CA2064247A1 - Ionic heparin coating - Google Patents
Ionic heparin coatingInfo
- Publication number
- CA2064247A1 CA2064247A1 CA002064247A CA2064247A CA2064247A1 CA 2064247 A1 CA2064247 A1 CA 2064247A1 CA 002064247 A CA002064247 A CA 002064247A CA 2064247 A CA2064247 A CA 2064247A CA 2064247 A1 CA2064247 A1 CA 2064247A1
- Authority
- CA
- Canada
- Prior art keywords
- heparin
- medical article
- complex
- carbons
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
- A61L33/0017—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using a surface active agent
Abstract
ABSTRACT OF THE DISCLOSURE
A non thrombogenic quaternary ammonium-heparln complex coating for a medical article comprising an amount of at least 50% by weight of one or more cationic quaternary ammonium organic salts having the following formula:
Wherein R1 is an alkyl group having from about 14 to about 22 carbons;
R2 is an alkyl group having from about 1 to about five carbons;
R3 is an alkyl group having from about 1 to about five carbons.
A non thrombogenic quaternary ammonium-heparln complex coating for a medical article comprising an amount of at least 50% by weight of one or more cationic quaternary ammonium organic salts having the following formula:
Wherein R1 is an alkyl group having from about 14 to about 22 carbons;
R2 is an alkyl group having from about 1 to about five carbons;
R3 is an alkyl group having from about 1 to about five carbons.
Description
IMPRQVED IONIC HEPARIN COATING
This is continuation-ln-part of serlal no. 097,295 filed September 14, 1987.
BACKGROUND OF ~HE INVENTION
In recent years great advances in medical technology have produced man made materials that make direct contact with human blood. For example, medical devices must be used in temporarily conduct~ng the blood out of the body or used as substituted artificial organs in the body thereby necessitating the devices making direct contact with blood. Such materials include by way of example, monitoring tubes, artificial kidneys, heart valves, lS blood by-pass tubes and dialysis membranes.
The present state of medical technology indicates that polymers, both natural and synthetic, particularly certa~n synthetic plastics, have come into prom~nence as preferred materials for prosthetic dev~ces. It is also known that upon contact w~th such materials, the blood easily coagulates and forms a thrombus or a clot on the surface of such materials. The thrombus or clot creates the ser~ous r~sk of blood current blockage or, alternzt~vely, moves along w~th the blood flow to cause equally dangerous complications such as pulmonary thrombosis, cerebral thrombosis or myocardial infarct~on.
In the use of blood contacting medical devices it has always been conventional medical practice to prevent thrombus formation by systematically admin~stering to a patient an anticoagulant agent such as heparin, coumar~ne, and similar compositions.
However, direct and systematic adm~nistration of these anti-coagulants also increases the risks of bleeding in a sub~ect.
20~2~
Heparin is the most well known anticoagulant and a polysaccharide not having a un~form molecular structure. It is generally consldered a mixture of polymers of varying size and slight differences exist between the polymers and in the individual sugars within a part~cular polymer grouping. It is current expert opinion that heparln is composed of alternating derivatives of D-glycocyamine (N-sulfated or N-acetylated) and uranic ac~d (L-iduron~c acid with varying sulfate or D-glucuronic acid) joined by glycosidic linkages.
In an effort to counteract thrombogenicity and engendered bleeding, caused by direct administration of heparin, many researchers developed methods of attaching and binding heparin in the form of a coating to the walls of medical articles. Dr.
Vincent Gott made the original advance in the preparation of non-thrombogenic materials by treating a graphite plastlc surface with benzalkonium chloridP and then wlth heparin.
Materials treated in this way were non-thrombogenic in vitro for prolonged periods of time.
Further developments followed, Two patents issued to Ericksson et al U.S. Patent Nos. 3,810,781 and 4,11~,485, where a medical article is rendered non-thrombogenic by applying a heparin coating prepared by providing a dialdehyde. Another patent issued to Eriksson et al, U.S. Patent 4,265,927, issued on May 5, 1981, teaches reacting a charged surface with a colloidal aqueous solution of a cationic surface active agent and heparin. The surface actlve agent of choice is specifically mentioned as one of a primary amine type.
