US 3815315 A
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 packaged 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 and remains 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 DEG F. and ambient humidity outside the package. The contents may be sterilized by using ethylene oxide.
Description (OCR text may contain errors)
[ June 11, 1974  Inventor: Arthur Click, Danbury, Conn.  Assignee: American Cyanamid Company,
 Filed: Mar. 28, 1973  Appl. No.: 345,604
Related US. Application Data  Continuation-impart of Ser. No. 138,425, April 29, 1971, Pat. No. 3,728,839, which is a continuation-in-part of Ser. No. 788,501, Jan. 2, 1969, abandoned.
 US. Cl. 53/21 FC, 21/58, 53/22 B, 206/633  Int. Cl B65b 55/10  Field of Search 53/21 FC, 22 B; 21/58; 206/633  References Cited UNITED STATES PATENTS 3,043,067 7/1962 Rynkiewic2...-. 53/21 FC X 3,613,879 10/1971 Kremble 206/633 mum/er- E'fl/YLENE OXIDE STERIL/ZAT/O/V ETI-IYLENE OXIDE STERILIZATION OF MOISTURE SENSITIVE SURGICAL ELEMENTS PrimaryExatniner-Travis S. McGehee Attorney, Agent, or Firm-Samuel Branch Walker 5 7] 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 packaged in an air-tight sealed container which is substantially impervious to water vapor such as a laminate film having a metallic foillayer. The gaseous contents of the envelope are,
prior to sealing the suture within the envelope, either I 3 Claims, 10 Drawing lFigures ETHYLEA/E 1 0x105 STER/L/ZATION or surums- 4/10 DRY ENVELOPE 2/ 23 DIN/AREA STER/LE AREA 2? l lllllIlllllllllllllllIllllllllllll lll GASEOUS CONTENTS OF ENVIELOPE ARE EVACMTE'D 4N0 7H5 ENVELOPE SEALED PATENTEDMH I914 3.815315 SHEET 1 0F 5 ALUMINUM F OIL LOW os/vsxrr POL-YE 7' H YLE IVE BLEACHED POUCH PAPER f E, E vmam SULPHATE PULP) PATENTEDJum 1 m4 3Q815L3 l 5 =1!|lIIINIllilllllllllllllmllll llllIll"lllllllllllllllllllllill ETH Y1. ENE
0x/0 STER/L IZAT/ON PRODUCT minnow" I 1 1914 3.815315 swan: 5'
EFFECT OF comma/vs wvosn WH/GH A any 3-0 SUTURE IS sronso PRIOR r PACKAGING UPON & PACKAGE STRAIGHT PULL srnmarr/ RETENTION I00 Q m I 80 onr STORAGE Ar ROOM TEMPERATURE E IDESICCATOR) g 70 m E 60 sromae: Ar 50% RELATIVE HUMIDITY AND ROOM TEMPERATURE q 50 q 3 40 g aromas A7 20-30% RELATIVE HUMIDITY m 30 AND ROOM TEMPERATURE s k 20 a2 [a ---EXTRAPOLAT/0N o l I I I I I I l 0 2 a 4 5 s 7 a WEE/(S STORED Ar 132:
(AFTER FAG/(AGING) fIEi. 4A
EFFECT OF CONDITIONS UNDER WHICH A DRY 3-0 SUTURE IS STORED PRIOR TO PACKAGING UPON I5 DAY IN-V/I/O STRAIGHT PULL STRENGTH RETENTION 90 DRY STORAGE AT ROOM TEMPERATURE (DES/GOA TORI STORAGE AT RELATIVE HUMIDITY AND ROOM TEMPERATURE 95 OF ORIGINAL STRENGTH RETAINED 20 STORAGE AT RELATIVE HUMIDITY AND ROOM TEMPERATURE o I I l I I l I O I 2 3 4 7 8 5 6 WEEKS STORED AT I32F (AF TE R PACKAGING) PATENT EDJUM I 1 1314 96 F ORIGINAL STRENGTH RE TAM/ED 0F QR/Gl/VAL STRENGTH RETAINED SHEHHUF 5v /00 ,P0L Y6LY60L/C AC/0 PAC-K465 STRAIGHT 90 caraur POLYGLYCOL/C My 70 40/0 m/v/v0 STRAIGHT 60 PULL OT l l l l I /0 DAYS STORED AT I00F M0 100% RH. (AFTER PACKAGING) fIE. Sn
100 /POL YGL rc0L/c ACID PACKAGE 9o STRAIGHT PULL CA rear 80 POLr0LYc0L l0 ACID /5 DAY 50 l/V- V/VO iZ/Zi/GHT 50 v Araur DAYS STORED 47' /32F AND /0% RH.
