the adhesive components are batch sterilized by heat in glass vials or metal tubes. These are then placed in or with applicators to facilitate clinical use, which are also packaged in overpacks to allow for sterile "dropping" into the sterile field. These assemblies are then batch sterilized again by gas, usually ethylene oxide gas (although chlorine dioxide is an alternative). This second gas batch sterilization cycle is cooler and places little or no additional stress on the reactive monomer components of the tissue adhesive. Typical batch heat sterilization cycles used in the first stage are 160°C for 2 hours, or 170°C for 1 hour. Of course, each of these commercial processes requires significant heating and cooling times along with the large ovens and large volumes of product that must be processed to make it commercially viable, thus increasing the heat load on the product. Furthermore, individual units within a batch experience different heating and cooling depending on where they are located within a large commercial oven, leading to large batch-to-batch performance variability. It is widely recognized that the performance variability seen after sterilization is further amplified over time, exacerbating unit-to-unit differences.

[0012] Fortunately, while chemical reactions typically follow the Arrhenius law, accelerating approximately twice as the temperature increases by 10° C., this is not the case for the death of infectious microbial agents, which die at a much faster rate as the temperature increases and approaches 200° C. Thus, the present invention takes advantage of the determination that sterilization is not dependent on general reaction kinetics at higher temperatures, and the lower heat loads of shorter sterilization times at higher temperatures, and can be used to improve the performance of certain materials that need to be sterilized and are sensitive to thermal degradation.

[0013] Current thermal sterilization methods for cyanoacrylate tissue adhesives in glass ampoules are premised on "Arrhenius-like" reaction kinetics, where the reaction rate (i.e., in this case the "kill rate") doubles for every 10°C increase in temperature. Thus, treatment is typically at 160°C for 120 minutes, or 170°C for 60 minutes, to achieve the required "overkill" level of sterilization. Excluding heating and cooling times, this equates to a Time Averaged Sterilization Temperature (TAST) heat flow of 2231947C*min / mmol (assuming environment = 25°C).

[0014] Including heating and cooling times, the heat flow of TAST is very large, 4408289 C*min / mmol. Such high heat loads and the variations between them explain both the deleterious effects of sterilization and the batch-to-batch variability.

[0015] Therefore, there is a need to develop a sterilization method that has minimal effect on the viscosity of the tissue adhesive. There is also a need for a sterilized cyanoacrylate adhesive that has a longer shelf life and greater uniformity than existing sterilized cyanoacrylate adhesives. Summary of the Invention

[0016] A method for sterilization of a cyanoacrylate tissue adhesive is provided, the method comprising heating a container containing a quantity of tissue adhesive to a maximum temperature between 180° C. and 230° C. such that the time-averaged sterilization temperature heat flow is less than 500,000 C*min / mmol for said quantity of tissue adhesive (excluding heating and cooling times). The container is cooled after sterilizing the tissue adhesive.

[0017] A composition of matter is provided that includes a container with a hermetic seal, wherein a quantity of a sterile tissue adhesive is provided within the container and has a shelf stability of at least 36 months at standard temperature and pressure.

[0018] [Brief description of the drawings] The invention is further detailed with respect to the following non-limiting drawings. [Brief description of the drawings]

