RU2786402C2 - Method and device for polyester sterilization - Google Patents

Abstract

FIELD: biomaterials.

SUBSTANCE: invention relates to biomaterials, in particular biodegradable polyesters intended for use for medical purposes, which need for sterilization, and it concerns a container for orientation and cooling of polyesters during sterilization and a method for polyester sterilization. The container includes: a number of packages, each of which contains polyester, and a case defining a socket for reception of the number of packages, wherein the case contains at least one partition located between adjacent packages to separate them and a compartment located from an inner side of at least one of several walls, in which a cooling device is located, wherein the cooling device is not located directly above and directly under the socket, so that the socket can be subjected to irradiation from top to bottom or bottom up, without passage of radiation through the cooling device. The method for polyester sterilization includes irradiation with a bundle of electrons of polyester having a glass transition temperature (T_g), wherein a polyester temperature is maintained lower than its T_g, using the cooling device, and the bundle of electrons does not pass through this cooling device, and polyester is added to the container before irradiation.

EFFECT: invention provides a possibility of avoidance of side effects, when irradiating polyester with a bundle of electrons in the presence of oxygen, such as rupture and/or cross-linking of polymer chains, which provides a possibility of saving, during irradiation, of certain physical properties of polyester, such as characteristic viscosity, molecular weight, and/or polydispersity.

14 cl, 8 dwg, 8 tbl, 2 ex

Description

Prerequisites for the creation of the invention

Biomaterials intended for medical use need to be sterilized before use. In one method, sterilization is carried out by using electron beam (EB) radiation. However, EP sterilization of biomaterials such as biodegradable polyesters can result in harmful side effects that may preclude its use.

Disclosure of invention

One object of the invention is a container (packaging kit) for orienting and cooling polyester during its sterilization process. The container includes a number of packages, each of which contains polyester granules, and a body that defines a nest (receptacle) for receiving a number of packages. The housing defines an upper region located above the socket, a lower region located under the socket as a whole opposite the upper region, and has several walls (faces) located around the socket between the upper and lower regions. The housing includes at least one partition located between adjacent packages for the purpose of separating them, and a compartment located on the inner side of at least one of several walls. This compartment houses the cooling medium. The cooling means is not located directly above and directly below the socket, so that the socket can be irradiated from top to bottom or from bottom to top without radiation passing through the cooling means.

Another object of the invention is a method for sterilizing polyester, which comprises irradiating an electron beam with a polyester having a glass transition temperature (T _g ), wherein the temperature of the polyester is maintained below its T _g by means of a cooling means, and the electron beam does not pass through this means.

Another object of the invention is a method for sterilizing polyester, which includes irradiating the polyester with an electron beam, and the polyester is placed in an essentially oxygen-free bag.

Brief description of the drawings

The drawings show:

fig. 1 is an exploded perspective view of a packaging system containing a container for orienting and cooling the polyester during the sterilization process and a container for storing and transporting the container,

fig. 2 is a side view of the container shown in FIG. one,

fig. 3 is a sectional view of the container along line 3-3 of FIG. 2,

fig. 4 is a sectional view of the container along line 4-4 of FIG. 2,

fig. 5 is a plan view of the first container divider shown in FIG. 2,

fig. 6 is a plan view of the second container divider shown in FIG. 2,

fig. 7 is a graph showing the effect of electron beam irradiation dose on the intrinsic viscosity (IV) of various polyesters,

fig. 8 is a series of images showing: A) raw polyester, B) polyester treated at 25 kGy, C) polyester treated at 25 kGy using dry ice as a cooling agent.

Detailed description of the invention

Before proceeding to a detailed description of the embodiments of the invention, it should be noted that the invention is not limited in its application to the details of construction and the configuration of the components presented in the following description or shown in the attached drawings. There are other embodiments of the invention, which can be practiced in different ways.

1. Terms and definitions

Unless otherwise indicated, all technical and scientific terms used in the present description have the meaning commonly used by those of ordinary skill in the art. In case of conflict, the present description, including definitions, takes precedence. The preferred methods and materials are those set forth in the following description, although similar or equivalent methods and materials may be used in the practice or testing of the present invention. All publications, patent applications, patents and other sources of information mentioned in the present description are incorporated herein by reference in their entirety. The materials, methods, and examples provided herein are for illustrative purposes only and are not intended to be limiting in any way.