While such medical research has resulted in improved stabilization of the heparinized surface, the covalent bonding which takes place with the stabilizing dialdehyde results in reductlon of the physiologlcal activity of the heparln.
Additionally, such a procedure is complicated in that many steps are involved and, consequently, ~s relatively costly.
206~247 One presently available heparin complex used to treat blood contacting surfaces is formed from benzalkonium chloride. This available complex ~s actually a m~xture of alkylben~yldimethylammonium chloride of the general formula, [C6H5CH2 N (CH3)2 R] Cl, in which R represents a mixture of alkyls, including all or some of the groups comprising Cg and greater, with Cl2, Cl4 and Cl6 compr~sing the major portion.
Generally, the composition breaks down to more than 20% Cl4, more than 40%, Cl2 and a less than 30X mixture of C8, Clo and Cl6. The use of benzalkonium chloride is taught in U.S. Patent 3,522,346, issued to Chang on July 28, 1970; and in the articles "Semipermeable AqueQus Microcapsules", Chang et al, Canadian Journal of Physiology and Pharmacology, Vol. 45, 1967, Pages 705-715; and "A Simple Non-thrombogenic Coating", Amplatz, MD, Investigative Radiology, Vol. 6, No. 4, July-August 1971, Pages 280-289. While the use of benzalkonium chlor~de/heparin complex coatings on medical art1cles has been effective, esp~cially for short duration applications, they still demonstrate limited stability.
The binding of hepar~n onto a plastlc polymer surface in a fully stable way has presented cons~derable diff~culties. One ma~or disadvantage w~th plastic materials coated with currently available heparin-benzalkonium complexes is that these coatlng complexes are unstable and sub~ect to desorption or leaching.
Consequent1y, ~n contact with biological fluids such coating can lose up to one half of the heparin content in a period of 20 minutes. The offered explanat~on for this phenomena is that the ~onic bonding of the an~onic heparin to the cationic organic quaternary ammon~um groups ~n the plastic surface ~s so unstable that heparin is continuously lost with fluid flow. Only short term appl~cations involv~ng blood contact of short duration can be carried out with such unstable heparinized surfaces.
Other ~nvestigators have suggested us~ng additional types of ammon~um salts which are complexed with heparin. A group of 20S~2~7 surface active agents was suggested ~n U.S. Patent No.
3,717,502, ~ssued to Masuhara et al on February 20~ lg73. This list broadly includes dimethyl alkylbenzyl ammonium chloride, benzyldimethyl-2-~2-(p-1,1,3,4-tetramethylbutyl phenoxy) ethoxy]
ammon~um chloride, alkyl-tr~methylammon~um chloride, dilauryldimethyammonium chloride or the l~ke. Alkyl-ammonium salts were suggested ~n U.S. Patent Nos. 4,302,368, issued to Dudley, deceased et al on November 24, 1981; and 3,634,1239 and in article "A Thrombogen~c Index For Blood Contacting Mater~als", Roohk et al, Amer~can Society Artificial Internal Organs, Vol. XXIII, 1977, page 152-161.
As demonstrated above, benzalkonium chloride/hepar~n complex coatings, while providing adequate biocompatibility, were not sufficiently stable in sal~ne. Other investigators have demonstrated that some alkyl ammonium salts, e.g.
tr~dodecylmethyl ammon~um salts, do not ~nh~bit thromb~gensis.
St~ll other ~nvest~gators have complexed hepar~n with esters, see U.S. Patent No. 3,835,112, ~ssued to Mand~gu~an et al on September 10, 1974: U.S. Patent No. 4,440,926, ~ssued to Mand~gu~an on Apr~l 3, 1984 and French Patent No. 010792 ~ssued on November 20, 1981, to Pharm~ndustr~e. In U.S. Patent No.