[0019] [Figure 1] A comparison of the standard current batch sterilization method using 170°C for 1 hour with the high temperature, short time method of the present invention, shown as a plot of temperature versus time; [Figure 2A-2C] 1 is a plot of temperature as a function of time of a sterilization profile of the present invention for a cyanoacrylate adhesive, shown as temperature versus time in accordance with an embodiment of the present invention; [Figure 3A] 1 is a schematic diagram of a first inventive system; [Figure 3B] 2 is a schematic diagram of a second inventive system including a conveyor; [Figure 4A] 1 is a graph of viscosity versus time (change over time) for a set of samples of a 100% butyl cyanoacrylate tissue adhesive formulation, separated into the following groups: a non-sterile control group, a group batch sterilized with a standard thermal profile, and a group of samples processed with a sterilization thermal profile of the present invention in accordance with an embodiment of the present invention; [Figure 4B] 4B is a graph of viscosity versus time (change over time) for a group batch sterilized with a standard thermal profile and a group of samples processed using a sterilization thermal profile of the present invention in accordance with an embodiment of the present invention, of the percentage difference from the non-sterile control group shown in FIG. 4A; [Figure 5A] 1 is a graph of viscosity versus time (change over time) for a set of samples of a mixture of 80% butyl / 20% octyl cyanoacrylate tissue adhesive formulation, separated into the following groups: a non-sterile control group, a group batch sterilized with a standard thermal profile, and a group of samples processed with a sterilization thermal profile of the present invention in accordance with an embodiment of the present invention; [Figure 5B] 5B is a graph of viscosity versus time (change over time) for a group batch sterilized with a standard thermal profile and a group of samples processed using a sterilization thermal profile of the present invention in accordance with an embodiment of the present invention, of the percentage difference from the non-sterile control group shown in FIG. 5A; [Figure 6A] 1 is a graph of viscosity versus time (change over time) for a set of samples of 100% octyl cyanoacrylate tissue adhesive formulation, separated into the following groups: a non-sterile control group, a group batch sterilized with a standard thermal profile, and a group of samples processed with the sterilization thermal profile of the present invention in accordance with an embodiment of the present invention; [Figure 6B] 6B is a graph of viscosity versus time (change over time) for a group batch sterilized with a standard thermal profile and a group of samples processed using a sterilization thermal profile of the present invention in accordance with an embodiment of the present invention, of the percentage difference from the non-sterile control group shown in FIG. 6A; and [Figure 7] 1 is a graph illustrating the temperature and time limits of the present invention in one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention is useful as an improved method for sterilization of cyanoacrylate tissue adhesives, resulting in a shelf-stable product with a similar shelf life as non-sterile cyanoacrylate adhesives. The sterilization method of the present invention provides a shorter period of high heat to reduce the overall time-averaged sterilization temperature (TAST). In a specific embodiment of the present invention, a peak temperature of 185° C. is applied for 1 minute. The heating profile of the present invention has a higher peak temperature than conventional sterilization temperature profiles, but for a shorter period of time to reduce the area of ​​heating. The present invention provides heat flow values ​​in the range of 400 C*min / mmol to 500,000 C*min / mmol, which can sterilize tissue adhesives without inducing premature curing reactions. The lack of premature curing reactions manifests as a shelf-stable product of at least 36 months, and in a specific embodiment, between 36 and 72 months, at standard temperature and pressure. This range of heat flow is idealized, and assumes that the pre-heating and post-cooling events are instantaneous. For the purposes of these calculations, molar amounts relate to amounts of pure butyl cyanoacrylate, and the container in which the butyl cyanoacrylate is contained is assumed to have instantaneous and infinite thermal conductivity.

[0021] In specific embodiments of the present invention, the shelf life of the sterile cyanoacrylate tissue adhesive formulation is at least doubled over current sterile cyanoacrylate tissue adhesive products and the levels of potentially toxic stabilizers are reduced, with shelf lives of 60 and even 72 months being achieved depending on the stabilizer selected.

[0022] Numerical ranges cited herein are intended to include not only the endpoints of such ranges, but also the individual values ​​encompassed within the ranges and the unitary variations at the last significant digit. For example, the range of 0.1 to 1.0 in any unit according to the present invention also includes 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9; each independently being the lower and upper limit of the range.

[0023] The following description of various embodiments of the invention is not intended to limit the invention to those specific embodiments, but rather to enable those skilled in the art to make and use the invention through its illustrative aspects.

[0024] Unless otherwise indicated expressly or by context, the following terms are used herein as defined below.

[0025] As used in the description of the present invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0026] Also, as used herein, "and / or" refers to and includes every possible combination of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0027] Figure 1 is a comparison of a standard current batch sterilization method using 170°C for 1 hour with the high temperature, short time method of the present invention, shown as a plot of temperature versus time. The range of "heat flow" (taking into account heating and cooling times) for the conventional batch method has a "heat flow" value of 4408289 C*min / mmol; excluding pre-heating and post-cooling, the "heat flow" value is 2231947 C*min / mmol.

[0028] In contrast, in the present process, as shown in Figure 1, a hold temperature of 180°C for 240 seconds = 157549 C*min / mmol; while a hold temperature of 230°C for 0.5 seconds = 419 C*min / mmol. According to the specific present process at 185°C for 1 minute, the "heat flow" value, including heating and cooling of the product, is 381670 C*min / mmol. If heating and cooling are excluded, the "heat flow" value is 40481 C*min / mmol.