As used herein, the terms "comprise(s)", "include(s)", "having", "has", "may", "accommodate(s)" and variations thereof are intended to be used as non-limiting transitional terms. phrases, terms or words that do not exclude the possibility of performing additional actions or adding constructive elements. Unless the context clearly implies otherwise, singular forms include references to plural forms. The present invention also extends to other embodiments, "comprising", "comprising" and "essentially including", whether explicitly or implicitly, the embodiments or elements presented in the present description.

The union "or" implies the inclusion of any and all combinations of one or more of the listed elements associated with this union. For example, the phrase "device contains A or B" could refer to a device that has A but does not have B, a device that has B but does not have A, or a device that has both A and B. The phrases " at least one of A, B, ... and N" or "at least one of A, B, ... N", or combinations thereof, define in the broadest sense one or more elements selected from the group consisting of A, B, ... and N, that is, any combination of one or more elements A, B, ... or N, including any element alone or in combination with one or more other elements, and may also include additional elements not mentioned in the list.

The "approximately" modifier, used in conjunction with a quantity, includes the specified numerical value and has a meaning determined by the context (eg, it includes at least a fraction of the error associated with the measurement of a particular numerical value). The "approximately" modifier should also be considered as an input range defined by the absolute values at the two endpoints. For example, the expression "from about 2 to about 4" also refers to the range "from 2 to 4." The term "approximately" may mean plus or minus 10% of the specified number. For example, "about 10%" could indicate a range of 9% to 11%, and "about 1" could range from 0.9 to 1.1. Other meanings of "approximately" may follow from the context and mean, for example, rounding: "approximately 1" may also mean a range from 0.5 to 1.4.

The term "substantially oxygen-free" or "substantially oxygen-free" as used herein means "substantially oxygen-free" or "substantially oxygen-free" within the limitations of vacuum packaging processes that remove oxygen from a space. "Substantially anoxic" may refer to an oxygen content of less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, less than 1 ppm, less than 0.9 ppm, less than 0.8 ppm, less than 0.7 ppm, less than 0 .6 ppm, less than 0.5 ppm, less than 0.4 ppm, less than 0.3 ppm, less than 0.2 ppm, less than 0.1 ppm, less than 0.05 ppm, less than 0.01 ppm, or 0 ppm.

2. Packaging systems

In FIG. 1 shows a packaging system 10 comprising a container 12 for orienting and cooling the polyester during the sterilization process and a container 14 for storing, transporting and cooling the container 12.

The container 14 includes a frame 16, such as a cardboard box or other structural component or material defining an interior space 18 and an exterior space 20. The frame 16 may be formed from other paper materials or otherwise constructed from other materials such as a polymer. The frame 16 as a whole defines the shell for the container 12 placed in the inner space 18 of the frame 16. The frame 16 shown in the drawing is structurally a hexagonal, in particular rectangular, parallelepiped. In another design, the frame 16 may have a different shape. In the illustrated design, container 14 measures approximately 26 inches (length L1) by approximately 15 inches (height H1) by approximately 24 inches (width W1). With regard to the dimensions of the packaging system, container, container, etc. the term "approximately" should be understood to mean plus or minus 2 inches. In other designs, L1 is 22 to 30 inches long, H1 is 11 to 19 inches high, and W1 is 20 to 28 inches wide. In other constructions, any suitable dimensions are possible, not exceeding 60 inches in any direction.

The frame 16 may include an insulating pad 22, such as STYROFOAM® (closed cell extruded polystyrene foam) or other suitable insulating material having a lower thermal conductivity than the frame material. An insulating pad 22 may be located on the inside of the frame 16 and adjacent to one or more of its six walls. In the illustrated design, insulating pad 22 is located on the inside of all six walls of frame 16. In other designs, insulating pad 22 may be located on the outside of frame 16. Container 14 also includes means 24 for cooling it, such as dry ice (carbon dioxide), adjacent to the liner 22 on the inside of the frame 16. The dry ice as container cooling means 24 may be in any suitable form, such as pellets, briquettes, etc. In other designs, the container cooling means 24 may include other components such as cooling blankets, gel cool packs, and the like. The container cooler 24 may abut one or more of the six walls of the insulating pad 22. In the illustrated design, the container cooler 24 is located on the inside of all six walls of the insulating pad 22.

