CA2279300C

CA2279300C - Polyesteramides from cyclic monomers and surgical articles made therefrom

Info

Publication number: CA2279300C
Application number: CA002279300A
Authority: CA
Inventors: Mark S. Roby; Ying Jiang
Original assignee: United States Surgical Corp
Current assignee: United States Surgical Corp
Priority date: 1997-01-28
Filing date: 1998-01-27
Publication date: 2006-12-19
Anticipated expiration: 2018-01-27
Also published as: EP0960146B1; CA2279300A1; WO1998032778A1; AU6048298A; US5902874A; DE69827772D1; DE69827772T2; EP0960146A4; EP0960146A1; ES2232932T3

Abstract

Cyclic monomers prepared by novel methods are useful in making polyesteramides which can be made into shaped articles, particularly, shaped articles suitable for use as surgical devices.

Description

POLYESTERAMIDES FROM CYCLTC MONOMERS
AND SURGICAL ARTICLES MADE THEREFROM
TECHNICAL FIELD
Polyesteramides prepared from cyclic monomers and methods for their preparation are described herein. The polyesteramides are suitable for use in forming shaped articles, such as, for example, surgical devices.
BACKGROUND
Polyesteramides are polymers containing both ester linkages and amide linkages. Their significance for technology of surgical devices stems from the fact that the susceptibility of their ester linkages to hydrolysis confers upon them the ability to be eventually absorbed, or resorbed by a body into which they have been implanted and their amide linkages confer upon them the desirable mechanical properties characteristic of polyamides.
Fiber-forming polyesteramides obtained from the single stage reaction of approximately equimolar amounts of a monoalkanolamine and a dicarboxylic acid are known from U.S. Patent No. 2,386,454. Polyesteramides indicated to be useful for the manufacture of absorbable sutures and other surgical devices are disclosed in U.S. Patent No. 4,226,243 as obtained from the reaction of~a bis-oxyamidodiol (itself derived from the reaction of diethyl oxalate with a monoalkanolamine such as ethanolamine) with a dicarboxylic acid ester. U.S. Patent No 4,343,931 discloses absorbable surgical devices manufactured from polyesteramides obtained by reacting a diamine with lactic or glycolic acid to produce a diamidediol, which is then reacted with a bischloroformate or a compound selected from the group consisting of dicarboxylic acids, diacidchlorides and dicarboxylic acid anhydrides.

NylonT~" refers to a family of high strength, resilient synthetic materials, the long chain molecules of which contain recurring amide groups. NylonT"" has been widely accepted for a variety of applications. Certain surgical applications, however, require a surgical device that is bioabsorbable. NylonT"" is not bioabsorbable and is therefore unacceptable in such circumstances.
It would be desirable to provide a surgical device that has strength and resiliency characteristics similar to those of NylonT"", but which is bioabsorbable.
SUMMARY
It has now been found that polyesteramides derived from cyclic monomers are useful in making shaped articles, particularly, shaped articles suitable for use as surgical devices. The cyclic monomers are of the formula:
O
C
(It-C-R), NH
O ~.
C
II