[0029] 2A-2C are plots of the sterilization profile of the present invention for a cyanoacrylate adhesive, shown as temperature versus time, with a peak temperature of 185°C, where the integral area of ​​the theoretical profile is Similar profiles exist for other tissue adhesives, and routine experimentation applied to specific formulations will achieve the results shown below for an exemplary material of a cyanoacrylate tissue adhesive, with the primary aspect of short bursts of sterilizing heat. Other classes of such tissue adhesives include acrylic bone cements and methylidene malonate. FIG. 2A is tightly controlled to achieve sterilization while achieving extended shelf life. This corresponds to a controlled energy input in units of heat input of the time-averaged sterilization temperature per mmol of cyanoacrylate, as shown in FIG. 2A, and does not take into account the heat capacity of the container housing the cyanoacrylate. This value is easily determined experimentally and depends on factors such as the container material, wall thickness, and cross-sectional shape.

[0030] Temperature profile zoning can be achieved with separate heat baths for the specific zones, or by moving between separate heating or cooling blocks, or with separate zones in a heat chamber using rapidly circulating air to ensure rapid heat transfer.

[0031] The method was first validated by using small vials as containers, heating them to 185 °C for 30 s in a cavity in a heating block and then cooling, resulting in the sterilization of Bacillus atrophaeus spore strips (106 bacteria count, D value 2).

[0032] For this to be a commercially viable method acceptable to regulators, one must go beyond reaching the temperature required to kill all spores in the biological indicators of heat resistance. Regulators expect "overkill," a level of sterilization that ensures complete destruction of all microorganisms or their spores many times over. Accordingly, in some embodiments, the method of the present invention exposes a container of tissue adhesive to >185° C. for at least 1 minute.

[0033] Suitable containers herein illustratively include: those formed from borosilicate glass or quartz; metals, such as stainless steel, aluminum, or tin; ceramics, such as alumina or titania; or high temperature resistant plastics, such as polyetherimide, polyetheretherketone, polytetrafluoroethylene, polybenzimidazole, polydicyclopentadiene, and copolymers in which any of the foregoing, each alone or in combination, constitutes greater than 50% of the copolymer.

[0034] For small glass containers containing less than 10 g of tissue adhesive, individual containers can be sterilized continuously on a conveyor belt through a forced air oven with several zones, with very close monitoring using thermocouples in the major zones to ensure that the containers experience the proper thermal profile for the proper amount of time. The containers containing the cyanoacrylate are heated rapidly to a peak temperature between 185-210°C, with the heating and cooling ramps being so rapid that they approach the theoretical vertical ramp shown in FIG. 2A. The method of the present invention, in some embodiments, is performed without the addition of chemical antimicrobial agents, which can complicate curing and affect the shelf life of the product. The rapid rate of change is achieved, in some embodiments, through a technique in which the container is immersed in a controlled temperature bath. Heat transfer within the container volume is further enhanced by rotation or agitation of the container after or simultaneously with immersion. It has been surprisingly found that this type of impact treatment is as effective as conventional techniques, while extending the shelf life of the resulting cyanoacrylate and resulting in less unit-to-unit variability than batch methods, since the units are treated individually.

[0035] If heat and time are properly apportioned in the method according to the invention, no fundamental changes occur to the cyanoacrylate. The following method is contemplated for sterilization of an exemplary cyanoacrylate tissue adhesive:

[0036] Ultra-high temperature (UHT) sterilization at 180-230°C is from 120 seconds at 180°C to as little as 0.5 seconds at 230°C, followed by rapid cooling to 0°C in 15-120 seconds to rapidly cool the container as long as the container and contents are not damaged. Cooling rates defined as 50% or more of the TAST heating rate are defined herein as shock cooling.

[0037] The range of TAST heat flows determined to be effective for sterilizing tissue adhesives with minimal damage by the methods of the present invention is less than 500,000 C*min / mmol, not including pre-heating and post-cooling. The calculated TAST heat flow for the example at 185° C. for 60 seconds, excluding pre-heating and post-cooling, is a TAST heat flow of 40,481 C*min / mmol, compared to a batch process of over 2 million C*min / mmol.

