JPH05103825A - Method for improving stability to storage of polymer article - Google Patents

Abstract

PURPOSE: To improve the storing stability of a polymer object which is likely to make hydrolysis. CONSTITUTION: An absorptive sewing thread is either in the whole or partially formed from a polymer or copolymer of a polymer article such as glycolic acid, glycollide, lactic acid, lactide, dioxanone, trimethylene carbonate, caprolactone, polyalkylene glycol or a combination thereof, and at least one sort of water soluble moisture-absorptive polyhydroxy compound and/or its ester, for example a mixture of glycerol and calcium lactate, is used as a storage stabilizer for the sewing thread. Thereby the intended method according to the invention can be accomplished with simplicity, economization, and production efficiency which have not been attained by the conventional technique.

Description

Detailed Description of the Invention

[0001]

The present invention provides a method of improving the storage stability of polymeric articles which have an inherent tendency to undergo degradation when exposed to water or a humid atmosphere, presumably as a result of hydrolysis. .. More specifically, the present invention relates to polymers susceptible to hydrolytic degradation, particularly glycolic acid (ie, hydroxyacetic acid), cyclic dimers of glycolic acid (“glycolide”), lactic acid, cyclic dimers of lactic acid (“ Lactide ")
And to improve the storage stability of articles and devices composed of polymers and copolymers of related monomers, such as absorbable surgical sutures, clips, staples, implants, prostheses and the like.

[0002]

BACKGROUND OF THE INVENTION Polymers and copolymers of the type described above and absorbable surgical devices made therefrom are well known. For example, US Pat. No. 2,668,162, 270331.
6, 2758987, 3225766, 329703
3, 3422181, 3531561, 356586
9, 3620218, 3626948, 363695
6, 3736646, 3772420, 377391
9, 3792010, 3797499, 383929
7, 3867190, 3878284, 398254
3, 4060089, 4137921, 415743
7, 4234775, 4237920, 4300565
And 4523591, British Patent No. 779,291 and D.M. K. Gilding et al., “Biodegradable”
Polymers for use in surge
ry --- polyglycolic / poly (lac
tic acid) homo- and co-po
lymers: 1, Polymer ", Volume
20, pages 1459-1464 (1979) and D.M. F. Williams (ed.), Biocom
pat-ability of Clinical I
mpplant Material-ls, Vol. II,
ch. 9: "Biodegradable Polym
-Ers ”(1981). The biodegradability of these polymers / copolymers appears to be due to the hydrolytic attack of their ester bonds by hydrous body fluids, but the exact mechanism involved is speculative. Do not leave.

Absorbable sutures (or other hydrous body fluid absorbable articles) experience long periods of storage prior to use, for example months and sometimes even years. Water or moisture in the environment of storage prevents the suture from being essentially moist to prevent it from contacting the suture and further reducing its in-vivo strength to the point where the suture is no longer usable. It is common practice to package in a tight seal. However, US Pat. Nos. 3,728,839 and 413
As described in 5622, any packaging material that impedes the entry of moisture will also prevent moisture from escaping. Therefore, any water absorbed by or associated with the suture when it is packaged will tend to remain in the package for the entire duration of its storage.

No. 3,728,839 and 41 mentioned above.
According to 35622, the in vivo strength of polyglycolic acid surgical elements, such as sutures, is due to the aforementioned tendency of moisture impermeable packaging to seal moisture with the suture, just prior to packaging,
Even the exposure of the contents to very small amounts of water for very short periods of time, eg 20 minutes or less, can be significantly degraded by long term storage in the packaging.