(4F TE R PACKAGING) fIE. 5B
ETHYLENE OXIDE STERILIZATION OF MOISTURE SENSITIVE SURGICAL ELEMENTS CROSS-REFERENCES 1 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. US. Pat. No. 3,297,033describes an absorbable surgical suture made from polyglycolic acid. The disclosure therein is incorporated 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 polyhydroxyacetic ester or polyglycolideand can be considered as essentially a product of polymerization of glycolic acid, that is, hydroxyacetic acid, which in simplified form is shown by the equation:
CHg-C-OH (in ('1 For use as a suture, preferably n is such that the molecular weight is in the range of 10,000 or more. Above 100,000 the polymer is difficult to extrude.
In these molecular weight ranges the polymer has a melt viscosity at 245C. of between about 400 and about 27,000 poises. Because the fiber is from a synthetic and controllable source, with a controlled molecular weight and is a homopolymer or has a controllable small percentage of comonomer, the absorbability, stiffness and other characteristics can be modified. In general, the higher the molecular weight, the slower the rate of absorption under a given set of conditions.
Among several methods by which polyhydroxyacetic ester can be prepared, one preferred route involves the polymerization of glycolide,
the cyclic dimericeoridensfiion prodict formed by de- 3 hydrating hydroxyacetic acid. During polymerization omocrn-q-on or methyl hydroxyacetic ester,
' or their homologs, such as higher alkoxyacetic acids, or
alkyl hydroxyacetic esters may be present during the polymerization as an end group stabilizer controlling the molecular weight and viscosity. Small quantities of other materials may be present in the chain, as for example d, l-lactic acid, its optically active forms. homologs, and analogs.
Said US. Pat. No. 3.297,033 incorporates :1 reference to US. Pat. No. 2,668,162 Lowe which quantifies a small amount of lactides as up to 15 percent, disclosing for example the preparation of a copolymer of 10 glycolide/lactideoffers two advantages over the homopolymer of glycolide. One advantage is that the melting point of the copolymer is lower than the homopolymer, being in the neighborhood of 200C; and the entire reaction can be conducted at approximatelythe melting point of the copolymer. Operation at the lower temperatures decreases the rate of degradation of the polymer which gives'a polymer of lighter color. Another advantage is that the copolymercan be successfully quenched when being extruded into film because the copolymer is less crystalline. On the other hand, the homopolymer shows a greater tendency to crystallize on extrusion and thereby tends to form opaque areas in the film.
Example 4 of said US. Pat. No. 2,668,162 shows reaction conditions.
Surgical elements of polyglycolic acid, including sutures, and other elements mentioned below can be better seen in most surgical fields if the element is colored so as to contrast with blood and tissue or bandages or other background materials.
' BRIEF DESCRIPTION OF PRIOR ART Surgical sutures and other surgical elements containing polymers of glycolic acid are described in:
US. Pat. No. 3,297,033, Jan. 10, 1967, Schmitt and Polistina, SURGICAL, SUTURES.
US. Pat. No. 3,463,158, Aug. 26, 1969, Schmitt and Polistina, POLYGLYCOLIC ACID PROSTHETIC DEVICES.
US. Pat. No. 3,565,077 Feb. 23, 1971, Glick, DENSIFIED ABSORBABLE POLYGLYCOLIC ACID SUTURE BRAID, AND METHOD FOR PREPARING SAME 1 US. Pat. No. 3,620,218, Nov. 16, 1971, Schmitt and Polistina, CYLINDRICAL PROSTHETIC DEVICES OF POLYGLYCOLIC ACID. US. Pat. No. 3,626,948, Dec. 14, 1971, Glick and McPherson, ABSORBABLE POLYGLYCOLIC ACID. SUTURE OF ENHANCED IN-VIVO STRENGTH RETENTION.
US. Pat. No. 3,728,739, Apr. 24, 1973, Semp, STERILE SURGICAL GLOVES.
Reference is made to these patents which show additional prior art and for the definitions therein set forth.
Related data incorporated herein by this reference on manufacturing of polyglycolic'acsid, producing surgical elements thereof and its use for surgical purposes aredisclosed in:
U.S. Pat. No. 3,414,939 Dec. 10, 1968, Chirgwin, APPARATUS FOR QUENCHING MELT-SPUN Fl- BERS.