[0038] The above information clearly shows that temperature and time play a very important role and are product-specific. Highly sensitive electronic devices for heat transfer and positive / overpressure values ​​(which are set very sensitively) are used in the method and / or device according to the invention. Of particular importance in the present invention is the selection of an appropriate amount of anionic inhibitor that can act in the gas phase at the sterilization temperature, in cooperation with an appropriate "dead volume" above the liquid in the ampoule, which prevents pre-curing denaturation of the cyanoacrylate.

[0039] Sterilization of the cyanoacrylate containers is accomplished with the aid of a multi-zone conveyor oven by rapidly heating the containers and holding them at the required sterilization temperature of ≥185°C for 1 minute, then allowing them to cool to a handleable temperature. The cooled containers may then be further assembled into the required applicators depending on the intended use of the product, and may be overpacked, or later sterilized by sterile gas or other terminal sterilization process that will not damage the tissue adhesive.

[0040] When using controlled batch or continuous processing for a given container and amount of cyanoacrylate therein, a thermal sensor such as a thermocouple, platinum resistance thermometer, or thermoluminescence spectroscopy system is used to monitor the thermal profile to which the container of cyanoacrylate is exposed. The sensor value, indicative of the cyanoacrylate temperature, is sent to a digital display and, in some embodiments, converted to temperature units so that all temperature values ​​can be monitored and stored using a graphical display and memory device in communication with the sensor. Proportional integral derivative (PID) values ​​are suitable for high control accuracy when the value defined by ΔT is determined to be equal to or less than 0.1.

[0041] As shown in FIG. 3A, a system for carrying out the present invention is generally shown at 10, where an ultra-high temperature (UHT) tank 12 adapted to receive one or more containers of cyanoacrylate is provided. It should be understood that uniformity of properties between containers is very important, whether batched or sequentially processed. A robotic handling system 14 functions to transfer the containers to a cooling tank 16. In some embodiments of the present invention, the tank 16 provides impingement cooling to containers placed therein. In some embodiments of the present invention, an agitation system 18 promotes uniform heat exposure within one or both of the tanks 12, 16. Temperature sensors 20 and 20' monitor the temperature within the tanks 12 and 16, respectively. In some embodiments of the present invention, the sensors 20 and 20' each independently provide feedback control to regulate the temperature of the tanks 12 and 16, respectively.

[0042] As shown in FIG. 3B, a conveyor-based system for carrying out the invention is generally shown at 30 with containers moving from right to left on conveyor 32. The containers are loaded and enter pre-heat warming zone 34 and then enter multi-zone oven 36 having temperature sensors therein. In some embodiments of the invention, the temperature sensors are thermocouples. In still other embodiments of the invention, two, three, or more temperature sensors are provided per oven zone. In some embodiments of the invention, temperature sensors such as thermocouples provide independent feedback control to regulate the temperature within a given zone of the multi-zone oven. After passing through multi-zone oven 36, the containers pass through cooling zone 38 and are then unloaded. It should be appreciated that the uniform movement of a single, same type of container, located at the same lateral position on conveyor 32, relative to the conveyor facilitates uniform heat exposure to the containers.

[0043] The present invention provides a method for heat treating a container containing uncured cyanoacrylate in a liquid or gaseous or vaporous medium in multiple steps, in which the container containing the cyanoacrylate is subjected to a heat treatment, i.e. an ultra-high temperature treatment, by heating the container containing the cyanoacrylate from 25°C to between 180°C-230°C and holding for a minimum of 0.5 seconds and a maximum of 240 seconds, after which the container containing the cyanoacrylate is cooled to between 65°C-0°C.

[0044] The invention also includes an apparatus for carrying out the method of the invention, the apparatus comprising an ultra-high temperature unit containing a medium and at least one compartment for heat transfer.

[0045] The invention will be explained in more detail below with reference to exemplary embodiments shown in the drawings, without however being limited thereto.

