Storage Stable Surgically Absorbable Polyglycolic Acid Products

Abstract

A dry absorbable synthetic surgical element of a polymer subject to hydrolytic degradation to non-toxic, tissue-compatible, absorbable components, such as a polyglycolic acid suture, is package in an air-tight sealed container which is substantially impervious to water vapor such as a laminate film having a metallic foil layer. The gaseous contents of the envelope are, prior to sealing the suture within the envelope, either evacuated or replaced with a gas which is inert towards said surgical element and which is substantially free from water. The water content should be below 0.5 percent by weight of the weight of the surgical element, and preferably is below 0.05 percent by weight. Polyglycolic acid sutures and other elements thus packaged retain acceptable levels of strength for at least one year at storage temperatures of 72.degree.F. and ambient humidity outside the package. The contents may be sterilized by using ethylene oxide.

Parent Case Text

CROSS-REFERENCES

This is a Continuation-in-Part of copending application Ser. No. 788,501 filed Jan. 2, 1969, and abandoned in favor hereof.

Description

BACKGROUND OF THE INVENTION

At the present time, virtually all absorbable sutures used in animal and human surgery are prepared from mammalian intestines, such sutures being commonly called catgut sutures. U. S. Pat. No. 3,297,033 describes an absorbable surgical suture made from polyglycolic acid. The disclosure therein is incorported by reference. This patent in column 3, lines 20 to 53 disclose other components which may be present in the suture. As set forth therein, polyglycolic acid is also properly named as poly(hydroxyacetic acid) or poly-hydroxyacetic ester.

Polyglycolic stures exhibit great uniformity of composition, as compared with catgut. They have excellent package strength, i.e. straight pull and knot pull, and desirable in-vivo strength retention.

It has now been found that the desirable package properties and in-vivo properties of polyglycolic acid surgical elements such as sutures deteriorate when exposed to moisture. Surprising, the exposure of dry polyglycolic acid sutures to small amounts of moisture for very short periods of time is sufficient to cause serious deterioration in the package and in-vivo strength of the sutures on long term standing.

If the polyglycolic acid suture for instance is again dried before packaging, the storage stability is regained. For instance, polyglycolic acid filaments may be braided at ambient temperature and humidity, in a New England climate, and if the finished braid is dried to remove all absorbed moisture, the dried braid is storage stable. For process uniformity and operator comfort, an air conditioned enviornment is preferred.

Although the reason for the aformentioned affect of moisture on the properties of polyglycolic acid sutures is not known with certainty, it is believed that several mechanisms may be involved. First, the water may hydrolytically attack the polymer structure to thereby degrade and weaken the polymer. It is also possible that the water may be reacting with unreacted glycolide monomer which can be present in the polymer in an amount up to about 8 percent to cleave the glycolide ring structure into the linear dimer of glycolic acid which is represented by the following formula: ##SPC1##

The linear dimer in turn can react with the polymer to break up the high molecular weight polymer into lower molecular weight chains thereby degrading the polymer and causing a reduction in strength. It is also possible that glycolide or the linear dimer of glycolic acid are formed in the polymer as a result of thermal degradation of the polymer which can occur during processing such as, for example, in a high temperature extrusion step.

The exact mechanism of hydrolytic attack is somewhat speculative, and not critical to an explanation or understanding of the present invention. One explanation of the hydrolytic attack is that two glycolic acid units can twist to cause a carbonyl carbon to be sterically approached by the second nearest oxygen in the backbone of the polymer and incipiently form a six membered ring. This anchiomeric attack weakens that carbonyl-oxygen bond, contributing towards hydrolysis of the bond,which thus breaks the polymer chain. [See: Mechanism and Structure in Organic Chemistry, Edwin S. Gould,Holt, Rinehart and Winston, N.Y., 1959, page 562 and reference therein to Winstein, Lindegren, Marshall and Ingraham, J. Am. Chem. Soc. 75 147 (1953)].

Glycolic acid links in any polymeric chain, particularly those having incipient six membered rings, contribute towards hydrolysis, and fragmentation of the polymer chain into links small enough to be handled by tissue chemistry. The fragmentation is hydrolytic, and does not require an enzyme system. The degradation of catgut requires an enzyme system.

In commercial use, a suture may not be used for months or sometimes years after it is packaged. In the meantime, the suture package may be stored under a variety of environmental conditions. Most of these storage environments expose the package to some moisture. It is mandatory that such sutures be packaged in a material which will prevent permeation of water vapor from the environment surrounding the package through the package and into contact with the suture contained therein. On the other hand, a package material which prevents the entry of water vapor will ordinarily also prevent the exit of water vapor; therefore, any water vapor which is present within the package when it is sealed will remain in the package in intimate contact with the suture. Applicant has further discovered that the exposure of a dry suture to moisture for even extremely brief times (i.e., 20 minutes or less) prior to packaging the suture can have deleterious effects upon the suture when it is packaged in a water impermeable package, especially if the package should happen to be stored at elevated temperatures.