U.S. Pat. No. 3,422,181 Jan. 14, 1969, Chirgwin, METHOD FOR HEAT SETTING OF STRETCH ORI- ENTEDPOLYGLYCOLIC ACID FILAMENT.
U.S. Pat. No. 3,435,008 Mar. 25, 1969, Schmitt. Epstein and Polistina, METHOD FOR PREPARA- TION OF ISOMERICALLY PURE B-GLYCOLIDE AND POLYMERIZATION METHOD FOR GLYCO- LIDE COMPOSITIONS EMPLOYING PARTIAL HY- DROLYZATE OF SAID B-GLYCOLIDE.
U.S. Pat. No. 3,442,871 May 6, 1969, Schmitt, Epstein and Polistina, PROCESS FOR POLYMERIZ- ING A GLYCOLIDE.
U.S. Pat. No. 3,457,280 July 22, 1969, Schmitt, Epstein and Polistina, a-GLYCOLIDE AND METH- ODS FOR THE ISOLATION THEREOF.
U.S. Pat. No. 3,468,853 Sept. 23, 1969, Schmitt and Polistina, PROCESS OF POLYMERIZING A GLYCOLIDE.
U.S. Pat. No. 3,565,869 Feb. 23, 1971, DeProspero, EXTRUDABLE AND STRETCHABLE'POLY- GLYCOLIC ACID AND PROCESS FOR PREPAR- ING SAME.
U.S. Pat. No. 3,597,449, Aug. 3, 1971, DeProspero and Schmitt, STABLE GLYCOLIDE AND LACTIDE COMPOSITIONS.
U.S. Pat. No. 3,597,450, Aug. 3, 1971, Schmitt, Polistina, Epstein and DeProspero, PREPARATION OF GLYCOLIDE POLYMERIZABLE INTO POLY- GLYCOLIC ACID OF CONSISTENTLY HIGH MO- LECULAR WEIGHT.
U.S. Pat. No. 3,600,223, Aug. 17, 1971, Glick and McCusker, PROCESS FOR CLEANING POLY- GLYCOLIC ACID FILAMENTS USEFUL AS AB- SORBABLE SURGICAL SUTURES.
U.S. Ser. No. 34,593, May 4, 1970, Schmitt and Bailey, SOLUTIONS OF POLYGLYCOLIC ACID, now abandoned.
U.S. Ser. No. 118,974, Feb. 25, 1971, Ramsey and Delapp, PREPARATION OF POLYGLYCOLIC ACID IN FINELY DIVIDED FORM, now U.S. Pat. No. 3,781,349, Dec. 25, 1973.
U.S. Ser.'No. 157,521, June 28, 1971, Schmitt and Polistina, POLYGLYCOLIC ACID PROSTHETIC DEVICE, now U.S. Pat. No. 3,739,773, June 19, 1973.
U.S. Ser. No. 171,320, Aug. 12, 1971, Schmitt and Bailey, POLYGLYCOLIC ACID IN SOLUTIONS, now U.S. Pat. No. 3,737,440, June 5, 1973.
U.S. Ser. No. 176,291, Aug. 30, 1971, Glick and Chirgwin, DOPE-DYED POLYGLYCOLIC ACID SU- TURES.
U.S. Ser. No. 190.290, Oct. 18, 1971, Schmitt and Epstein, now U.S. Pat. No. 3,736,646, June 5, 1973, METHOD OF ATTACHING SURGICAL NEEDLES TO MULTIFILAMENT POLYGLYCOLIC ACID AB- SORBABLE SUTURES.
U.S. Ser. No. 277,537, Aug. 3, 1972, Glick and Chirgwin, GREEN POLYGLYCOLIC ACID SU- TURES AND SURGICAL ELEMENTS.
Other United States and foreign patents disclose surgical elements in hich biodegradability and absorption results from the hydrolytic attack of tissue components on glycolic acid ester linkages in the polymer composing such surgical elements.
Polyglycolic sutures exhibit great uniformity of composition, as compared with catgut. They have excellent package strength, Le. straight pull and knot pull, and desirable invivo 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 environment is preferred.
Although the reason for the aforementioned effect 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 de grade and weaken the polymer. It is also possible that the water may be reacting with unreacted glycolide monomer which an 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:
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. [Seez 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. lt is mandatory that such sutures be packaged in a 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 man ufacture 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 ab sorbable gauze, or used in conjunction 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 ohe kin and underlying tissues are damaged or surgically removed.