Corner blocks 26 provide clearance between container 12 and container 14 when container 12 is placed in container 14. In addition, corner blocks 26 secure the container, as described in more detail below. Corner blocks 26 may be formed from foam or any other suitable material. Eight blocks 26 are used in the illustrated design. However, in other designs, the number of corner blocks 26 may be changed to best suit the changing geometry of container 14 and container 12.

The container 12 has a body 28 (FIGS. 1-4) including a base 30 and/or a lid 32 defining an inner space 34 and an outer space 36. In the illustrated design, the body 28 is a hexagonal, in particular rectangular, parallelepiped, but in other designs may have a different geometry and a different number of walls (faces). In the illustrated container design, 12 measures approximately 20 inches (length L2) by approximately 8 inches (height H2) by approximately 17 inches (width W2). In other designs, the length L2 is 16 to 24 inches, the height H2 is 4 to 12 inches, and the width W2 is 13 to 21 inches. In other constructions, any suitable dimensions are possible, not exceeding 48 inches in any direction.

Housing 28 defines (forms) a nest (receptacle) 38 for receiving a number of packets 40 (described in more detail below) in the interior 34. In FIG. 2 shows that the housing 28 generally defines an upper region 42 (eg, the first of six walls) located above the cavity 38, a lower region 44 (eg, another of the six walls) opposite the first wall below the cavity 38, and generally , opposite the upper region 42, and has several walls 46 (for example, the rest of the six) located around the socket 38 between the upper region 42 and the lower region 44. Several walls 46 generally form an annular space around the socket 38 between the upper region 42 and the lower region 44. It should be noted that in the context of the present description, the terms "upper", "lower", "above" and "under" are relative concepts based on any fixed reference point and do not require reference to the direction of gravity. On the contrary, these terms generally define areas and directions relative to each other.

Container 12 includes at least one partition (or insert) 48 located between adjacent packages 40 for the purpose of separating them. In the illustrated design, at least one baffle 48 includes a series of baffles 48 having substantially flat surfaces 50 (FIG. 5). The baffles 48 face each other with these surfaces and are parallel to each other in a row inside the nest 38, defining a gap 52 between each of two adjacent baffles 48, in which one of the packages 40 is located. In the illustrated design, the value of each gap 52 is from 1 to 2 inches (eg, approximately 1.5 inches), but may be more or less in other designs. A series of baffles 48 extends in a direction from one of the plurality of walls 46 to another such wall 46, which walls may be arranged opposite each other. In the illustrated design, 10 bags are placed between 11 partitions. However, in other designs, any suitable number of 40 bags may be used. For example, in other designs, 8 to 12 bags, 6 to 14 bags, and so on may be used. The container 12 also includes a pair of inserts 54 (FIG. 3 and FIG. 6 - only one insert shown) located across the row of baffles 48 (eg, perpendicular to the row of baffles 48).

The container 12 also includes a compartment 56 (FIGS. 1, 3 and 4) located on the inside of at least one of several walls 46. The compartment 56 may extend along part of one of the several walls 46, along one of the several walls 46, along two of several walls 46, along three of several walls 46, or along all walls 46. For example, the compartment 56 is located on the inside of all four walls 46 of the housing 28, forming an annular space surrounding the nest 38 from the side of the walls 46, but not from the side of the upper region 42 or lower region 44 (FIG. 1). Compartment 56 may be formed between baffles 48 located at the ends of receptacle 38 and body 28, as well as between inserts 54 and body 28. In other designs, other inserts, baffles, walls, or other structural elements may be used to separate compartment 56 from receptacle 38. .

Compartment 56 houses a cooling means 58, such as dry ice (carbon dioxide), located on the inside of the housing 28 and on the outside of the cavity 38. Cooling means 58 may include dry ice in any suitable form, such as granules, briquettes, etc. . In other designs, cooling means 58 may include other materials. The cooling means 58 is not located directly above and directly below the socket 38, so that the socket 38 can be irradiated from top to bottom or from the bottom up without radiation passing through the cooling means 58.