While primarily for sutures, other polyglycolic acid prosthetic devices need to be stored from time of manufacture until time of use.

As disclosed in said U.S. Pat. No. 3,297,033, the polyglycolic acid may be formed as tubes or sheets for surgical repair and may also be spun as thin filaments and woven or felted to form absorbable sponges or absorbable gauze, or used in conjuction with other compressive structures as prosthetic devices within the body of a human or animal where it is desirable that the structure have short-term strength, but be absorbable. The useful embodiments include tubes, including branched tubes or Tees, for artery, vein or intestinal repair, nerve splicing, tendon splicing, sheets for tying up and supporting damaged kidney, liver and other intestinal organs, protecting damaged surface areas such as abrasions, particularly major abrasions, or areas where the skin and underlying tissues are damaged or surgically removed.

In more detail, the medical uses of polyglycolic acid include, but are not necessarily limited to:

1. Solid Products, molded or machined

a. Orthopedic pins, clamps, screws and plates

b. Clips (e.g., for vena cava)

c. Staples

d. Hooks, buttons and snaps

e. Bone substituted (e.g., mandible prosthesis)

f. Needles

g. Non-permanent intrauterine devices (anti-spermocide)

h. Temporary draining or testing tubes or capillaries

i. Surgical instruments

j. Vascular implants or supports

k. Vertebral discs

l. Extracorporeal tubing for kidney and heart-lung machines

2. Fibrillar Products, knitted or woven, including velours

a. Burn dressings

b. Hernia patches

c. Absorbent paper or swabs

d. Medicated dressings

e. Facial substitutes

f. Gauze, fabric, sheet, felt or sponge for liver hemostasis

g. Gauze bandages

h. Dental packs

3. Miscellaneous

a. Flake or powder for burns or abrasions

b. Foam as absorbable prosthesis

c. Substituted for wire in fixations

d. Film spray for prosthetic devices

In Combination with other Components

1. Solid Products, molded or machined

a. Slowly digestible ion-exchange resin

b. Slowly digestible drug release device (pill, pellet)

c. Reinforced bone pins, needles, etc.

2. Fibrillar Products

a. Arterial graft or substitutes

b. Bandages for skin surfaces

c. Burn dressings (in combination with other polymeric films.)

The synthetic character and hence predictable formability and consistency in characteristics obtainable from a controlled process are highly desirable.

The most convenient method of sterilizing polyglycolic acid prostheses is by heat under such conditions that any microorganisms or deleterious materials are rendeted inactive. A second common method is to sterilize using a gaseous sterilizing agent such as ethylene oxide. Other methods of sterilizing include radiation by X-rays, gamma rays, neutrons, electrons, etc., or high intensity ultrasonic vibrational energy or combinations of these methods. The present materials have such physical characteristics that they may be sterilized by any of these methods.

Strippable packages for sutures are described in U. S. Pat. Nos. 3,043,067, Rynkiewicz and Ayres, Suture Package; 2,917,878, Carnarius and Kaufman, Method of Sterile Packing and 2,949,181, Suture Package and Process of Making Same. 2,734,649, Callahan and Rumpf, Moistureproof Vial Closure, shows an appreciation of the type of protection required for moisture sensitive materials.

It is an object of this invention to provide a package for polyglycolic acid products which insures acceptable retention of package and in-vivo strength for prolonged periods of time even under the most undesirable conditions of temperature and humidity. It is another acceptable retention of package and in-vivo strength for object of this invention to provide a method of preparing such a package.

SUMMARY OF THE INVENTION

The present invention is predicated upon the surprising and unexpected discovery that polyglycolic acid is extremely sensitive to hydrolytic attack, and that while for a period of weeks to months, depending on the temperature, may retain a high proportion of its strength, in the presence of as much as 0.5 percent water, based upon the weight of the polyglycolic acid; for a preferred storage life, the water or moisture content should be as low as 0.05 percent or less. With the small quantities of polyglycolic acid in a suture package, the total quantity of water is best described as bone dry. Exotic analytical techniques are required to detect and measure the water content.

This invention relates to a storage stable package for an absorbable sterile synthetic surgical element of a polymer subject to hydrolytic degradation to non-toxic, tissue-compatible absorbable components, such as a polyglycolic acid suture. More particularly the invention relates to a package which comprises an air tight sealed container fabricated from a material which is substantially impervious to water vapor, the container having therein A surgical element such as a polyglycolic acid suture which is substantially free from water, i.e. bone dry. The gaseous contents of the container are, prior to sealing the container, either evacuated to yield a vacuum packaged suture or replaced with a dry gas which is non-reactive with polyglycolic acid and which is substantially free from water. A particularly suitable container material is aluminum foil.