In order to prevent or minimize the hydrolytic degradation of sutures, US Pat. Nos. 3,728,839 and 4,135,622 disclose that less than 0.5% of the weight of the suture is sealed with water once 0.5%. It discloses the removal of water from the suture prior to sealing the package so that it stays in the package if desired. While effective, this approach to improving storage stability of sutures is difficult and expensive to perform. Prior to sealing the suture in its water-impermeable packaging, it is essential that the suture be "stretched" by heating the suture for a time sufficient to remove water from it ( For example, under vacuum of 26 inches for 1 hour at 180-188 ° C.). However, once water has been removed, sutures have a high moisture content, even for a limited duration, as even short exposures to water can lead to severe degradation of the in vivo strength of the suture, as described above. Not allowed to come into contact with the environment. Therefore, after the water removal step, it is necessary to store the suture in a dry area, i.e., an essentially moisture-free environment, in which the potential for contact with moisture is largely eliminated.

Taken together, these procedures for improving the storage stability of absorbable sutures and other surgical devices susceptible to hydrolytic degradation are time consuming for storage stability issues. It is a costly, expensive and relatively complex solution.

[0006]

SUMMARY OF THE INVENTION The present invention overcomes the above disadvantages associated with the storage stability process described in US Pat. Nos. 3,728,839 and 4,135,622.

The present invention is directed to polymeric articles which are susceptible to hydrolysis, such as polyester polymers or copolymers such as polyglycolic acid, lactide-glycolide copolymers, polydioxanone, polytrimethylene carbonate, copolymers thereof and the like. Or, a method of improving the storage stability of absorbable surgical articles, such as sutures, based on or in part, which reduces the moisture content of the article prior to packaging or is kept artificial prior to completion of the packaging operation. It does not require any temporary storage of the article in a harsh environment.

Accordingly, in accordance with the present invention, in a method of improving the storage stability of a polymer article susceptible to hydrolysis, the polymer article is provided with a storage-stable amount of at least one water-soluble agent. A method comprising applying a hygroscopic polyhydroxy compound and / or an ester thereof is provided.

Originally, the method described above had very low water content, either before or after applying the stabilizer to the polymeric article, eg, US Pat. Nos. 3,728,839 and 41356.
It can be done on polymeric articles without the need to reduce to a blunt state as in No. 22. This is because fully acceptable levels of storage stability can be achieved without resorting to such exhaustive moisture reduction efforts. Similarly, it is entirely unnecessary to keep the article in a hot environment at any time after its manufacture and before its packaging is complete, as in the aforementioned patents. one time,
The long-term hydration is increased when contacted with a storage stabilizer, which is then retained on and / or in the polymeric article, for example by adhering to its surface and / or being adsorbed by the polymeric composition of which the article is composed. Since all that is necessary to achieve degradative stability will be achieved by the application of storage stabilizers, the articles can be packaged immediately.
Therefore, the storage stabilization method of the present invention is disclosed in US Pat.
It has the advantage of simplicity, economy and level of production efficiency that cannot be achieved by the storage stabilization method described in 8839 and 4135622.

In addition to imparting increased storage stability to polymeric articles that undergo hydrolytic degradation, the practice of this invention also provides other advantages. For example, absorbable sutures filled with a storage-stable amount of glycerol by the method of the present invention have been found to exhibit better flexibility and "feel" properties than untreated sutures. Moreover, hygroscopic compounds useful in the practice of the present invention are generally capable of dissolving a number of medically-surgically useful substances so that they will not be sutured (or other absorbable surgical device) inside the body. When introduced, it can be used as a vehicle to deliver these substances to the wound or surgical site.

The term "filled," as used herein, refers to the association of a polymeric article with a storage-stable amount of a storage stabilizer, even though this association is such that the storage stabilizer is absorbed by the polymeric article. , A storage stabilizer may be present on the surface, or a combination of the two.

A common feature of polymeric articles to be contacted with storage stabilizers in accordance with the present invention is their relatively high likelihood of undergoing destructive hydrolysis over storage. Generally, this is a heavy chain having a significant number of short chain ester linkages, such as is the case for polyglycolic acid, lactide-glycolide copolymers, polydioxanone, polytrimethylene carbonate, their copolymers and related materials. It is an inherent feature of coalesce and copolymers. The present invention is particularly useful for application to absorbable sutures of both monofilament and multifilament types composed of polymers and copolymers of this type, eg braided types which are particularly hygroscopic. However, it is not limited to articles useful for other types of surgery (eg, absorbable surgical clips, staples, sponges, gauze, implants and prostheses for reconstructing bone tissue, blood vessels, etc.). US Pat. No. 4,135,622 including
Those disclosed in No.)).