The housing 28 includes a number of ventilation channels 60 in fluid communication with the compartment 56 and designed to ventilate the cooling means 58. In the illustrated design, the vents 60 are formed as openings in the base 30 and the cover 32, with each vent 60 having the shape of a generally oblong slot extending from top to bottom. In the illustrated design, there are ten vents 60, i.e. one vent 60 for each stack 40. However, in other designs, the number, size, and shape of the vents 60 may vary and need not correspond to the stacks 40.

The container 12 also includes a shelf 62 (FIG. 1) covering the slot 38 (and hence the bags 40) and preventing coolant 58 from entering the slot 38 from the compartment 56. The shelf 62 includes a lid portion 64 that may be substantially flat and located above the nest 38, closing it. The dimensions of the lid portion 64 generally coincide with the corresponding dimensions of the upper contour of the socket 38. The shelf 62 also includes flaps 66 extending from the lid portion 64 and may be perpendicular to the latter. The flaps 66 extend into the pocket 38 directly adjoining the baffles 48 at its ends. In this way, the shelf 62 protects the packages 40 in the nest 38 and creates a barrier preventing the coolant 58 from entering the nest 38. Shelf 62 may be made of paper material such as cardboard, cardstock, etc., or, in other constructions, other suitable materials such as polymers, fiberglass, etc. When placing the container 12 inside the container 14, the corner blocks 26 fix the container 12 in the container 14, preventing the penetration of the cooling means 58 into the nest 38 with the packages 40 placed in it.

Each bag 40 has first and second surfaces 68, with the bags 40 facing each other and adjacent baffles 48. The bags 40 may be made of foil, polymer, or other suitable material; each bag contains polyester pellets (described in more detail below) to be sterilized in a process described in more detail below. Each bag 40 is vacuum packed and sealed such that the polyester pellets are within the bag 40 in a substantially anoxic environment.

3. Polyester sterilization methods

In the present description, methods for sterilizing polymers, in particular polyesters, by using electron beam radiation are presented. One aspect of the invention is methods for sterilizing polyester, the method comprising irradiating an electron beam with a polyester having a glass transition temperature (T _g ), wherein the temperature of the polyester is maintained below its T _g by means of a cooling means, and the electron beam does not pass through the means.

During electron beam sterilization, large amounts of energy can be applied to the polymer to be sterilized. This energy can generate heat which can raise the temperature of the polymer and cause it to melt. Cooling the polymer (eg, below its T _g ) during the sterilization process can minimize melting in the samples. However, the packaging of the polymer cannot be carried out directly in a cooling medium, since this can lead to the absorption and scattering of electrons, which may result in uneven dose delivery to the sterilized polymer. The present methods can alleviate the problem of polyester melting during sterilization by keeping the temperature of the polyester below its _Tg and by preventing the electron beam from passing through the cooling means.

Therefore, in the proposed methods, fusion of the polyester (eg, in the form of pellets) during irradiation cannot occur.

These methods can use different doses of electron beam irradiation. For example, the polyester may be irradiated at a dose of from about 10 kGy to about 300 kGy, such as from about 15 kGy to about 250 kGy, from about 10 kGy to about 200 kGy, or from about 15 kGy to about 50 kGy. In some embodiments of the invention, the polyester may be exposed to radiation at a dose of more than 10 kGy, more than 12 kGy, more than 15 kGy, or more than 17 kGy. In some embodiments, the polyester may be exposed to a dose of less than 300 kGy, less than 250 kGy, less than 200 kGy, or less than 150 kGy.