A variety of different packaging materials was evaluated in an attempt to find a storage stable package for polyglycolic acid sutures. For example, when the suture was packaged in Saran (a vinyl chloride-vinylidene chloride copolymer) the suture had totally disintegrated after only 42 days storage at 100.degree. F. and 100 percent relative humidity. A similar result was observed with Scotch Pak film. Scotch Pak is a laminate of polyethylene and the polymeric ester of ethylene glycol and terephthalic acid. Other package materials also failed to protect the suture from similar adverse affects.

Prior to sealing the suture within the package of this invention, it is essential that the suture be bone dry. The suture can be rendered bone dry by heating for a sufficient period of time to remove the water therefrom. However it must be noted that once this water is removed, the suture cannot be allowed to contact an environment containing moisture for even a very brief period of time, since even such a brief contact can cause severe deterioration of suture package and in-vivo strength after the suture is sealed in a water impervious container and stored for a prolonged period of time. It therefore becomes necessary when a processing gap between when the suture is dried and when it is packaged is anticipated to provide for interim storage in a dry area where the possibility of contact with moisture is eliminated.

This invention also relates to a method for preparing a storage stable package containing therein a sterile polyglycolic acid suture. Such a package is prepared by inserting the suture into a container which is substantially impervious to water vapor, sterilizing the suture and container, removing substantially all of the water from the sterilized suture, and then maintaining the dried sterilized suture in a substantially dry environment until the container is to be sealed. Prior to sealing the container, the gaseous contents thereof are either evacuated or replaced with a gas which is non-reactive with polyglycolic acid and which is substantially free from moisture.

This invention also relates to a method for sterilizing an absorbable polyglycolic acid with ethylene oxide vapor without adverse effect upon the package or in-vivo strength of the suture. In accordance with this process, a non-sterile polyglycolic acid suture is contacted with a gas having as its active component ethylene oxide. The gas is maintained at a temperature of from about 70.degree. to 90.degree. F. The moisture content of the gas is the ambient moisture content and no additional water is added to the gas to establish any required relative hmidity therein. When a non-sterile polyglycolic acid suture is contacted with the gas described above, sterility of the suture can be achieved with a contact time of about 4 hours or more. Suitable sterilization is achieved when the pressure of the sterilizing gas is maintained at about 5 to 30 lbs. psig.

Previous gaseous ethylene oxide sterilization procedures have called for a sterilizing gas maintained at a relatively high pressure (25 psig) and high temperature (120.degree.-130.degree. F.). Ordinarily, a prescribed relative humidity (i.e. 50 percent) is achieved by adding to the gas that amount of water which is required to establish the desired relative humidity at the temperature of sterilization. Contact times of 20 hours or more are ordinarily used. In view of the aforementioned adverse effect of water, and especially of the effect of water coupled with high temperatures, upon polyglycolic acid, it becomes apparent that sterilizing polyglycolic acid sutures by such extreme conditions of pressure, temperature, relative humidity as previously used for prolonged periods of time would be most undesirable. It is known that when polyglycolic acid is contacted with water, and particularly at high temperatures, that degradation of the polymer will occur quite rapidly. The sterilization process of this invention permits polyglycolic acid sutures to be sterilized at significantly lower temperatures and pressures and shorter time cycles. Additionally, since no moisture is deliberately added to the sterilized gas and since the compounds of the sterilized gas are anhydrous, the amount of moisture present in the sterilized chamber is significantly less than would be available using prior ethylene oxide sterilization techniques. Applicant has found that polyglycolic acid sutures can be sterilized using the process of this invention without adverse effects upon the package or in-vivo properties of the suture.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a frontal view of a preferred embodiment of the suture package of this invention.

FIG. 2 is a sectional view taken along the line 2--2 of FIG. 1 and serves to illustrate the laminate structure of a preferred water impermeable container for the polyglycolic suture.

FIG. 3 is a schematic flow sheet depicting a process for preparing the storage stable polyglycolic acid suture package of this invention.

FIG. 4a shows the effect of the interim conditions which exist between drying the suture and packaging the suture in the package of this invention upon package straight pull of the suture after storage at 132.degree.F.

FIG. 4b shows the effect of the interim conditions which exist between drying the suture and packaging the suture in the package of this invention upon 15 day in-vivo straight pull after storage at 132.degree.F.

FIG. 5a compares the storage capabilities of the package of this invention with those of an acceptable catgut suture package under storage conditions of 100.degree. F. and 100 percent relative humidity.