Useful storage stabilizers are generally selected from water-soluble hygroscopic polyhydroxy compounds or esters of these compounds, preferably those which have no appreciable toxicity to the body in the amounts present. With these requirements in mind, one of ordinary skill in the art can readily identify all of the storage stabilizers useful in the practice of the present invention. Among the particular storage stabilizers which have been used in the present invention with generally good results are glycerol and its mono- and diesters derived from low molecular weight carboxylic acids such as monoacetin and diacetin (glyceryl monoacetate and glyceryl diacetate, respectively). ), Ethylene glycol, diethylene glycol, triethylene glycol, 1,3-propanediol, trimethylolethane, trimethylolpropane, pentaerythritol and sorbitol. Glycerol is particularly preferred. Mixtures of storage stabilizers, such as sorbitol dissolved in glycerol, glycerol in combination with monoacetin and / or diacetin, are also useful.

In order to prevent or minimize runoff or separation of the storage stabilizer from the suture, which is somewhat prone to relatively low viscosity compounds such as glycerol, it is desirable to combine the storage stabilizer with a thickener. , Is advantageous. Many types of pharmaceutically acceptable non-aqueous thickeners are available, water-soluble polysaccharides such as hydroxypropyl methylcellulose (HPMC), and European Patent Application No. 026 above.
Other materials of this type disclosed in 7015 include polysaccharide gums such as guar, xanthan, gelatin, collagen and the like. A particularly preferred group of thickeners is
They are saturated aliphatic hydroxycarboxylic acids having up to 6 carbon atoms and their alkali metal and alkaline earth metal salts and hydrates. Among this preferred group of compounds are compounds of the general formula

[0015]

[Chemical 1]

(Wherein R is hydrogen or a methyl group,
R'is hydrogen or a metal selected from the group consisting of alkali metals and alkaline earth metals, and n is 0 or 1.)
And hydrates thereof. Specific examples of these compounds are salts of lactic acid such as calcium lactate and potassium lactate,
Sodium lactate, salts of glycolic acid such as calcium glycolate, potassium glycolate and sodium glycolate, salts of 3-hydroxypropanoic acid such as its calcium, potassium and sodium salts, salts of 3-hydroxybutanoic acid such as its calcium, potassium and Including sodium salts and the like. As mentioned above, hydrates of these compounds can also be used. Calcium lactate, especially calcium lactate pentahydrate, is a particularly preferred thickener.

When a thickener is used, it is
It will be incorporated into the filling composition in an amount greater than that required to increase the total viscosity of the composition, to the point where the composition no longer easily flows away from the suture in a relatively short period of time. In the case of the preferred storage stabilizer-thickener combination, ie glycerol and calcium lactate, the weight ratio of glycerol to calcium lactate can vary from about 1: 1 to about 10: 1, preferably from about 6: 1 to about 8: 1. ..

If desired or desired, one or more stabilizers can be dissolved in any suitable non-aqueous solvent or combination of solvents prior to use. To be suitable, the solvent is
(1) Mixable with storage stabilizer at the concentration of storage stabilizer,
(2) has a vapor pressure high enough to be easily removed by evaporation, (3) does not appreciably affect the integrity of the polymeric article, and (4) is used in combination with a storage stabilizer for surgery. It must be able to wet the surface of the article. Applying these criteria to the preferred storage stabilizers, glycerol, lower alcohols such as methanol and ethanol are completely suitable solvent carriers.