where x is an integer from Z to 3 and y is an integer from 1 to 3 and R can be the same or different at each occurrence and is individually selected from the group consisting of hydrogen and C1 to Cq alkyl. Preferably, R is hydrogen at each occurrence and x + y = 3 .
Two novel methods are described herein for making the cyclic monomers. The first method of making the present _2_ cyclic monomers involves blocking the amino group of the amino acid, reacting with a hydroxy acid , removing the blocking group and then performing a ring closure reaction.
The cyclic monomer can then be purified and polymerized to form the polyesteramide.
The second method for preparing the cyclic monomers involves reacting an amino acid with a hydroxy alklanoyl halide halogenating the resulting product and then performing a ring closure reaction. The cyclic monomer can then be purified and polymerized to form the polyesteramide.
The resulting polyesteramide can be bioabsorbable and can be formed into shaped articles, for example by molding or extrusion. Particularly useful shaped articles include surgical devices such as sutures and other surgical implants.
DETA~CLED DESCRIPTION OF PREFERRED EMBODIMENTS
The cyclic monomers for making polyesteramides have the following general formula:
O (CHI.
c O
wherein x is an integer from 1 to 3 and y is an integer from 1 to 3 and R can be the same or different at each occurrence and is individually selected from the group consisting of the cyclic monomers described herein have the following general formula:
O R O
-ENH- (CHz) X-\C-O- (C) y-C~-n R
where x, y and R are as defined above.
In particularly useful embodiments, R is hydrogen at each occurrence. In such embodiments, the resulting polyesteramide has the general formula:
O p ~-NH- (CHZ) x-C-O- (CHz) y-~-~-~_ The cyclic monomer can be prepared in any manner known to those skilled in the art. In a particularly useful embodiment, the cyclic monomers are prepared using a novel reaction scheme that involves blocking the amino group of the amino acid, reacting with a hydroxy acid, removing the blocking group and then performing a ring closure reaction.
The cyclic monomer can then be purified and polymerized to form the polyesteramide.
In this reaction scheme, suitable starting materials include amino acids of the formula:
O
I
NHz- (CHi) x-~-OH
where x is an integer from 1 to 3. The amino acids wherein x is 1 or 2 is a particularly useful starting material.
The first step in making the cyclic monomer is to block the amino group of the amino acid. This will ensure that subsequent reaction with a hydroxy acid occurs only at the acid group of the amino acid. Introduction of a blocking agent onto the amino group can be accomplished using any of the techniques known to those skilled in the art. Suitable blocking agents include benzyl chloroformate. Benzyl chloroformate can be reacted with the amino acid in _q_ the presence of a metal oxide (e. g., Mg0) in an aqueous ether solution at reduced temperatures (e.g., around 5 degrees C.).
The protected amino acid is then converted to an acid halide. This can be achieved, for example, by refluxing the protected amino acid with SOXZ wherein X is F, Br, C1 or I, in methylene chloride.
The acid halide is reacted with a hydroxy acid.
Suitable hydroxy acids include those of the formula:
R O
I it HO- (C) y-C-OH
i R
wherein y is an integer from 1 to 3 and R can be the same or different at each occurrence and is individually selected from the group consisting of hydrogen and C1 to C4 alkyl.
Alpha-hydraxy acids in general, and glycolic acid in particular are the preferred hydroxy acids for making the cyclic monomers described herein. The reaction of the acid halide with the hydroxy acid can be carried out by refluxing in the presence of an inert diluent such as, for example, DMF and a tertiary amine, such as, for example, triethylamine (TEA).
The blocking agent is then removed using techniques known to those skilled in the art. For example, if benzyl chloroformate is used as the blocking agent, the blocking agent can be removed by reacting with HBr in acetic acid.
The resulting product has the general formula:
O R O
It 1 ti NH2- (CHZ) x-C-O- ( ~ ) y-C-OH
R
where x, y and R are as defined above. Preferably, x + y =
3.
This reaction product is then subjected to a ring closure reaction. For example, the product is heated in the presence of a metal catalyst such as, for example, stannous octoate. The cyclic monomer is then isolated and purified.
A second reaction scheme useful in preparing the cyclic monomers described herein involves reacting an amino acid with a hydroxy alkanoyl chloride to produce an amino acid with an ester linkage, halogenating that compound and then performing a ring closure reaction. The cyclic monomer can then be purified and polymerized to form the polyesteramide.
In this second reaction scheme, suitable starting materials include amino acids of the formula:
O

NHz- (CHZ) x-C-OH
where x is an integer from 1 to 3.
The amino acid is reacted with a hydroxy alkanoyl halide of the general formula:
O
il HO-CHz- (CHz) y-C-X
where X is F, C1, Br or I and y is an integer from 0 to 3.
This reaction can be achieved, for example by refluxing in the presence of an inert diluent such as, for example, DMF
and a tertiary amine, such as, for example, triethylamine (TEA). The resulting product is a amino acid with an ester linkage of the formula:

2 5 ~O O
HO-CH2- (CHZ)y-C-NH- (CH2) X-~-OH
where x and y are as defined above.
This compound is then halogenated, for example by reacting with SOXz where X is F, C1, Br or I, in methylene chloride to provide a compound of the formula:
O O
HO-CH2- (CHZ)y-~-NH- (CHZ)x-~'-X
where x and y are as defined above.
This halogenated compound can then be subjected to a ring closure reaction. For example, the above halogenated r r_ compound can be reacted in an THF and TEA at reduced temperatures (e. g., around 5 degrees C) to produce ring closure. The cyclic monomer is then isolated and purified.
The cyclic monomer should be purified, preferably to at least about 98 percent purity prior to polymerization. The monomer may be purified using any known technique such as multiple distillations and/or recrystallizations.
The cyclic monomer can be polymerized by heating in the presence of initiators such as alcohols or aminoalkanols and a metal catalyst (e. g., Sn(Oct)2) to produce a ring-opening polymerization reaction.
If desired, any portion of the cyclic monomer employed in the polymerization reaction, e.g., from about 1 to about 99 mole percent can be replaced with a like mole percentage of another difunctional reactant such as hydroxycarboxylic acid or lactone precursor thereof, e.g., glycolide, lactide, gamma-butyrolactone, epsilon-caprolactone, etc.
Further, if desired, the cyclic monomer can include one or more bioabsorbable polymer selected from the group consisting of homopolymers and copolymers of glycolide, lactide, trimethylene carbonate, dioxanone and caprolactone blended with the esteramide compound.
The polyesteramides can be formed into surgical articles using any known technique, such as, for example, extrusion, molding and/or solvent casting. The polyesteramides can be used alone, blended with other absorbable compositions, or in combination with non-absorbable components. A wide variety of surgical articles can be manufactured from the polyesteramides described herein. These include but are not limited to clips and other fasteners, staples, sutures, pins, screws, prosthetic devices, wound dressings, drug delivery devices, anastomosis rings, and other implantable devices. Fibers made from the present polyesteramides can be knitted or woven with other fibers, either absorbable or nonabsorbable to form meshes or fabrics. Compositions including these polyesteramides can also be used as an absorbable coating for surgical devices.
In any of the above embodiments, n is the degree of polymerization of the polymer.
Optional additives which may be present in compositions made from the polyesteramides described herein.
-7a-include plasticizers, release agents and other processing aids. Where the composition is used to make a surgical device, stearic acid or calcium stearate are particularly useful additives due to their biocompatibility.
In another aspect, compositions containing the polyesteramides described herein can be used to make reinforced composites. Thus, for example, the polyesteramide composition can form the matrix of the composite and can be reinforced with bioabsorbable or non-absorbable fibers or particles. Alternatively, a matrix of any bioabsorbable or non-bioabsorbable polymer composition can be reinforced with fibers or particulate material made from compositions containing the polyesteramides described herein.
In an alternative embodiment, the polyesteramides described herein are admixed with a filler. The filler can be in any particulate form, including granulate and staple fibers. While any known filler may be used, hydroxyapatite, tricalcium phosphate, bioglass or other bioceramics are the preferred fillers. Normally, from about 10 grams to about 400 grams of filler are mixed with 100 grams of polymer.
The filled, cross-linked polymers are useful, for example, as a molding composition.
It is further contemplated that one or more medico-surgically useful substances can be incorporated into compositions containing the polyesteramides described herein. Examples of such medico-surgically useful substances include, for example, those which accelerate or beneficially modify the healing process when particles are applied to a surgical repair site. So, for example, articles made from the composition can carry a therapeutic agent which will be deposited at the repair site. The therapeutic agent can be chosen for its antimicrobial properties, capability for promoting repair or reconstruction and/or new tissue growth. Antimicrobial _g_ _.._.._.......... T . C ..

agents s~.,:h as broad spectrum antibiotic (gentamycin sulfate, erythromycin or derivatized glycopeptides) which are slowly released into the tissue can be applied in this manner to aid in combating clinical and sub-clinical infections in a tissue repair site. To promote repair and/or tissue growth, one or several growth promoting factors can be introduced into the sutures, e.g., fibroblast growth factor, bone growth factor, epidermal growth factor, platelet derived growth factor, macrophage derived growth factor, alveolar derived growth factor, monocyte derived growth factor, magainin, and so forth. Some therapeutic indications are: glycerol with tissue or kidney plasminogen activator to cause thrombosis, superoxide dimutase to scavenge tissue damaging free radicals, tumor necrosis factor for cancer therapy or colony stimulating factor and interferon, interleukin-2 or other lymphokine to enhance the immune system.
It is also contemplated that it may be desirable to dye articles made from compositions containing the polyesteramides in order to increase visibility of article in the surgical field. Dyes, such as those known to be suitable for incorporation in sutures, can be used. Such dyes include but are not limited to carbon black, bone black, D&C Green No. 6, and D&C Violet No. 2 as described in the handbook of U.S. Colorants for Food, Drugs and Cosmetics by Daniel M. Marrion (1979). Preferably, articles made in accordance with this disclosure are dyed by adding up to about a few percent and preferably about 0.2% dye, such as D&C Violet No. 2 to the resin prior to extrusion.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments.
Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
_g_