The polyester can be any polyester that tends to agglomerate at elevated temperatures, as well as any polyester that tends to break and/or crosslink polymer chains in the presence of oxygen. Examples of polyesters include, but are not limited to, polylactic acid, polyglycolic acid, polycaprolactone, poly(dioxanone), poly(trimethylene carbonate), copolymers of polylactic acid, polyglycolic acid and/or polycaprolactone, such as poly(lactic-co-glycolic acid) - PLGA, copolymers of PLGA and polyethylene glycol (PEG), copolymers of PLGA and poly(dioxanone), copolymers of PLGA and poly(trimethylene carbonate), and combinations of the above. In some embodiments, the polyester may be polylactic acid, PLGA, or combinations thereof. The polyester may have an M _w in the range of from about 1 to about 500 kD, such as from about 2 to about 400 kD, or from about 3 to about 300 kD. In addition, in embodiments of the invention, including a copolymer, this copolymer may have a varying ratio of different monomers in the original mixture, depending on the goal in relation to the final product.

The polyester may further be present in a wide variety of forms. For example, the polyester may be present in the form of granules, powder, pellets, bulk material, or combinations of the foregoing. The polyester may also be placed in a substantially oxygen-free bag in the manner described above. In some embodiments, the polyester may be present in the form of granules placed in a substantially oxygen-free bag. The bag may be substantially free of oxygen due to its vacuum sealing. In some embodiments of the invention, the bag can be vacuum sealed and then purged with an inert gas such as nitrogen and/or argon. In other embodiments, the bag may be purged with an inert gas followed by vacuum sealing. The package may contain an inner bag and an outer bag. The inner bag may contain polyethylene, nylon, or a combination thereof. The outer bag may contain foil.

The package may have useful characteristics that allow it to be used to irradiate polyesters. For example, the inner bag may have a bond strength in the range of about 10 to about 15 lbf/in before, during, and/or after electron beam irradiation. In addition, the outer bag may have a bond strength in the range of about 13 to about 20 lbf/in before, during and/or after electron beam irradiation. The bond strength value for the inner and outer bags can be measured on either side of the bag (eg top, bottom, etc.).

The methods according to the invention make it possible to avoid the occurrence of side effects when polyester is irradiated with an electron beam in the presence of oxygen, such as breaking and/or crosslinking of polymer chains. Therefore, the methods of the invention make it possible to maintain certain physical properties of the polyester during irradiation, such as intrinsic viscosity, molecular weight and/or polydispersity. For example, the change in intrinsic viscosity of the polyester after irradiation can be about 0 to about 15% relative to the value of intrinsic viscosity before irradiation, such as about 0.1 to about 13%, or about 0 to about 12%. In addition, the change in M _w of the polyester after irradiation may be from about 0 to about 20% relative to the M _w before irradiation, such as from about 0.1 to about 17%, or from about 0 to about 16%.

These methods may use, as described above, a number of cooling means to keep the temperature of the polyester below its T _g . For example, suitable cooling means include, but are not limited to, dry ice, cooling blankets, gel cool packs, and the like. and their combinations. In some embodiments, the cooling means may be dry ice.

The method may also include adding polyester to the container, as described above, prior to irradiation. For example, the method may also include adding polyester prior to irradiation to a container containing a body defining a nest for receiving a number of packets, as well as defining an upper region located above the nest, a lower region located below the nest as a whole opposite the upper region, and several walls located around the nest between the upper and lower regions, and the housing includes at least one partition located between adjacent packages for the purpose of separating them, and a compartment, which is located on the inner side of at least one of several walls and in which a cooling means is placed, moreover, the means cooling is not located immediately above and immediately below the socket, so that the socket can be irradiated from top to bottom or from bottom to top without radiation passing through the cooling means.

Other objects of the present invention are methods for sterilizing polyester, the method comprising irradiating the polyester with an electron beam and placing the polyester in a substantially oxygen-free bag.

The above description relating to polyester, pouches, electron beam doses, and post-irradiation properties of polyester generally applies to methods involving electron beam irradiation of polyester placed in a substantially oxygen-free bag. This description is not repeated below for reasons of brevity.