Application of the storage stabilizer to the polymeric article can be accomplished in a number of ways. Thus, for example, an article may have at least a storage-stabilizing amount, even after any removal of all excess agent and / or accompanying solvent (if any) by draining, wiping, evaporation, etc. It can be submerged in the storage stabilizer or its solution until the agent is obtained by the article or otherwise retained. In many cases, contact times on the order of just a few seconds, for example about 10 seconds to a few hours, for example about 2 hours and longer, of the treated article compared to the same type of article not treated with the storage stabilizer. Sufficient to give a substantial improvement in storage stability.

The above submersion method of contacting the polymeric article with a storage stabilizer is carried out continuously or in a batch. Thus, for absorbable sutures, a length of suture will
The storage stabilizer is continuously passed through an amount of stabilizer at a rate already determined to provide the suture with the required degree of exposure or contact time. As it emerges from the suture or storage stabilizer, it passes through a wiper or similar device to remove excess agent prior to the packaging operation. In a batch operation, an amount of suture is simply submerged in the storage stabilizer for the required time and any excess agent is removed if desired.

Alternatively, the storage stabilizer and its solution are applied by spraying, brushing, wiping, etc. onto the surface of the polymeric article, the latter receiving and retaining at least a storage stabilizing amount of the agent. Another method that can be used to apply the storage stabilizer is to insert the polymeric article in a package containing an effective amount of the agent such that intimate contact between the polymeric article and the agent is achieved. Including doing.

Whatever contact method is used, the article to be treated is required to obtain a storage stabilizing amount of storage stabilizer. Generally, one or more storage stabilizers (excluding all solvents) in an amount of from about 2 to about 25, preferably from about 5 to about 15% by weight of the polymer article contacted therewith are compared to that of the untreated article. And is sufficient to result in significantly improved storage stability.

The method of the present invention can be practiced in combination with other well known and conventional methods, such as sterilization. Known and conventional packaging techniques and materials are also envisioned. As previously mentioned, the advantage of the present invention is that it removes most of the small amount of moisture from the article and must be kept in a particularly dry environment until the final packaging and sealing operation as disclosed in US Pat. Nos. 3,728,839 and 4,135,622. It is in its ability to provide increased storage stability to polymer articles that are susceptible to hydrolytic degradation without failing. Although the present invention may be practiced with sutures or other articles treated in this manner, it need not be, and for reasons of simplicity, economy and efficiency of production, contact with storage stabilizers according to the present invention. It is preferred that the article does not undergo the treatments described in the aforementioned patents.

The process of the present invention is preferably carried out on a polymeric article whose water content is equilibrated to that of the surrounding atmosphere, eg, about 5 to about 40% relative humidity or higher. This water content in the atmosphere will typically result in a stabilized surgical article having an amount of water in the range of about 0.3 to about 1.0 wt% or more. Moisture content within this range is unacceptable for the packaging methods and packaged synthetic surgical elements of US Pat. Nos. 3,728,839 and 4,135,622, but may affect the long-term in vivo strength of polymeric articles in contact with the storage stabilizers of the present invention. It has no appreciable harmful effect.
Thus, the polymeric article treated with the storage stabilizer can, if desired, be packaged at a relatively high level of relative humidity, such as those mentioned above.

If particular functionality is desired, it is advantageous to apply one or more coating compositions to the storage-stabilized article of the present invention. Thus, for example, in the case of absorbable sutures treated with glycerol for improved long-term storage, storage-stabilized articles may be coated with polyethylene oxide-polypropylene oxide block copolymers or polyalkylene glycols. , Both of which further polymerize with a glycolide monomer and a lactide monomer or a glycolide / lactide copolymer to improve the lubricity of the surface and fix the bond. Materials suitable for these purposes are disclosed in U.S. Patent No. 3867190, 3942532.
4047533, 4452973, 4624256, 4
649920, 4716203 and 4826945.