[0046] The present invention will be described in further detail with reference to the following examples, which are not intended to limit the scope of the invention as claimed, but rather to illustrate specific embodiments of the invention. EXAMPLES

[0047] [Example 1] Comparative studies were conducted to determine the effect of the sterilization method on the stability of the cyanoacrylate tissue adhesive, as indicated by the change in viscosity of the cyanoacrylate tissue adhesive over time. Three formulations of cyanoacrylate-based tissue adhesive were used in the comparative studies and are summarized in Table 1 below:

[0048] JPEG2025506071000002.jpg59166

[0049] Three sets of three 0.8 ml samples are sealed in glass ampoules as containers for each of the three formulations in Table 1: · The first set, designated as a control sample set from each of the three sets, is set aside and does not undergo the sterilization process. The second set is three samples of the three formulations in Table 1, designated the batch sample set, sterilized using the conventional sterilization profile shown in Figure 1, with a peak temperature of 170°C for 60 minutes. This has a TAST heat flow of 4408288C*min / mmol, including heating and cooling for comparison. The third set is three samples of the three formulations in Table 1, referred to as the invention sample set, sterilized using one embodiment of the inventive sterilization profile shown in Figure 2A, with a peak temperature of 185°C for 1 minute. For comparison, the TAST heat flow in this case is ∼381670C*min / mmol.

[0050] After sterilization of the two sample sets (batch sample set and inventive sample set), three sample sets (control, batch, inventive) are placed in a temperature chamber and undergo accelerated aging to simulate the equivalent of two years of storage to determine the product stability of the three sample sets. Accelerated aging is performed at 60°C and is determined by using the Arrhenius equation to calculate the real time (25°C) equivalent aging (RTE) up to 24 months with a conservative Q10 factor of 2. The Q10 factor ("rule of 10") is used in accelerated testing and is the factor by which the reaction rate increases for every 10°C increase in temperature. The acceleration rate (also called the accelerated degradation rate, accelerated degradation factor, or acceleration factor) is defined as the ratio of the actual life to the test period. The higher the acceleration rate, the less reliable the test.

[0051] In this experimental accelerated aging study, the effect of aging is measured by the change in viscosity (measured in centipoise) of the adhesive formulation. As shown in the table and graph below for three formulations of adhesive (100% butyl cyanoacrylate, 80% butyl / 20% octyl cyanoacrylate, or 100% octyl cyanoacrylate), the surprising result is that there is no increase in viscosity with aging when compared to batch sterilized formulations and is nearly identical to the non-sterile control when using the sterilization profile of the present invention.

[0052] 4A is a graph of viscosity versus time (change over time) for a set of samples of 100% butyl cyanoacrylate tissue adhesive formulation, divided into the following groups: a non-sterile control group (Control), a group that was batch sterilized with a standard thermal profile (Batch), and a group of samples that were processed using the sterilization thermal profile of the present invention as described above (Invention). Table 2 summarizes the results of the sample testing for the 100% butyl cyanoacrylate tissue adhesive formulation.

[0053] JPEG2025506071000003.jpg93166

[0054] As can be seen from the graph in FIG. 4A and Table 2, the viscosity of the batch sterilized with the standard thermal profile shows a steadily increasing viscosity over time in months, as expected, indicating premature aging of the 100% butyl cyanoacrylate tissue adhesive formulation. However, the sample group processed with the sterilization profile of the present invention, which has a higher peak temperature of 185° C. but a shorter time compared to the standard temperature profile, had a nearly identical aging profile to the control group. FIG. 4B is a graph of viscosity versus time (aging) for the group batch sterilized with the standard thermal profile and the group of samples processed with the sterilization thermal profile of the present invention, as a percentage difference from the non-sterile control group shown in FIG. 4A. As can be easily seen from FIG. 4B, the viscosity of the samples processed with the sterilization profile of the present invention remains within a few percent of the non-sterile control. Meanwhile, the group batch sterilized with the standard thermal profile shows an increase in viscosity as the samples age, eventually hardening before their use.

[0055] Figure 5A is a graph of viscosity versus time (change over time) for a set of samples of a mixture of 80% butyl / 20% octyl cyanoacrylate tissue adhesive formulation, separated into the following groups: a non-sterile control group, a group batch sterilized with a standard thermal profile, and a group of samples processed using a sterilization thermal profile of the present invention. Table 3 summarizes the results of the sample testing for the mixtures.