In more detail, the medical uses of polyglycolic acid include, but are not necessarily limited to: i
1. Solid Products, molded or machined a. Orthopedic pins, clamps, screws and plates b. Clips (e.g., for vena cava) c. Staples (1. Hooks, buttons and snaps e. Bone substitutes (e.g., mandible prosthesis) f. Needles g. Non-permanent intrauterine devices (spermocide) h. Temporary draining or testing tubes or capillaries i. Surgical instruments j. Vascular implants or supports k. Vertebral discs 1. 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 i. Sutures, including ligatures 3. Miscellaneous Flake or powder for burns or b. Foam as absrbable prosthesis c. Substituted for wire in fixations d. Film spray for prosthetic devices In Combination with other Components 1. Solid Products, molded or machined Slowly digestible ion-exchange resin abrasions a b. Slowly digestible drug release device (pill, pellet) OU'NNO sterilize using a gaseous sterilizing agent such as ethylene oxide. Gther 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. No. 3,043,067, Rynkiewicz and Ayres, Suture Package; U.S. Pat. No. 2,917,878, (Carnarius and Kaufman, Method of Sterile Packing and U.S. Pat. No.
2,949,181, Suture Package and Process of Making Same. US. Pat. No. 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 forpolyglycolic 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 object of this invention to provide a method of sterilizing polyglycolic acid surgical elements using ethylene oxide.
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 asmuch 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 said 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 100F. and 100 percent relative humidity. A similar result was observed with Scotch Pak film. Scotch Pak is a laminate of poly ethylene 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 invivo 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'v apor, 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 replacedwith 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 invivo 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 to 90 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 humidity 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 (l20l30 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 ofthe 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 degradatio 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 invivo properties of the suture.
BRIEF DESCRIPTION OF THE DRAWING 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 132F.
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 l32F.
FIG. 5a compares the storage capabilities of the package of this invention with those of an acceptable catgut suture package under storage conditions of 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 [32F. 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.
DESCRlPTlON OF THE PREFERRED EMBODIMENTS FIGS. 1 and 2 present a preferred embodiment 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 preferred 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 ve hicle 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 i 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 suitable.
A particularly suitable laminate of polyethylenealuminum 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 l2. Braid 12 is then wrapped around suture mounting 13. The mounted suture is laced 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 by volume I 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 7'090F. 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 diluene and. of course, other suitable diluents such as carbon dioxide or other members of the Freon family and their mixtures 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 to 188F. 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, until the final sealing of envelope 1]. At this point the bacteria proof container containing envelope 111 and suture 12 is removed from the dry area 21 and transferred into sterile area 22 whereupon envelope 1] 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 a sealed to produce an air-tight vacuum packaged polyglycolic acid suture. Alternately 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 l2 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 lope 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 1 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.
the storage period in a rabbit for periods of 7 or 15 days after which the rabbit was sacrificed and the suture re moved. 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 132F. 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, satisfactory TABLE L-EFFECT OF VARIOUS STORAGE CONDITIONS UPON STRENGTH RETENTION OF PACKAGED POLYGLYCOLIC ACID SUTUBES Iu-vivo properties Alter 7 days After 15 days Package properties implantation implantation Percent Percent Percent of original oi original 0! original Months Suture Straight strength Straight strength Straight strength Storage condition stored size pull (p.s.i.) retained pull (p.e.i.) retained pull (p.s.i.) retained 76 F.-% RH 0 3-0 89, 700 60, 200 28, 300 r 3 3-0 88, 600 99 04, 900 108 200 08 v 6 8-0 84, 500 95 04, 900 108 25, 000 88 96 F.Ambient R.H 0 3-0 89, 700 60, Z00 28, 300 3 3-0 93, 000 104v 50, 960 500 48 6 3-0 80, 100 96 62, 400 104 19, 500 69 Warehouse 0 3-0 89, 700 80, 200 28, 300
132 F.-10% R.H o 3-0 89,100 60,200 28,300 23 3-0 87, 800 98 05, 700 109 24, 600 87 70 3-0 84, 94 63, 100 88 7, 900 28 1. 4 3-0 79,200 88 40, 800 68 1, 900 7 76 F.50% R.H.--- 0 1-0 71, 300 49, 200 13, 400 3 1-0 70, 400 99 52, 700 107 11, 000 82 6 1-0 71, 300 100 104 13, 100 98 96 F.Amblent R.H.-; 0 1-0 71, 300 49, 200 13, 400
Warehouse o 1-0 71, 300 49, 2'00 13, 400 3 1-0 800 98 52, 100 106 11, 900 89 6 1-0 97 53, 300 108 12, 500 93 132 F.10% R.H 0 1-0 71,300 13,400 23 1-0 100 101 50, 700 103 10,950 82 70 1-0 65, 200 91 42, 500 86 6, 100 38 11 4 1-0 87 60 870 6 storage can be achieved. An analysis of these data show that the package of this invention adequately prevets 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, oc-
curs despite the ability of the package to prevent the entry of moisture into the contents of the package.