4. Examples

Polymers used in examples 1 and 2

Polymer 1: poly(D,L-lactide) - intrinsic viscosity (IV) 0.22 dl/g - M _w 19 kDa

Polymer 2: poly(D,L-lactide) - IV 0.33 dl/g - M _w 32 kDa

Polymer 3: poly(D,L-lactide-co-glycolide) - IV 0.20 dl/g - M _w 18 kDa - initial lactide to glycolide ratio 50:50

Polymer 4: poly(D,L-lactide-co-glycolide) - IV 0.37 dl/g - M _w 41 kDa - initial lactide to glycolide ratio 50:50

Polymer 5: same as polymer 3, thickened

Polymer 6: same as polymer 4, thickened

Polymer 7: poly(D,L-lactide-co-glycolide) - IV 0.20 dl/g - M _w 14 kDa - initial lactide to glycolide ratio 75:25

Polymer 8: poly(D,L-lactide-co-glycolide) - IV 0.38 dl/g - M _w 38 kDa - initial lactide to glycolide ratio 75:25

Polymer 9: branched poly(D,L-lactide-co-glycolide) with initiator (glucose) - IV 0.50 dl/g - M _w 66 kDa - initial lactide to glycolide ratio 55:45.

Example 1 Electron Beam Sterilization (Experiment I)

The most pronounced effects of polymer degradation are a decrease in molecular weight and intrinsic viscosity. Irradiated and unirradiated samples were tested using a standardized inherent viscosity (IV) method in which the samples were dissolved in chloroform (0.1% w/v) at 25° C. and measured in an Ubbelohde capillary viscometer. The packaging was carried out in three different ways: 1) vacuum packaging, 2) vacuum packaging with a purge of nitrogen (N ₂ ) and 3) air packaging. Samples packaged in different ways were sterilized by electron beam irradiation at two different doses, 40 kGy and 200 kGy. Table 1 shows the XB data for materials that have been irradiated. As shown in columns 1-3 of the table, after irradiation with an electron beam, the sample in the case of air packing has a lower IV compared to the samples in the cases of vacuum packing and vacuum packing with nitrogen purge. When the dose was increased from 40 kGy to 200 kGy, the IV of the sample in the case of vacuum packaging retained a value of 0.29 dl/g (column 4). However, the IV of the sample in the case of airpacking dropped to 0.25 dl/g (column 5). This indicates that less degradation of the polymer may be due to the removal of oxygen. A similar trend was observed in the case of sterilization of polymer 10. It was also found that the decrease in IV of the sample in the case of vacuum packaging (column 6) is less pronounced than that of the sample in the case of air packaging (column 7).

It was expected that due to the chain breaking and degradation caused by the electron beam treatment, IV would decrease significantly with increasing dose, however, the decrease in IV was minimal. It has been suggested that vacuum packaging of samples reduces the number of oxygen free radicals, thereby reducing the number of damage caused by free radicals.

Example 2 Electron Beam Sterilization (Experiment II)

In this example, the effect of electron beam sterilization on various polymers is further evaluated. More specifically, in this experiment, various controlled release polymers were evaluated and changes in their appearance, molecular weight and intrinsic viscosity were examined. In addition, the packages were tested for the strength of the connection.

Methods

Receipt of Materials: The polymer samples came from the sterilizer and were kept refrigerated. Table 2 below lists the resulting polymers.

The samples obtained were intact and had no visible defects. The samples were cold to the touch and were stored at 4°C.

Packaging: Twenty grams of the sample listed in Table 3 were packaged in polyethylene/nylon bags used as inner packaging and in foil bags. Both the inner and outer bags were vacuum sealed.

Transport: Kits containing three samples for each item listed in Table 3 were placed in a bag labeled with the specific exposure dose. To avoid confusion after irradiation, each sample was labeled with the exposure dose. Exposure doses were 17.5 kGy, 25 kGy and 35 kGy. The packages were stored in a refrigerator at 4° C. until placed in a suitable shipping container containing 8 frozen cooling bags. Until irradiation, the samples were stored at 4°C.

Irradiation: samples were stored at 4°C, sorted and irradiated with an electron beam at doses of 17.5 kGy, 25 kGy and 35 kGy. Then the samples were returned to the refrigerator for subsequent transportation in the same transport container containing 8 frozen cooling bags.

Obtaining materials after electron beam treatment: the obtained cold samples were removed from the foil bag. In some samples, agglomeration of materials was noted. Agglomeration obviously became more pronounced with increasing dose. Approximately 2-3 grams of each of the extracted samples were placed in labeled glass vials with plastic screw caps and sent for analysis.

results

The irradiated samples, along with a set of control non-irradiated samples, were sent for analysis to determine the IV and perform Gel Permeation Chromatography (GPC) (with chloroform as solvent and calibrated against polystyrene standards). The results are shown in Table 4 below.