[0056] JPEG2025506071000004.jpg83166

[0057] As can be seen from the graph in FIG. 5A and Table 3, the viscosity of the batch sterilized with the standard thermal profile shows a steadily increasing viscosity over time in months, as expected, indicating premature aging of the mixed cyanoacrylate tissue adhesive formulation. However, the sample group processed with the sterilization profile of the present invention, which has a higher peak temperature of 185° C. but a shorter time compared to the standard temperature profile, had a nearly identical aging profile to the control group. FIG. 5B is a graph of viscosity versus time (aging) for the group batch sterilized with the standard thermal profile and the group of samples processed with the sterilization thermal profile of the present invention, as a percentage difference from the non-sterile control group shown in FIG. 5A. As can be easily seen from FIG. 5B, the viscosity of the samples processed with the sterilization profile of the present invention remains within a few percent of the non-sterile control. Meanwhile, the group batch sterilized with the standard thermal profile shows an increase in viscosity as the samples age, eventually hardening before their use.

[0058] Figure 6A is a graph of viscosity versus time (change over time) for a set of samples of 100% octyl cyanoacrylate tissue adhesive formulation, divided into the following groups: a non-sterile control group, a group batch sterilized with a standard thermal profile, and a group of samples processed using a sterilization thermal profile of the present invention. Table 4 summarizes the results of the sample testing for the 100% octyl cyanoacrylate tissue adhesive formulation.

[0059] JPEG2025506071000005.jpg85166

[0060] As can be seen from the graph in FIG. 6A and Table 4, the viscosity of the batch sterilized with the standard thermal profile shows a steady increase in viscosity over time in months, as expected, indicating premature aging of the octyl cyanoacrylate tissue adhesive formulation. However, the sample group processed with the sterilization profile of the present invention, which has a higher peak temperature of 185° C. but a shorter time compared to the standard temperature profile, had a nearly identical aging profile to the control group. FIG. 6B is a graph of viscosity versus time (aging) for the group batch sterilized with the standard thermal profile and the group of samples processed with the sterilization thermal profile of the present invention, as a percentage difference from the non-sterile control group shown in FIG. 6A. As can be easily seen from FIG. 6B, the viscosity of the samples processed with the sterilization profile of the present invention remains within a few percent of the non-sterile control. Meanwhile, the group batch sterilized with the standard thermal profile shows an increase in viscosity as the samples age, eventually hardening before their use.

[0061] Experiments with three different formulations of cyanoacrylate tissue adhesive conclusively demonstrated that the sterilization profile of the present invention has little effect on the shelf life of the adhesive product.

[0062] Further examples include the use of ethoxyethyl cyanoacrylate tissue sealant thickened to a viscosity of approximately 120 cP with 8% polymethyl methacrylate (PMMA). The tissue sealant formulation is not designed for aggressive sterilization using high energy and therefore does not contain high levels of toxic stabilizers. 0.7 ml samples of this are sealed in onion skin glass ampules as containers and exposed to batch sterilization or simulated sterilization conditions according to the present invention. The samples are cooled and kept refrigerated until their viscosity is tested. The simulated batch sterilization involves heating to 170°C, followed by cooling to ambient temperature by turning off the oven and opening the oven door. The sterilization conditions of the present invention involve rapid heating to 185°C, holding for 1 minute, followed by cooling using a fan.

[0063] The following table shows the viscosity (in centipoise) of the tissue sealant when exposed to two different sterilization methods:

[0064] JPEG2025506071000006.jpg121166

[0065] As can be easily seen, sterilization by the method of the present invention results in a slight increase in viscosity, but the sample is still usable and the viscosity is very uniform. In contrast, traditional sterilization methods result in products that are too viscous to spread and / or are very variable between small batches. This is consistent with user concerns that current products are very variable in performance.

[0066] The four formulations used in the examples are merely simple examples of the many possible cyanoacrylate or other adhesive formulations that can be sterilized by the method of the present invention. The cyanoacrylates used in the formulations by the inventors include congeners with side chains ranging from 2 carbons to 12 carbons, with or without branching and oxygen groups. The inventors and others skilled in the art are very familiar with stabilizers, thickeners, plasticizers, colorants, accelerators, and initiators that can be used to tailor the clinical performance of tissue adhesives. Many of these are detailed in Zhang, but the most commonly used free radical stabilizer is butylated hydroxyanisole, and the most common anionic stabilizer is sulfur dioxide.