FIG. 5b compares the storage capabilities of the package of this invention with those of an acceptable catgut suture package under storage condition of 132.degree.F. and 10 percent relative humidity.

FIG. 6 shows a suture on a reel label in a single strippable envelope.

FIG. 7 shows several separate reel labels packaged in a single strippable envelope.

FIG. 8 shows several moistureproof envelopes packaged in an outer sterile strippable envelope.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIGS. 1 and 2 present a preferred embodiement of the package of this invention. Referring to these figures, the package comprises sealed envelope 11 containing therein sterile needled polyglycolic acid suture braid 12 wrapped around paper mounting 13. The package is sealed by peripheral heat seal 14. The material from which envelope 11 is fabricated is a four layered water impervious laminate as best seen by reference to FIG. 2. The laminate comprises a first layer 15 of heat sealable polyethylene, a second layer 16 of aluminum foil, a third layer 17 of polyethylene and a fourth layer 18 of printable paper. Envelope 11 is conveniently formed by placing two pieces of the aforementioned laminate on top of each other with heat sealable polyethylene layers 15 contacting each other. Three of the four edges are then sealed together using a standard heated die to form an envelope into which mounted suture 12 is inserted. After evacuating the contents of the envelope or replacing them with an anhydrous inert gas, the fourth edge of the envelope is sealed to produce a completely sealed package.

Polyethylene layer 15 is preferably comprised of 15 lb. low density polyethylene having a thickness of about 1.5 mils. The function of this layer is to provide a vehicle for heat sealing the package; of course, any other suitable heat sealable thermoplastic which will achieve this goal is also suitable. Examples of such other materials are Saran, medium and high density polyolefins, tetrafluoroethylenes, and such.

Aluminum foil layer 16 should have a thickness of at least about 0.35 mils in order to insure suitable water barrier properties with prefered thicknesses of about 0.35 to 1.5 mils and a highly preferred thickness of about 0.5 mils.

Polyethylene layer 17 preferably has a thickness of about 0.5 mils. Its function is to serve as an adhesive vehicle for joining together aluminum layer 16 and paper layer 18. Of course, any other suitable adhesive would be operable.

Paper layer 18 is preferably 25 lb. super-calendered Bleached Pouch Paper (Virgin Sulphate Pulp) having a thickness of about 1.1 mils .+-. 20 percent. The function of paper layer 18 is to permit direct printing of labels and such on the external surface of the package and hence any printable paper would be sutiable.

A particularly suitable laminate of polyethylene-aluminum foil-polyethylene-paper is available from the Riegal Paper Corp., New York, N. Y., under the trade designation of Pouchpak.

A convenient method for preparing the package of this invention is shown schematically in FIG. 3. Referring to FIG. 3, surgical needle 19 is affixed to braided polyglycolic acid suture 20 to produce needled polyglycolic acid suture braid 12. Braid 12 is then wrapped around suture mounting 13. The mounted suture is placed in envelope 11, said envelope being prepared as described above.

Envelope 11 containing mounted suture 12 is then placed within a sealed container which is permeable to sterilizing gas but not to bacteria. This container is then placed in a suitable ethylene oxide sterilizing oven. The oven is evacuated after which a mixture of 12 percent by volume ethylene oxide and 88 percent volume dichlorodifluoromethane (Freon 12) is admitted to the oven. The oven pressure is raised to about 10 psig by admitting more of the gas mixture. The temperature of the gas mixture is maintained at 70.degree.-90.degree.F. The ethylene oxide-Freon mixture is non-flammable and explosion proof and is safe in all proportions when mixed with air. The Freon is essentially a diluent and, of course, other suitable diluents such as carbon dioxide are also quite suitable. The important aspect about the sterilization process is that the polyglycolic acid suture can, surprisingly, be sterilized in a relatively dry environment at low temperatures, moderate pressures, and with very brief sterilization time cycles.