All analytical data were reviewed and some input GPC data were re-evaluated in order to streamline baseline parameters where discrepancies could lead to erroneous results.

A number of asymmetric results were noted due to the specifics of analytical methods for determining M _n and polydispersity and associated with the formation of diffuse backgrounds ("tails") during GPC in the case of polymers of acids with low molecular weight. This fact is a well-known GPC problem with such polymers. This was clearly shown in the data for Polymer 3, Polymer 5 and Polymer 7, for which high PDI values were obtained. This data can be used to compare and show trends.

Intrinsic viscosity: The most pronounced effects of polymer degradation are the reduction in molecular weight and intrinsic viscosity. It was expected that due to the chain breaking and degradation caused by the electron beam treatment, IV would decrease significantly with increasing dose, however, the decrease in IV was minimal. As in Example 1, it is suggested that the vacuum packaging of the samples reduces the number of oxygen free radicals, thereby reducing the number of damage caused by free radicals. Table 5 lists the IV values of products before and after irradiation, along with specifications for each. The effect on IV was minimal and IV values for all products remained within specification.

The above effects can also be displayed graphically (FIG. 7). It is noted that large changes in IV occur for polymers with higher initial IV.

Particle fusion: Electron beam sterilization is the preferred method for sterilizing polymeric materials due to the low amount of heat generated. The proportion of heat generated can be calculated from the specific heat capacity of a particular polymer. From the equation Δ°C=0.239*kGy/h (where h=0.27964 cal/g°C and 0.5497 cal/g°C) given in the publication incorporated herein by reference in its entirety (Thomas S., Thomas S., Yang W., "Advances in polymer processing: from macro to nanoscale", Cambridge, UK, Woodhead Publishing, 2009, p. 414), it follows that the expected maximum rise in polymer temperature at 35 kGy is from about 15.2°C to about 29.9°C.

The polymer was placed in a sterilization unit at 4°C, however, fusion occurred even at low doses. It was assumed that the fusion occurred due to the temperature exceeding the glass transition point. Temperature changes greater than expected may be due to system design, such as packaging and foiling. To prevent this fusion, a second set of materials was sent with instructions to pack it in dry ice. Samples irradiated in dry ice showed no fusion even at 35 kGy (see FIG. 8).

Closure system: 20 gram samples of polymer 9 were packaged in bags as described above. Irradiated and unirradiated specimens were tested according to ASTM F88/F88M-15 "Standard Test Method for Joint Strength of Flexible Shielding Materials". The results showed that during electron beam sterilization, the bond strength varied slightly from bag to bag used as the outer packaging, regardless of dose (see Table 6). Changes in the inner bags were minor. These data are confirmed by the manufacturer of the closing system. Therefore, this closure system is suitable for the sterilization of polyesters.

In this example, the effect on polymers of sterilization by an electron beam at doses of 17.5, 25 and 35 kGy was studied. The doses of 17.5 and 25 kGy were expected to be appropriate for sterilization based on the estimated bioburden, while the dose of 35 kGy was an overexposure. Sterilization by ionizing radiation can lead to the formation of free radicals that promote chain scission, crosslinking, or a combination of both, which can be expressed in an increase or decrease in the molecular weight of the polymer. Since IV is proportional to molecular weight, similar changes should be observed for it.

For all doses, IV values either remained unchanged or showed a slight decrease. As shown in Table 5, all IVs of the polymers remained within the original specification. A similar decrease was observed for molecular weight (table 7). The largest percentage decrease in molecular weight was observed for polymers with higher values of the latter.

Packaging tests have demonstrated its suitability at all doses used. The samples were subjected to vacuum sealing in order to reduce the oxygen content and, consequently, weaken the influence of its free radicals, which, according to the assumption, is a protective factor during electron beam sterilization.

In addition, it was noted that while the IV of all products remained within specification, there was physical fusion for products sterilized at ambient temperature due to the heat generated during the process. This problem was partly solved by using dry ice in the system and process.