As mentioned above, storage stabilizers as carriers for one or more medically / surgically useful substances, such as those which accelerate or otherwise beneficially modify the healing process when applied to the wound or surgical site. It is advantageous to use
In general, all biologically active substances which are soluble and otherwise compatible with the chosen storage stabilizer can be incorporated in therapeutically useful amounts. Thus, for example, the suture is filled with a storage stabilizer containing a therapeutic agent that is stored at the sutured site. The therapeutic agent may be selected for its antibacterial properties, wound repair and / or tissue growth or particular indications such as thrombolysis. Antibacterial agents that are slowly released into tissues, such as broad spectrum antibiotics (gentamicin sulphate, erythromycin or derived glycopeptides), are applied in this manner to prevent clinical and subclinical infections at the site of surgical or trauma wounds. Help fight. In order to promote wound repair and / or tissue growth, one or several growth promoting factors are added to the storage stabilizers, for example fibroblast growth factor, bone growth factor, epidermal growth factor, platelet derived Growth factor, macrophage-derived growth factor, alveolar-derived growth factor,
Examples include monocyte-derived growth factor and magainin. Certain therapeutic indications include glycerol and tissue or renal plasminogen activators that cause thrombolysis, superoxide dismutase that scavenges tissue-damaging free radicals, tumor necrosis factor for cancer treatment or colony stimulation that enhances the immune system. Factor and interferon, interleukin-2 or other lymphokines.

The production of the storage stabilizer of this embodiment is a relatively simple method. For example, in the case of glycerol and calcium lactate, the desired amount of glycerol is first introduced into the container and then the desired amount of calcium lactate is added thereto. If no solvent is used, the mixture is then thoroughly mixed. When a solvent is desired, a solvent such as methanol is added to the mixture of glycerol and calcium lactate and the solution is then thoroughly mixed to dissolve the compound.

In general, the stabilizers of this embodiment include compounds in the above formula, such as calcium lactate and water-soluble hygroscopic polyhydroxy, in a weight ratio of about 1: 1 to about 1:10, and most preferably 1: 7, respectively. It consists of a mixture of compounds such as glycerol. When a solvent such as methanol is used to make the stabilizer, the solvent is about 20 based on the total weight of the solution.
To about 50%, preferably about 30 to about 45% (by weight) of a compound of the above formula, such as glycerol, in an amount to provide a solution concentration.

[0030]

EXAMPLES The following examples are illustrative of the storage stabilizing method and storage stabilizing polymeric articles of the present invention. Tables 2 and 3 illustrate the storage stabilizing effect of hygroscopic polyhydroxy compounds. Tables 4 and 5 illustrate the storage-stabilizing effect of mixtures containing hygroscopic polyhydroxy compounds and compounds represented by the above formula.

Example 1-5

In the examples below, five samples of absorbable sutures were prepared, packaged, sealed and kept under accelerated storage conditions and tested for in vitro strength as described below. Was tested (U.S.P. Knot Pu
ll Test).

[0033]

[Table 1]

In the table, (1) VICRYL (Ethico
n, Inc. ) Is a braided absorbable suture that appears to be composed of a copolymer derived from 90 mol% glycolide and 10 mol% lactide. When wrapped, the suture is coated with a lubricant to improve bond integrity. Size 1-0 was used for these evaluations.

(2) A VICRYL suture with the original coating substantially removed.

(3) The VICRYL suture was unwrapped and then resealed after equilibration at the indicated relative humidity.

To simulate the effect of long term storage on in vivo strength, wrapped suture was
Stored at 2 ° F and 10% relative humidity for the times indicated in the table below.

To simulate in vivo strength, sutures were placed in 98.6 ° F buffered saline. The results of the Knot Pull test were as follows.

[0039]

[Table 2]

As shown by these data, the suture of Example 2 was measured despite the 6-fold higher water content of the suture of Example 2 compared to the commercially available control sample of Example 1. The in-vivo strength was about the same as or better than that of the suture of Example 1. Compared to the data of Example 2 with that of Example 4, despite its high water content, the glycerol-treated sutures of the invention show a significantly higher percentage of their initial in vivo compared to untreated sutures. Retained its strength. Even when the suture has a water content of 1.0% by weight (Example 3), the amount is the same as the suture storage stabilization method and storage stabilized sutures of US Pat. Nos. 3,728,839 and 4135622. Maximum 0.
Twice as much as 5% by weight, which is much better in storage stability than the suture with a much lower water content (Example 5), even though both sutures were packaged in the same relative humidity environment. Had sex.