After the suture has been in contact with the sterilizing mixture for at least 4 hours and preferably 8 hours, the sealed container containing suture 12 is removed from the ethylene oxide oven and placed in a drying oven whereupon it is heated at 180.degree. to 188.degree.F. for one hour under a 26 inch vacuum. Sterility of the suture is maintained during this drying step since bacteria cannot permeate the container surrounding suture 12. The container having suture 12 therein is then stored in a dry area 21, i.e. an environment substantially free from moisture, unitl the final sealing of envelope 11. At this point the bacteria proof container containing envelope 11 and suture 12 is removed from the dry area 21 and transferred into sterile area 22 whereupon envelope 11 containing suture 12 is removed from its bacteria-proof container. The gaseous contents of envelope 11 are evacuated in sterile area 22 and envelope 12 is heat sealed to produce an air-tight vacuum packaged polygly-colic acid suture. Alternatively in sterile area 22, the gaseous contents of envelope 11 can be replaced by an anhydrous gas which is inert towards polyglycolic acid such as nitrogen, argon, xenon, helium, hydrogen, carbon dioxide, air, or the like after which envelope 11 is heat sealed to produce a non-vacuum packaged polyglycolic acid suture. Sealed envelope 11 is then removed from sterile area 22 and inserted into folded plastic sheet 23. Sheet 23 is heat sealed around envelope 11 by means of cathedral seal 24 to form outer strippable envelope 25 containing therein sealed, suture containing, inner envelope 11. a variety of materials is suitable for use as outer strippable envelope 25. For example various plastic, paper, and metallic foil materials can be used for this purpose. A particularly suitable material for use as outer envelope 25 is described in U. S. Pat. No. 2,949,181 said patent herein incorporated by reference. The dual envelope suture package is then placed in an ethylene oxide oven in order to sterilize the outer surfaces of envelope 11, the inner surface of envelope 25 and the void volume defined by said surfaces. The ethylene oxide vapor permeates outer envelope 25 to achieve this sterilization. The mechanics of this sterilization step are well known and are outlined in greater detail in U. S. Pat. No. 2,917,878, said patents herein incorporated by reference. When sterilization is complete a storage stable polyglycolic acid suture package is provided which is entirely sterile except for the outer surface of envelope 25. Such package is particularly suitable for serving a sterile suture to a surgeon for use.

In reference to the above process, it is apparent that the sequence and nature of the process steps can be changed somewhat without effecting the nature of the finished packaged product. For example, suture 12 and envelope 11 may be separately sterilized and then assembled in sterile area 22. Alternatively, suture 12 contained in envelope 11 can be vacuum dried prior to sterilization except that, in that event, a subsequent drying step would be required if any moisture was picked up by suture in the sterilization process. Also, suture 12 can be dried prior to inserting it into envelope 11. Of course, a variety of sterilization techniques can be used such as heat sterilization, X-rays, beta or gamma radiation and such. However, the preferred method of sterilization is by gaseous ethylene oxide. Such variations in the sequence and nature of the process steps are apparent to those skilled in the art and are deemed to fall within the scope of the claims appended hereto.

The polyglycolic acid suture itself may be in any form whatsoever such as a multifilament braid or a monofilament. It may further be needled, dyed, coated, or otherwise treated in accordance with standard suture techniques.

Data are presented in Table I which indicate the effect of various storage conditions upon the package and in-vivo strength of polyglycolic acid sutures stored in the package of this invention. ##SPC2##

Values are presented as the percent of the original strength retained. In reference to package properties, this terminology means that on day zero of the storage period, the package strength of a control (packaged) suture was measured. As storage time progressed, package strength (i.e., knot pull and straight pull) was measured at prescribed intervals and compared to the value of the control package strength on day zero to give a "percent of strength retained." In reference to in-vivo strength, this terminology means that a control suture (no storage time) was implanted on day zero of the storage period in a rabbit for periods of 7 or 15 days after which the rabbit was sacrificed and the suture removed. The tensile strength of the removed suture was then measured and used as a standard control. As storage progressed, sutures at prescribed storage intervals were implanted in rabbits as described above and their strength measured after 7 or 15 days. This strength was then compared to the strength observed with the control suture from day zero to give a "percent of strength retained."

The data of Table I show the effect of various storage conditions upon the package and in-vivo straight pull of a size 3-0 and 1-0 suture. The strength retention both in the case of package and in-vivo properties is generally satisfactory over all the conditions studied except at 132.degree.F. and 10 percent relative humidity. The data clearly indicate the extremely rapid deterioration in suture strength to be expected even with the preferred package of this invention when the relative humidity on the outside of the package is low while the temperature on both the inside and outside of the package is high. The data also indicate that where temperatures are low but the external relative humidity is high, satisfacotry storage can be achieved. An analysis of these data show that the package of this invention adequately prevents the moisture existing in either a high or low moisture environment surrounding the package from contacting the suture therein. However, as storage temperatures are raised, rapid deterioration of the suture strength, and in particular the in-vivo strength of the suture, occurs despite the ability of the package to prevent the entry of moisture into the contents of the package.

Data are presented in Table II which indicate why such rapid deterioration of suture properties occurs after storage at 132.degree.F. Certain of these data are presented in FIG. 4a (package straight pull) and FIG. 4b (15 day in-vivo straight pull) and clearly indicate the importance of keeping the suture dry up to the point of packaging it in the package of this invention if suture strength is to be retained during prolonged storage at elevated temperatures such as 132.degree.F. ##SPC3##

The data of Table II detail a study of the effect of the interim conditions to which the suture is exposed between when it is dried and when it is sealed in the package of this invention. In one case, the dried suture was exposed to an environment maintained at room temperature but having 50 percent relative humidity for 24 hours. The envelope containing the suture was then sealed, packaged in any outer strippable envelope, and stored at 132.degree.F. and 10 percent relative humidity; after only one week storage at these conditions, the suture had retained virtually no in-vivo strength while simultaneously its packaged strength had severely deteriorated.