Example 3 Electron Beam Sterilization (Experiment III)

For polymers subjected to electron beam irradiation, a carrier has been developed to provide cooling during the process. The carrier means holds the samples in a certain orientation with respect to the electron beam. In addition, the carrier means holds the cooling means in a certain orientation, so that the latter is isolated from the electron beam that passes through the samples. Therefore, the samples are cooled in such a way that the heat generated due to the passage of the electron beam does not lead to agglomeration, aggregation or melting of the samples. In this case, the samples to be sterilized can be used as blown powder or granular material.

Polylactic and poly(lactic-co-glycolic) acid polymer samples were packaged as powder or granules. The samples were packed in a cardboard box. This box was placed in another box containing a physical barrier to prevent mixing with the coolant. The materials were sent for sterilization by irradiation with an electron beam at doses of 17.5, 25, 35, 50, 100, or 200 kGy. Electron beam sterilization results are shown in Table 8.

Therefore, the carrier provides an environment that provides an advantage in terms of obtaining a sterile polymer with minimal changes in physical characteristics. This can facilitate the incorporation (without the need for further processing) of sterile excipients into aseptic processes such as grinding or milling the product.

Claims (17)

1. A container for orienting and cooling polyester during a polyester sterilization process, comprising: a series of bags, each of which contains polyester, and a body that defines a nest for receiving a number of packages, as well as defining an upper region located above the nest, a lower region located under the nest as a whole opposite the upper region, and several walls located around the nest between the upper and lower areas, and the body contains: at least one partition located between adjacent packages to separate them, and a compartment located on the inner side of at least one of several walls, in which the cooling means is located, and the cooling means is not located directly above and immediately below the nest, so that the nest can be irradiated from top to bottom or from bottom to top without radiation passing through the cooling means. 2. A container as claimed in claim 1, wherein the housing includes a number of vents in fluid communication with the compartment for ventilating the cooling means. 3. The container of claim. 1, in which the packages essentially do not contain oxygen, so that the oxygen content is less than 5 ppm. 4. The container of claim. 1, in which at least one partition includes a number of generally flat and parallel partitions, and the package is located between adjacent partitions. 5. A container as claimed in claim 4, wherein the partitions and pouches face each other and are arranged in a row extending in a direction from one of said multiple walls to another of said multiple walls. 6. A method for sterilizing polyester, comprising irradiating with an electron beam a polyester having a glass transition temperature (T _g ), wherein the temperature of the polyester is maintained below its T _g by means of a cooling means, and the electron beam does not pass through this cooling means, and the polyester is added, before irradiation , in a container having a body that defines a nest for receiving a number of packages containing polyester, and also defines an upper region located above the nest, a lower region located under the nest as a whole opposite the upper region, and several walls located around the nest between the top and bottom areas, and the housing contains at least one partition located between adjacent packages for their separation, and a compartment located on the inside of at least one of several walls, in which the cooling means is located, while the cooling means is not located directly above and directly under the nest, so the nest can be irradiated from top to bottom or from bottom to top without radiation passing through the cooling means. 7. The method of claim 6 wherein the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, copolymers of polylactic acid, polyglycolic acid and/or polycaprolactone, copolymers of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG), PLGA and poly(dioxanone) copolymers, PLGA and poly(trimethylene carbonate) copolymers, and combinations thereof. 8. The method of claim 6 or 7, wherein the cooling means is dry ice, gel cold packs, cold blankets, or combinations thereof. 9. The method according to one of paragraphs. 6-8, wherein the polyester is irradiated with a dose of from about 10 kGy to about 300 kGy. 10. The method according to one of paragraphs. 6-9, in which the polyester is present in the form of granules, powder, pellets, bulk material, or combinations thereof. 11. The method according to one of paragraphs. 6-10, wherein the polyester is packaged in a substantially oxygen-free bag such that the oxygen content is less than 5 ppm. 12. The method of claim 11 wherein the bag is vacuum sealed or vacuum sealed followed by a nitrogen purge. 13. The method of claim 11 or 12, wherein the pouch comprises an inner bag and an outer bag. 14. The method of claim 13, wherein the inner bag contains polyethylene, nylon, or a combination thereof and the outer bag contains foil.

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