Examples 6 to 7

A sample of 1-0 Vicryl knitted absorbable sutures (water content of about 0.05% by weight when initially packaged) stripped of their original coating was
Copolymer made from about 10 wt% glycerol and made from equal parts by weight of polyethylene glycol (molecular weight about 7500) and 20/80 glycolide-lactide copolymer to enhance bond reduction and bond immobilization of sutures. Was coated with. The coated suture was then equilibrated at ambient temperature and relative humidity of 15 and 20% respectively (Example 6).
And 7). Finally, suture samples were subjected to accelerated storage and tested for in vivo strength as in Examples 1-5. The test results are shown in Table 3 below.

[0043]

[Table 3]

These data further demonstrate the effectiveness of applying glycerol to sutures according to the present invention to improve the storage stability of absorbable sutures.

Example 8

[0046] Glycerol-filled and glycerol / calcium lactate-filled braided sutures were tested on Clay Ada to compare retention as% of baseline fill.
Centrifuge using a ms Bench Top Lab centrifuge. Four samples were spun after collecting baseline data for the centrifuged samples. Centrifugal force is centrifugal force 3
Performed for 15 minutes at top speed at 000 Gs. The results are shown in Table 4.

[0047]

[Table 4]

The above data show that the addition of calcium lactate to glycerol increases glycerol retention.

Example 9

The calcium lactate / glycerin filled knit suture samples show equally improved storage stability as compared to the glycerin filled knit without calcium lactate as shown in Table 5 ( (Compare C and D with A and E). In both cases, the stability is superior to the knit yarn without glycerin and equilibrates at about the same water content.

[0051]

[Table 5]

Obviously, other modifications and variations of the invention include:
It is possible from the above teaching. It will therefore be appreciated that changes may be made in the particular embodiments of this invention which are within the full intended scope of the invention as defined by the claims.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Donald Escaplan, Connecticut, USA 06883 Weston White Oak Lane 7 (72) Inventor, Los Earl Mass, Connecticut, USA 06804 Burtsk Field, Art Day 2, Clear View Drive 97

Claims (10)

[Claims] 1. A method for improving the storage stability of a hydrolytically susceptible polymer article, wherein the polymer article has a storage stable amount of at least one water soluble hygroscopic polyhydroxy compound as a storage stabilizer therefor. And / or applying an ester thereof. 2. An absorbent wherein the polymeric article is wholly or partly composed of a polymer or copolymer of glycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate, caprolactone, polyalkylene glycol or combinations thereof. The method of claim 1 which is a possible suture. 3. The method of claim 1, wherein the storage stabilizer further comprises at least one thickener. 4. The thickener has the general formula: (Wherein R is hydrogen or a methyl group, R ′ is hydrogen or a metal selected from the group consisting of alkali metals and alkaline earth metals, and n is 0 or 1) and its hydration The method according to claim 3, which is an object. 5. The method of claim 4, wherein the storage stabilizer comprises a mixture of glycerol and calcium lactate. 6. A hydrolytically susceptible polymeric article containing a storage stable amount of at least one water-soluble hygroscopic polyhydroxy compound and / or its ester as a storage stabilizer. 7. An absorbable suture composed wholly or partly of a polymer or copolymer of glycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate, caprolactone, polyalkylene glycol or a combination thereof. The polymeric article of claim 7, wherein: 8. The polymeric article of claim 6, wherein the storage stabilizer further comprises at least one thickener. 9. The thickener has the general formula: (Wherein R is hydrogen or a methyl group, R ′ is hydrogen or a metal selected from the group consisting of alkali metals and alkaline earth metals, and n is 0 or 1) and its hydration The polymer article according to claim 7, which is a product. 10. The polymeric article of claim 9, wherein the storage stabilizer comprises a mixture of glycerol and calcium lactate.