4,326,532, ~ssued to Hammar on Apr~l 27, 1982, heparin and ch~tosan were reacted together to form a non-thrombogen~c coat~ng.
Still further invest~gators have suggested attach~ng heparin covalently or ~onically to polymers, see U.S. Patent Nos.
4,415,490, ~ssued to Joh on November 15, 1983; 3,853,804, ~ssued to Yen et al on December 10, 1974, 4,350,806, ~ssued to Wagener on September 21, 1982 and Japanese Patent 043041, ~ssued to Toray Industr~es Inc. on November 4, 1979.
206~2~7 Other attempts of attach~ng heparin to device surfaces have ~nvoled prepar~ng the substrate surface to react with cationic or anionic compounds, e.g. heparin. In U.S. Patent 4,565,740, ~ssued to Golander et al on January 21, 1986 a complex formed by treating the substrate surface with a polymeric cation~c surfactant and a dialdehyde could then be subsequently reacted wlth cat~onic or an~onic compounds, including heparin. U.S.
Patent No. 4,254,180, ~ssued to Kline on March 3, 1981, disclosed a mixture of a resin and colloidal graphite used to form objects. The exposed surface was made heparin recieptive by treatment w~th a cationic surface act~ve agent.
Derivatlves of heparin have also been suggested as providing ant~-thrombogenlc properties. For example, ~n U.S. Patent 4,331,697, issued to Kudo et al on May 25, 19~2, a spec~fic derivative of heparin was disclosed which in the presence of actinic light was applied to the surface of medical devices.
The above references demonstrate the keen ~nterest ~n developing a hepar~n, or s~m~lar type reagent, b~ocompatible coat~ng.
However, ava~lable heparin coatings do not prov~de adequate sal~ne stab11~ty or non-thrombogen~c propertles. Aga~nst th~s background ~t ~s 1mportant to find new hepar~n coating compos~t~ons which optimize stability, part~cularly ~n saline, and provide assured protect~on aga~nst thrombogens~s. These compositions should be capable of being applied sat~sfactorily and consistently to a variety of materials such as natural polymers and synthetic plastics and will result ~n complete coverage of a med~cal art~cle substrate surface with an adhes~ve film coating.
In co-pending appl~cat~on U.S. Ser~al Number 097,295, f~led on September 14, 1987, which is a continuation of U.S. Ser~al Number 820,670 non-thrombogen~c quaternary ammon~um/heparin complexes were disclosed. These complexes were demonstrated as providing ~mproved sal~ne stab~lity and biolog~cal act~vity over 20~42~7 previously disclosed heparin materials. These disclosed complexes were alkylbenzyldimethyl ammon;um cat~on~c ~ons having the formula:
, R--N-CH
Where R is a un~form a1kyl group conta~n~ng between 16 to 18 carbon atoms.
The present invention relates to add~tional alkylbenzyl ammonium/heparin complexes useful as coat~ng composit~on having improved surface adhesion and ant~-thrombogen~c than heparin composit~ons heretofore known. These compositions have the d~st~nct advantages of being relatively simple to prepare and easily applied as coatings to medical article surfaces.
SUMMARY OF THE INVENTION
In accordance w~th the present ~nvent~on non-thrombogenic quaternary ammonium/heparin complexes are provided having ~n excess of fifty percent by we~ght of one or more alkylbenzyl ammon~um cation~c ~ons having the formula:
Rl-- N~ --R3 Wherein Rl ls an alkyl group having from about 14, 15 or l9 to about 22 carbons;
R2 ~s an alkyl group having from about l to about five carbons; and ~ 7 -2a6~2~7 R3 is an alkyl group having from about l to about five carbons;
Additionally, methods are provided for preparing the present complex and rendering the surface of a medical article non-thrombogen~c. These processes e~ther ~nvolve coating the surface of such a device with the present trialkylbenzyl ammonium-heparin complex, or coating the surface with a representative trlalkylbenzyl ammonium salt and subsequently treating this surface with heparin salt.