Data are presented in Table 11 which indicate why such rapid deterioration of suture properties occurs one week storage at these conditions, thesuture 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 TABLE II.EFFECT OF FEE-PACKING ENVIRONMENT UPON STRENGTH RETENTION OF PACKAGED POLYGLYCOLIC ACID SUTURES AFTER STORAGE UNDER A VARIETY OF CONDITIONS In-vivo properties after 15-day Package properties implantation Percent Percent Percent Straight of original Knot of original Straight of original Weeks Condition of suture prior to Suture pu strength pull strength pull strength Storage conditions stored packaging size (p.s.1.) retained (p.s.1.) retained (p.s.i.) retained- 1 3-0 95 9 l a Heated at 168 F. roione hour 3-0 68,000 95 42,000 a? 5,100 68 6 under vacuum and then ex- 3-0 63, 400 88 46, 700 97 2, 900 39 posed for 24 hours to an enviirorglugiiia having 50% rela- 2:8 gi, Egg 56. iii, 7, 508 .:..6 1 t ve ity. 3 3.0 (5) (a; (a) 6 3-0 0 a? as e.-
a a 1 9 800 100 F' 100% RlHn-u g Heated at 188 F. for one hour 3%*% 32 gig. 33 2 5 88 g; under vacgum itmdiplaced in a ever-pa con am ng an en- 9 g'g a: ea "er 0 n g, 200 Z, 3% 1 l. 54 100 ,Flulm '0- 3 Heated at 188 F. for one hour H 000 91 800 931 000 m7 6 under vacuum and then im- 600 91 600 900 145 r 0 medlately placed in a dessi- H 71, 600 48. 200 7, 500 F R H 1 packaged' 3-0 06, 600 03 45, 600 0r. 2, 700 as 3 (H1 65, 500 01 44, 800 031 5, 800 7 I Suture not tested due to unsatisfactory streggth values after one week storage.
* Suture disintegrated and could not be teste TABLE TIL-COMPARISON OF THE STORAGE CAPABILITIES OF THE PACKAGE OF THIS INVENTION WITH THOSE OF A TYPICAL PACKAGE USED WITH CATGUT SUTURES 15-day in-vivo Package properties properties Percent Percent Suture Straight of original Straight of original Days diameter p l strength pull strength Packaging material Storage conditions stored Suture material (mils) (psi retained (p.s.i.) retained 0 11. 9 59, 700 8, 270 7 12. 6 57, 000 95 6, 100 74 Scotch-Pak 100 F.100% 11.11.... 14 Catgut 12.6 57,300 96 8,600 104 21 12. 7 52,900 89 3, 550 43 42 12. 7 50, 540 84 4, B90 59 O 10. 1 78,700 12,000 7 10. 2 75, 900 96 9,700 81 Package of this invention 100 F.100% R.H..-. 14 Polyglyeolie acid 10. 5 68,200 87 14, 000 117 21 10.2 74, 700 95 6, 360 53 42 10. 2 75, 900 96 7, 600 63 0 11.9 59,700 8,270 7 12. 7 60, 500 84 4, 250 51 Scotch-Paid 132 F.-10% R.I-I..... 14 Catgut 12.7 60,900 85 5,750 60 r 21 12. 9 61,300 86 l, 090 24 42 12. ll 47, 460 70 4, 060
, 0 10.1 78,700 12,000 7 10. 2 76. 000 00 I0, 700 88 Package oi this invention.'...... 132 F.10% R.II 14 Polyglycollc acid... 10. 5 71,700 00 13,200 110 21 10. 4 76, 600 97 8, 000 07 42 10. 4 75, 400 06 0, 040 58 The data of Table II detail a study of the effect of the packaged as above. The same rapid deterioration in suinterim 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 132F. and I0 percent humidity: after only ture 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 ackage. As can be seen from FIGS. 4a and 4b, after 6 weeks storage at l32F., the package and in-vivo strength retention of rioration 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 cat gut package referred to'is that described in US. Pat. No. 2,917,878.