[0067] Other tissue adhesives include methylidene malonate and its derivatives, which are similarly susceptible to degradation under sterilization conditions.

[0068] [Cited documents] Hawkins, Surgical Adhesive Compositions. U.S. Patent No. 3,591,676

[0069] McDonnell, Sterilized Cyanoacrylate Adhesive Composition and a Method of Making such a composition. U.S. Patent No. 5,530,037

[0070] Askill, Methods of Draping Surgical Incision Sites. U.S. Patent No. 5,730,994

[0071] Kotzev, Heat Sterilization of Cyanoacrylate. U.S. Patent No. 5,874,044

[0072] Hickey, Electron Beam Sterilization of Liquid Adhesive Compositions. U.S. Patent No. 6,143,805

[0073] Greff, methods for sterilizing cyanoacrylate compositions. U.S. Patent No. 6,248,800

[0074] Zhang, Sterilized Liquid Compositions of Cyanoacrylate Monomer Mixtures. U.S. Patent No. 8,652,510

[0075] The patent documents and publications mentioned in this specification are indicative of the level of those skilled in the art to which this invention pertains. These documents and publications are herein incorporated by reference to the same extent as if each individual document and publication was specifically and individually incorporated by reference.

[0076] The above description is an illustration of specific embodiments of the present invention, but is not meant to be limiting of its practice. The following claims, including all equivalents thereof, are intended to define the scope of the present invention.

Claims

1. 1. A method for sterilization of a tissue adhesive comprising: The method comprises: heating a container containing a quantity of said tissue adhesive to a maximum temperature between 180° C. and 230° C. such that the Time Averaged Sterilization Temperature heat flow is up to 500,000 C*min / mmol for said millimolar quantity of tissue adhesive; and cooling the container to sterilize the quantity of the tissue adhesive; Including, method.

2. 2. The method of claim 1, The cooling is shock cooling. method.

3. 2. The method of claim 1, said time-averaged sterilization temperature heat flow must not exceed 250,000 C*min / mmol for said amount of tissue adhesive; method.

4. The method according to any one of claims 1 to 3, The tissue adhesive is one of an acrylic bone cement, methylidene malonate, or a cyanoacrylate ester. method.

5. 1. A composition of matter comprising: A container with an airtight seal; a quantity of sterile tissue adhesive in said container; Including, said amount of sterilized tissue adhesive having a shelf life of at least 36 months at standard temperature and pressure; composition of matter.

6. 6. A composition of matter as claimed in claim 5, The storage stability is between 36 and 72 months. composition of matter.

7. 6. A composition of matter as claimed in claim 5, The container is formed from borosilicate glass, metal, ceramic, or high temperature resistant plastic. composition of matter.

8. 6. The composition according to claim 5, the tissue adhesive is a cyanoacrylate; composition.

9. 9. The composition according to claim 8, The cyanoacrylate is butyl cyanoacrylate, octyl cyanoacrylate, or a combination thereof; composition of matter.

10. 6. A composition of matter as claimed in claim 5, further comprising a free radical stabilizer, composition of matter.

11. 11. A composition of matter as claimed in claim 10, comprising The free radical stabilizer is BHA, BHT, 4-methoxyphenol, hydroquinone, 4-ethoxyphenol, 3-methoxyphenol, catechol, or a combination thereof; composition of matter.

12. 6. A composition of matter as claimed in claim 5, Further comprising a preservative, composition of matter.

13. 13. A composition of matter as claimed in claim 12, comprising The preservative is SO ２ , boron trifluoride, or at least one strong acid selected from the group consisting of perchloric acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, phosphoric acid, and combinations thereof; composition of matter.

14. 6. A composition of matter as claimed in claim 5, Further comprising a thickener, composition of matter.

15. 15. A composition of matter according to claim 14, comprising The thickening agent is PMMA, polyvinyl acetate, polycyanoacrylate polymers and copolymers, or combinations thereof; composition of matter.

16. A composition of matter according to any one of claims 5 to 15, further comprising at least one of a plasticizer, a citrate, a sebacate, a colorant, an accelerator, or a combination thereof; composition of matter.

17. A composition of matter according to any one of claims 5 to 15, 2. A method according to claim 1, composition of matter.

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