Claims

WHAT IS CLAIMED IS:

1. A compound of the general formula:
wherein x is an integer from 1 to 3 and y is an integer from 1 to 3 and R can be the same or different at each occurrence and is individually selected from the group consisting of hydrogen and C1 to C4 alkyl.

2. The compound in accordance with claim 1, wherein R
at each occurrence is hydrogen.

3. The compound in accordance with claim 1, wherein x +
y = 3 and R at each occurrence is hydrogen.

4. The compound in accordance with claim 1, wherein x =
2, y = 1 and R at each occurrence is hydrogen.

5. A compound comprising repeating units derived by ring-opening polymerization of a compound in accordance with claim 1.

6. The compound in accordance with claim 5, further comprising repeating units derived from one or more monomers selected from the group consisting of hydroxycarboxylic acids and lactone precursors thereof.

7. The compound in accordance with claim 5, wherein R
at each occurrence is hydrogen.

8. The compound in accordance with claim 5, wherein x +
y = 3 and R at each occurrence is hydrogen.

9. The compound in accordance with claim 5, wherein x =
1, y = 2 and R at each occurrence is hydrogen.

10. A method of making a cyclic monomer suitable for producing a polyesteramide comprising:
a) blocking the amino group of an amino acid;
b) halogenating the blocked amino acid to provide a halogenated acid;
c) reacting the halogenated acid with a hydroxy acid to provide a monomer;
d) de-blocking the product from step c); and e) subjecting the product of step d) to a ring closure reaction.

11. The method in accordance with claim 10, wherein step a) comprises blocking the amino group of an amino acid of the general formula:
where x is an integer from 1 to 3.

12. The method in accordance with claim 10, wherein step a) comprises reacting an amino acid with benzyl chloroformate.

13. The method in accordance with claim 10, wherein step b) comprises reacting the blocked amino acid with a compound of the formula SOX2 wherein X is selected from the group consisting of F, Cl, Br and I.

14. The method in accordance with claim 10, wherein step b) comprises chlorinating the blocked amino acid.

15. The method in accordance with claim 10, wherein step d) comprises reacting the acid halide with an alphahydroxy acid of the general formula:
wherein R can be the same or different at each occurrence and is individually selected from the group consisting of hydrogen and C1 to C4 alkyl.

16. The method in accordance with claim 10, wherein step d) comprises reacting the acid halide with glycolic acid.

17. A method of making polyesteramide comprising:
preparing a cyclic monomer in accordance with claim 10;
polymerizing the cyclic monomer to produce a polyesteramide.

18. A composition comprising:
a compound in accordance with claim 5.

19. The composition in accordance with claim 18, further comprising at least one medico-surgically useful compound.

20. The composition in accordance with claim 18, further comprising a plasticizer.

21. The composition in accordance with claim 18, further comprising a filler.

22. The composition in accordance with claim 18, further comprising one or more bioabsorbable polymer selected from the group consisting of homopolymers and copolymers of glycolide, lactide, trimethylene carbonate, dioxanone and caprolactone blended with the esteramide compound.

23. A composition in accordance with claim 18, wherein the composition consists essentially of repeating units of the general formula:

24. The surgical device comprising a shaped article made from the compound of any one of claims 5 to 9.

25. The surgical device comprising a shaped article made from the composition of any one of claims 18 to 23.

26. Use of a compound of the general formula:
for the manufacture of absorbable sutures.

27. Use of a compound of the general formula:
for making shaped articles to be absorbed.

28. Use of a compound of the general formula:
for molding articles.