The data of Table III are presented in FIGS. a and 5b. Referring to these Figures, it is noted that at both storage conditions studied (i.e. 100F. 100 percent relative humidity and 132F. 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, 311, 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 techniquesbut is by no means the only system of serving sutures to the surgeon.
For instance, three 36 inches lengths of size 2-0 polyglycolic acid braided sutures, each having a medium size 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 l8 inches 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 operatingroom 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. I
Whereas this invention is particularly described in reference to sutures, including ligatures, other polyglycolic acid surgical elements such as described in Schmitt and Polistina US. 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. I
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.
Thedetermination of the moisture content of polyglycolic and sutures in their envelopes is quite exotic.
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 and difficult to measure. Chemistry in a moisture free environment is-indeed a rare and exotic phase of science.
Certain samples were run in which 0.2 gram of a sam- 5 braid with a blank reel label in each envelope. in each pie was sealed in a moistureproof envelope of the type moisture-proof foil laminate envelope were placed two herein described and the quantities of moisture were suture lengths of about 7 feet 2 inches to give approxi- -determined. mately 0.2 grams of braid in each suture length, with 0.02 percent of moisture, based on the weight of the two such lengths in each envelope. The sutures were suture is 200 parts per million by weight and with 0.2 10 cut, wound, tied in bundles and weighed. A group of grams of sample,corresponds to 40 micrograms of waenvelopes containing sutures were placed in' a fiber ter. glass cloth sleeve, as a bacteria shield and sterilized Polyglycolic acid suture braid is hygroscopic and abwith a 12 percent ethylene oxide, i88 percent Freon l2 sorbs water from its environment even during the transmixture for 10 hours at 20 pounds gauge and ambient fer to analytical equipment to determine moisture con- 15 temperature. After sterilization, the sutures were vactent.- uum dried for 2 V2 hours at a temperature of about Certain analyses were made on a CBC/Analytical ln- 80C. and less than 1 millimeter mercury total pressure. struments Division of Bell & Howell Corporation Type Immediately after vacuum drying, the envelopes were 26-32IA Moisture Analyzer which reads to 0.] microplaced in moisture chambers at 72F. containing the grams of water on adigital readout. This device uses an relative humidity indicated in the table. These relative electrolytic cell with a phosphorous containing electrohumidities were chosen to use convenient salt mixtures lyte to absorb water and measures the amount 0 elecwhich maintain the indicated relative humidity. The entricity required to electrolyze the absorbed water. Dry velopes were permitted to equilibrate for 72 hours, pronitrogen is swept over' a Samp e e e 1 o tected by the fiber glass cloth sleeve to keep the packwhich takes upthe water with the water being absorbed ages sterile, after which under sterile conditions, the from the nitrogen in the electrolytic cell, which is then fib r glass cages were opened and the envelopes sealed. electrolyzed. With a suitable conversion factor this Th sealed foiled envelopes with their moisture equiligives direct reading of the quantity of water. brated contents were then packed in an outer strippa- Inasmuch as the polyglycolic acid itself as well as the ble polyesterpolytheylene laminate package which was paper label are organic, high temperatures will decomsterilized through the laminate for 18 hours at 125C. pose the materials to yield water even though the water at 26 pounds gauge pressure fter hi h h test kis not present as Such at lowe mp r r ages were either used for immediate tests, or stored at Results obtained appears internally consistent, and 56C, ith bi t l tiv h idit f 1, 3 d 6 were consistent with those found by radio-tracer techweeks as Shown i h bl Th l ti h idit f hiqhes in which the P l/g y acid was exposed to the ambient conditions is essentially immaterial inastritiated water; for Various lengths of time and the much as moisture does not pass into or pass out of the water content computed from scintillation count of tri- Sealed f0 envglope and accordingly it is only h tium decay. H perature which is controlling.
The difficulty with accurate analysis can be illus- Table IV following shows the moisture of the test trated by results in a test in which 0.2 gram of polychamber in which each set of brai-d was dried and the glycolic acid suture braid was transferred from the approximate parts per million of water in the atmomoistureproof envelope to a sample chamber for moissphere at 72F.