In another case a dried suture was stored in a container at room temperature in an environment having 20 to 30 percent relative humidity. The suture was then packaged as above. The same rapid deterioration in suture strength which was noted with interim storage under conditions of 50 percent relative humidity was also observed in this case.

In a final case, the dried suture was removed from the drying oven and immediately placed in a dessicator where it remained until sealed in its package. As can be seen from FIGS. 4a and 4b, after 6 weeks storage at 132.degree.F., the package and in-vivo strength retention of the sutures were at satisfactory levels. Storage for one week at 132.degree.F. and 10 percent relative humidity is equivalent to storage for one year at 72.degree.F. and ambient hmidity.

The above results are provided to clearly indicate the importance of preserving the suture in a dry state once it has been dried until it is sealed within its water-impervious package. In some cases, even very brief exposure of dried sutures to moist environmental conditions has, surprisingly, produced extremely rapid deterioration of suture strength when the sutures are subsequently packaged and stored, particularly when storage occurs under conditions of high temperature which accelerate the undesirable effect upon the polyglycolic acid suture.

Table III presents data which compares the storage capabilities of the package of this invention with those of a typical package which is in widespread use for catgut sutures under various storage conditions. The cutgut package referred to is that described in U. S. Pat. No. 2,917,878. ##SPC4##

The data of Table III are presented in FIGS. 5a and 5b. Referring to these Figures, it is noted that at both storage conditions studied (i.e. 100.degree.F. - 100 percent relative humidity and 132.degree.F. - 10 percent relative humidity), the storage capabilities of polyglycolic acid sutures with respect to both package and in-vivo strength were at least equal to that of catgut sutures and, in fact, appear to be somewhat better.

The data shown in FIGS. 5a and 5b serve to clearly indicate the ability of the package of this invention to provide prolonged stable storage of absorbable polyglycolic acid surgical sutures.

FIG. 3 shows a single moistureproof package containing a single polyglycolic suture being packaged in a single strippable outer envelope 25.

As shown in FIG. 8, if surgical procedures consistently require several sutures of a given size or pattern of sizes and needle types to be used at about the same time, several sealed moistureproof envelopes 26, 27 and 28 containing a suture may be sealed in a sterile strippable outer envelope 29 for simultaneous transfer to a sterile operating area and release.

As shown in FIG. 7 also several individual sterile absorbable polyglycolic acid sutures, not necessarily the same size, on several reels, 30, 31, 32 may be packed in a single moistureproof envelope 33 for substantially simultaneous serving the several sutures to a surgeon. The packaging of a single suture in a single moistureproof envelope to be served from a single strippable envelope permits greater flexibility and adaptability in operating room techniques--but is by no means the only system of serving sutures to the surgeon.

For instance, three 36 inch lengths of size 2-0 polyglycolic acid braided sutures, each havung a medium size 1/2 circle taper point needle and packaged on separate paper mountings 13, or reels, are packaged in a single sealed moistureproof envelope for surgical repair after childbirth. The group of three is often used for the surgical procedure, and can conveniently be served together. A back-up supply of other sizes, and needle configurations is available on short notice from the operating room supply as needed.

A group of three 18 inch lengths of unneedled suture braid size 3-0 are conveniently packaged together to be used as ligatures in surgery. A plurality of bleed points often requires several tie-offs.

Present operating room techniques are adapted to the presentation of a sterile inner moistureproof envelope, with release of the suture from this sterile inner envelope at time of use.

As shown in FIG. 6 another economical serving technique is for the moistureproof envelope 36 itself to be the sterile barrier, as well as the moisture barrier, with the reel-label 35 having the individual sutures wound thereon. Types of such reel-labels are shown in U. S. Pat. No. 3,357,550, Holmes & Murphy, Combination Reel and Label for Surgical Sutures, Dec. 12, 1967. One or more such reel-labels carrying sutures permits individual sutures to be served from reels when needed, but the single envelope permits smaller packages, and economy of packaging materials. Because polyglycolic acid sutures do not require a tubing fluid, an inner envelope to hold such fluid is traditional but anachronistic, and can be eliminated, as surgical procedures in the operating room are adapted to these streamlined packaging concepts.

Whereas this invention is particularly described in reference to sutures, including ligatures, other poly-glycolic acid surgical elements such as described in Schmitt and Polistina U. S. Pat. No. 3,463,158 "Polyglycolic Acid Prosthetic Devices," must be packaged in a dry environment for long term storage stability, with retention of full strength. This patent describes reinforcing elements such as fabrics for tissue reinforcement or arterial splices which consists in part of polyglycolic acid and in part of non-absorbable filaments designed for long term emplacement and retention in tissue elements.