TABLE IV Controlled air conditions for 72 hrs. during packaging Percentmoisture in Package strength-knot Percent Parts per package on braid wt. pull in pounds aiter 56 C. 15-day in-vivo strength in pounds H at million H20 Size of storage for straight pull after 56 0. storage for- Sample 73 F. at 73 F braid By CEC By tracer number (23 C.) (23 C.) 1n mils percent percent Initial 1 wk. 3 wks. 6 wks. Initial 1 Wk. 3 wks. 6 Wks.
40 0,900 13.1 0.53 0.00 0.4 2.7 0 0 .23 0 NT NT 21 3,000 13.1 0. 25 0.10 0.4 0.2 4.7 2.8 .90 .s 0 0 10 1,700 13.0 0.10 0.14 0.0 0. 05 0.0 5.7 1.0 3.0 .s 0 3 500 12.8 0.05 0.02 7.0 5.9 7.0 0.5 2.7 3.3 as 2.0 0.10 30 10.0 0.02 0.0012 0.9 6.8 7.1 0.0 V 2.0 3.2 3.5 3.0
ture analysis. With a dry braid, with the sample exposed As shown by Table IV, it can be seen that when the for 5 seconds during the transfer to ambient room conmoisture content is below about 0.05 percent by weight ditions of 48 percent relative humidity and 70F., temof moisture based on the weight of the suture, even perature, the braid absorbed 0.037 percent moisture. when stored for 6 weeks at 56C., the sutures still main- With a 15 second transfer, the braid absorbed 0.076 60 tain a good knot strength and maintains good strength percent moisture. With an exposure of 35 minutes, the on in-vivo straight pull tests. The in-vivo tests were conmoisture rose to 0.39 percent. Because of the almost ducted by implanting the suture in rabbits for 15 days universal occurence of moisture, and its innocuous and then removing the suture from the rabbits and de presence under so many conditions, conditions under termining the residual strength. With the sutures in which its effect isdeletcrious are difficult to ascertain, which 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 safetyfor 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 56C. 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 years storage under such transient conditions.
In accordance with the usage set up by the Federal Trade Commission, and set forth in Title 16 of the Code of Federal Regulations, pages 462 and 463 of the 1972 edition, fibers are generally classified with the generic name if they contain over 85 percent content of one monomer. Here the term polyglycolic acid indicates at least 85 mol percent glycolic acid linkages. The
7 term homopolymeric is used to indicate 100 percent glycolic content, where the meaning may be ambiguous.
As the package strength characteristics approximate the inherent viscosity of the polymer. it is often convenient to mesure the inherent viscosity of polymers in powdered form rather than extruding and spinning to form a fiber, and sutures.
Good surgical elements are obtainable if the inherent viscosity is at least about 0.4. Very high grade sutures are obtained if the inherent viscosity of the polymer is at least about 1.0. Polymers with an inherent viscosity of about 1.4 are hard to spin, as extrusion requires normally high pressures, but make a superior quality of suture with very good 21 day strengths on implantation.
Tests were run on a group of polymers of about the same inherent viscosity, with varying ratios of moles of glycolide to moles of lactide. The following Table V shows the inherent viscosity after the listed number of days when the polymer is powdered form was stored in either sealed envelopes, or opened envelopes at a temperature of 100F. and relative humidity of 100 percent.
TABLE V.-INHERENT VISCOSITY-AFTER 100 F.100% R.H. EXPOSURE Time,
days F G H J M. glycolide/m. lact1de- 100/0 95. 8/4. 2 87. 0/13. 0 83. 2/16. 8 81. 2/18. 8 Initial IV 0. 42 0.51 0. 42 0. 44 0. 44 Sealed envelope .41 .51 .42 44 42 3 Open envelope .34 .41 .35 .37 .35 Percent retained. 82. 3 79. 9 83. 3 84. 1 82. 0 Sealed envelope 41 51 42 44 42 6 Open envelope. 29 34 29 .32 29 Percent retained 70. 7 66. 7 69. 1 72. 7 69. 1 Sealed envelope- 41 52 42 44 42 7 Open envelope 24 23 .28 .24 24 Percent retained 58. 1 44.8 54. 8 54. 6 56. 3 Sealed envelope 42 52 42 .43 15 Open envel0pe 14 15 131 15 14 Percent retained 33. 3 28. 9 31. 0 33. 3 32. 6 Sealed envelope- 41 52 .42 45 42 21 Open envelope- 093 097 099 098 095 22 7 18. 7 21. 8 22. 6
Percent retained Because the temperature of the storage can vary con- As can be seen from thee data, the longer the storage siderably, 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 acidbraid can be considered as essentially bone dry. This permits sealing the dried suture containing envelopes at a relative hu' midity of about 2.5 percent at 72F., 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 utures are storage stable for at least 5 years.
in open envelopes, the more the polymer is degraded, the less satisfactory the suture characteristics.
Animal implantation tests on sutures made from such polymers confimi the pattern.
In general, any exposure to moisture vapor tends to degrade the polymer, causing lower strength, and more rapid absorption.
When protected by the packages of this invention and kept dry, a storage life of at least five years under all reasonable commercial storage conditions is to be expected. if during processing and storage, the sutures are permitted to stand with. absorbed moisture, the storage life is decreased, and the in vivo strength is reduced.
Obviously for uses which do not require strength, such as a surgical powder, storage requirements are less rigorous. Where strength is desired, moisture is to be excluded and bone dryness for storage is preferred for eral years.
1. In a method for preparing a storage stable sterile package containing a sterile synthetic surgical element of a polymer subject to hydrolytic degradation to nontoxic, 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,
d. sealing said container with an air and moisture resistant seal,
f. the improvement comprising sterilizing said element and container by contacting with a gas containing about 12 percent by volume ethylene oxide and 88 percent by volume dichlorodifluoromethane for 4 to 20 hours at 70 to 100F. an 5 to 30 psig, said gas having ambient moisture content, and
g. heating said envelope and its contents for about one hour at 82-88C. and an absolute pressure of 1 to 5 mm Hg.
2. The method of claim 1 in which the sterile surgical element is a polyglycolic acid suture, and the water contentis less than 0.05 percent.
3. The method for making a dual envelope suture package comprising 1. a sterile, sealed, air-tight moisture proof inner envelope fabricated from a polyethylene aluminum foil polyethylene paper laminate containing therein a dry sterile polyglycolic acid suture, the gaseous contents of the inner envelope having been evacuated to yield a vacuum packaged suture, the inner layer of said inner envelope being polyethylene and the outer layer being paper in 2. a strippable outer envelope fabricated from a laminate of polyethylene and the polymeric ester of ethylene glycol and terephthalic acid; and wherein the interenvelope space of said dual envelope package is sterile, which comprises:
a. inserting a polyglycolic acid suture into the inner envelope described above,
b. sterilizing the inner envelope and its contents by contacting them with a gas containing about 12 percent by volume ethylene oxide and 88 percent by volume dichlorodifuloromethane for 4 to 20 hours at to F. and 5 to 30 psig, said gas having ambient moisture content,
c. heating said envelope and its contents for about one hour at 82-88C. and an absolute pressure of l to 5 mm Hg,
d. maintaining the dry suture ina substantially dry and sterile environment while awaiting completion of packaging,
e. evacuating the gaseous contents of the inner envelope and sealing said envelope with an air-tight moisture proof seal to produce a vacuum pack aged suture,
f. sealing the sealed inner envelope within the outer envelope described above to form a dual envelope package, and
g. sterilizing the inter space of the dual envelope package by contacting the package with a gas containing 12 percent by volume ethylene oxide and 88 percent by volume dichlorodifluoromethane for 16-24 hours at 72-l00F. and 10-27 psig, said gas having an ambient relative humidity, which permeates the seals of the outer envelope, and sterilizes the interenvelope space.
, UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 5,5 5,515 r. i ....o.. mlunetlle 127. .1...
[nven to r s It is certified that error appears in the above-identified patent and that said'Letters Patent are hereby corrected as shown below:
Col. 5, l. 64, for "hich" read which Col, 5, 1. 59, for "one kin read the skin Col. 6, l. 5, for "E", read a Col. 10, 1.6, for "diluene" substitute diluent Col. 12, l. 58, for "prevets" read preventj- Table II, Under first Straight Pull column, for "65,000" read 65,500 6th number up.
Table II, right hand column, last two lines, for "'7 and. "6 read 7?; and 6 -1 Col. 15, l. 68', after "10%" insert relative Col. 14, l. 66, for ackage read package Table IV, under Package strength----, 1 wk. column, fourth line,
001. 19, 1. 59, for "acidbraid" read acid braid i Col. 19, 1. 6'7, for "utures" read sutures Col. 20, 'l. 28, for "is" read in Signed and sealed this 1st day of October 1974.
MCCOY M. GIBSON JR. 0. MARSHALL DANN Attesting Officer Commissioner of Patents FORM PO-IOSO (10-69) USCOMM-DC 60375-P69 9 U.5v GOVERNMENY PRINTING OFFICE 2 199 O36G-3J4