For surgical items in which strength is not significant, dry storage is not required. For example for a glove powder, to dust surgical gloves, the material is already in powdered form, and if the powder has low strength, and is rapidly absorbed, the product is completely acceptable.

Similarly, if a surgical element, such as a heart valve, is to be used within a few days of manufacture, dry storage is not required. Also, storage at low temperatures, as for example in a refrigerator or freezer, gives longer useful life, and sutures can be stored even if not dry, for a useful period if kept cool.

Usually, dry packaging to give a useful shelf life of at least three years to five years at room, shipping, and warehouse temperatures is preferred, as controlled storage conditions can add to costs.

Also it is desirable that for surgical supplies, all precautions to supply the highest standard of product under all conditions be used. Hence a product with short term or special storage characteristics should not be used where modern packaging techniques permit greater storage stability.

A unique and unexpected additional advantage of the present moistureproof package is that the needles never rust. Carbon steel needles often rust in tubing fluid, and additives to prevent rust are sometimes used. Here the package is moisture free, and rusting on storage is no longer a problem.

An additional advantage of vacuum packaging in foil is that the outline of the suture and needle show through the foil laminate. If the foil laminate as supplied has a pinhole in it, the loss of vacuum changes the shape of the package permitting visual inspection.

Other hermetic packages can be used, such as sealed glass tubes, sealed tin cans, and the like, but such packages are more expensive and less convenient than a foil laminate package.

The determination of the moisture content of polyglycolic acid sutures in their envelopes is quite exotic. Certain samples were run in which 0.2 gram of a sample was sealed in a moistureproof envelope of the type herein described and the quantities of moisture were determined.

0.02 percent moisture, based on the weight of the suture is 200 parts per million by weight and with 0.2 grams of sample, corresponds to 40 micrograms of water.

Polyglycolic acid suture braid is hygroscopic and absorbs water from its environment even during the transfer to analytical equipment to determine moisture content.

Certain analyses were made on a CEC/Analytical Instruments Division of Bell & Howell Corporation Type 26-321A Moisture Analyzer which reads to 0.1 micrograms of water on a digital readout. This device uses an electrolytic cell with a phosphorous containing electrolyte to absorb water and measures the amount of electricity required to electrolyze the absorbed water. Dry nitrogen is swept over a sample heated to 125.degree.C., which takes up the water with the water being absorbed from the nitrogen in the electroytic cell, which is then electrolyzed. With a suitable conversion factor this gives direct reading of the quantity of water.

Inasmuch as the polyglycolic acid itself as well as the paper label are organic, high temperatures will deocmpose the materials to yield water even though the water is not present as such at lower temperatures.

Results obtained appears internally consistent, and were consistent with those found by radio-tracer techniques in which the polyglycolic acid was exposed to tritiated water, for various lengths of time, and the water content computed from scintillation count of tritium decay.

The difficulty with accurate analysis can be illustrated by results in a test in which 0.2 gram of polyglycolic acid suture braid was transferred from the moistureproof envelope to a sample chamber for moisture analysis. With a dry braid, with the sample exposed for 5 seconds during the transfer to ambient room conditions of 48 percent relative humidity and 70.degree.F., temperature, the braid absorbed 0.037 percent moisture. With a 15 second transfer, the braid absorbed 0.076 percent moisture. With an exposure of 35 minutes, the moisture rose to 0.39 percent. Because of the almost universal occurence of moisture, and its innocuous presence under so many conditions, conditions under which its effect is deleterious are difficult to ascertain, and difficult to measure. Chemistry in a moisture free environment is indeed a rare and exotic phase of science.

A series of tests were run to determine how much moisture is absorbed by the suture braid from the ambient atmosphere, and the effect of moisture on the sutures. A group of sutures were prepared using a size 2-0 braid with a blank reel label in each envelope. In each moisture-proof foil laminate envelope were placed two suture lengths of about 7 feet 2 inches to give approximately 0.2 grams of braid in each suture length, with two such lengths in each envelope. The sutures were cut, wound, tied in bundles and weighed. A group of envelopes containing sutures were placed in a fiber glass cloth sleeve, as a bacteria shield and sterilized with a 12 percent ethylene oxide, 88 percent Freon 12 mixture for 10 hours at 20 pounds gauge and ambient temperature. After sterilization, the sutures were vacuum dried for 2 1/2 hours at a temperature of about 80.degree.C. and less than 1 millimeter mercury total pressure. Immediately after vacuum drying, the envelopes were placed in moisture chambers at 72.degree.F. containing the relative humidity indicated in the table. These relative humidities were chosen to use convenient salt mixtures which maintain the indicated relative humidity. The envelopes were permitted to equilibrate for 72 hours, protected by the fiber glass cloth sleeve to keep the packages sterile, after which under sterile conditions, the fiber glass cages were opened and the envelopes sealed. The sealed foiled envelopes with their moisture equilibrated contents were then packed in an outer strippable polyester-polytheylene laminate package which was sterilized through the laminate for 18 hours at 125.degree.C. at 26 pounds gauge pressure after which the test packages were either used for immediate tests, or stored at 56.degree.C. with ambient relative humidity for 1, 3 and 6 weeks as shown in the table. The relative humidity of the ambient conditions is essentially immaterial inasmuch as moisture does not pass into or pass out of the sealed foil envelope and accordingly it is only the temperature which is controlling.

Table IV following shows the moisture of the test chamber in which each set of braid was dried and the approximate parts per million of water in the atmosphere at 72.degree.F. ##SPC5##

As shown by Table IV, it can be seen that when the moisture content is below about 0.05 percent by weight of moisture based on the weight of the suture, even when stored for 6 weeks at 56.degree.C., the sutures still maintain a good knot strength and maintains good strength on in-vivo straight pull tests. The in-vivo tests were conducted by implanting the suture in rabbits for 15 days and then removing the suture from the rabbits and determining the residual strength. With the sutures in whcih the interior of package was too moist, either the pull strength turned out to be essentially 0, or in some marked NT the suture had degraded so far that no test could be conducted because the suture was too weak to be emplanted in the test animal.

The above test shows that a useful degree of strength for short term storage can be obtained with as much as 0.5 percent moisture in the envelope but for long term storage stability, it is preferred that the moisture content be not greater than 0.05 percent. An even lower content of 0.02 percent of moisture based on the weight of the braid in the envelope gives an extra margin of safety for the storage stability of the package.

It is to be noted that the paper of the reel label can act as a moisture trap and will also hold moisture which can aid in degrading the suture if there is a comparatively high moisture content in the envelope. Where the moisture in the envelope is below about 0.05 percent, the amount of moisture absorbed on the label is acceptably low and does not lead to degradation of the suture. As the loss of strength is a function of the time and the moisture, the higher moisture content is acceptable where it is known that the storage life requirements are for short duration of storage only. It is preferable that the moisture content is kept below 0.05 so that the sutures in their envelopes are storage stable for a period of years, which insures sutures remaining in hospitals for a prolonged length of time before use are still good.

The six weeks tests at 56.degree.C. is regarded as being equivalent to at least 3 years storage under ambient conditions which would include warehouses, shipping conditions and hospital storage and is regarded as probably equal to at least 5 years storage under such transient conditions.

Because the temperature of the storage can vary considerably, depending upon whether the suture is stored in a tropical climate such as Bombay, India, or one of the cooler Alaskan regions, the worst case must be considered as controlling in order that the suture will stand up under the worse set of conditions for a desirable length of time, at least 3 to 5 years, and will stand up under less demanding storage conditions for extended periods.

A moisture content of below about 0.05 percent water by weight of the polyglycolic acid braid can be considered as essentially bone dry. This permits sealing the dried suture containing envelopes at a relative humidity of about 2.5 percent at 72.degree.F., which corresponds to about 450 parts per million of water in the air. A preferred operating range is about 50 parts per million, so that even if complete equlibration is not attained, the sutures are storage stable for at least 5 years.

Claims

I claim:

1. A method for preparing a storage stable sterile package for a sterile synthetic surgical element of a polymer subject to hydrolytic degradation to non-toxic, tissue-compatible absorbable components, said polymer having glycolic acid ester linkages, which comprises:

a. inserting a synthetic surgical element of a polymer subject to hydrolytic degradation to non-toxic, tissue-compatible absorbable components, said polymer having glycolic acid ester linkages, in a container which is substantially impervious to water vapor,

b. sterilizing said surgical element and container,

c. removing water until not more than 0.5 percent of water by weight of said surgical element remains,

d. maintaining said surgical element in its dry environment and,

e. sealing said container with an air and moisture resistant seal.

2. The method of claim 1 in which the sterile surgical element is a polyglycolic acid suture.

3. The process of claim 1 in which the water content is less than 0.05 percent.

4. The method of claim 3 in which the sterile surgical element is a polyglycolic acid suture.

5. A method for preparing the storage stable surgical element package of claim 3 which comprises additionally

flushing substantially all of the gaseous contents out of said container and replacing with a gas which is non-reactive with polyglycolic acid, and

sealing said container with an air-tight seal.

6. The method of claim 3 which comprises evacuating the container before sealing, to form an evacuated package.