As will be discussed ~n deta~l below, surfaces of medlcal articles so treated w~th the ~nstant heparin complex have prolonged non-thrombogenicity, improved adhesion to polymer surfaces, decreased desorption and improved biological compatibility.
DETAILED DESCRIPTION OF THE INVENTION
As ~ndicated above, the present ~nvent~on relates to a hydrophob~c, organ~c solvent soluble coat~ng complex compr~sing an~on~c hepar1n and at least 50X by we~ght of one or more alkylbenzyl ammon~um cat~on~c salts of the follow~ng formula:
Rl-- N+ --R3 Where~n Rl ~s an alkyl group hav~ng from about 14 to about 22 carbons;
R2 ~s an alkyl group hav~ng from about l to about five 3C carbons;and R3 ~s an alkyl group hav~ng from about l to about five carbons.
205~2~
In the above referred to co-pending application U.S. Serial Number-0~7~295, the alkylbenzyl ammonium cationic salts consisted of those wherein Rl is an alkyl group having from about 16 to about 18 carbons, while R2 and R3 are methyl groups. It has now been determined that additional trialkylbenzyl ammonium cat~onic salts are useful for the purposès of the present ~nvention. These cat~onic salts are of the formu1a:
Rl-- N+ --R3 Wherein Rl is an alkyl group having from about 14, 15 or l9 to about 22 carbons;
R2 is an alkyl group having from about l to about five carbons;and R3 is an alkyl group having from about l to about five carbons.
When medlcal art1cles are coated wlth the instant hepar1n complex they are found to have the following characteristics when compared with presently used heparin coatings:
(l) tmproved adhesion and surface retention:
This is continuation-ln-part of serlal no. 097,295 filed September 14, 1987.
BACKGROUND OF ~HE INVENTION
In recent years great advances in medical technology have produced man made materials that make direct contact with human blood. For example, medical devices must be used in temporarily conduct~ng the blood out of the body or used as substituted artificial organs in the body thereby necessitating the devices making direct contact with blood. Such materials include by way of example, monitoring tubes, artificial kidneys, heart valves, lS blood by-pass tubes and dialysis membranes.
The present state of medical technology indicates that polymers, both natural and synthetic, particularly certa~n synthetic plastics, have come into prom~nence as preferred materials for prosthetic dev~ces. It is also known that upon contact w~th such materials, the blood easily coagulates and forms a thrombus or a clot on the surface of such materials. The thrombus or clot creates the ser~ous r~sk of blood current blockage or, alternzt~vely, moves along w~th the blood flow to cause equally dangerous complications such as pulmonary thrombosis, cerebral thrombosis or myocardial infarct~on.
In the use of blood contacting medical devices it has always been conventional medical practice to prevent thrombus formation by systematically admin~stering to a patient an anticoagulant agent such as heparin, coumar~ne, and similar compositions.
However, direct and systematic adm~nistration of these anti-coagulants also increases the risks of bleeding in a sub~ect.
20~2~
Heparin is the most well known anticoagulant and a polysaccharide not having a un~form molecular structure. It is generally consldered a mixture of polymers of varying size and slight differences exist between the polymers and in the individual sugars within a part~cular polymer grouping. It is current expert opinion that heparln is composed of alternating derivatives of D-glycocyamine (N-sulfated or N-acetylated) and uranic ac~d (L-iduron~c acid with varying sulfate or D-glucuronic acid) joined by glycosidic linkages.
In an effort to counteract thrombogenicity and engendered bleeding, caused by direct administration of heparin, many researchers developed methods of attaching and binding heparin in the form of a coating to the walls of medical articles. Dr.
Vincent Gott made the original advance in the preparation of non-thrombogenic materials by treating a graphite plastlc surface with benzalkonium chloridP and then wlth heparin.
Materials treated in this way were non-thrombogenic in vitro for prolonged periods of time.
Further developments followed, Two patents issued to Ericksson et al U.S. Patent Nos. 3,810,781 and 4,11~,485, where a medical article is rendered non-thrombogenic by applying a heparin coating prepared by providing a dialdehyde. Another patent issued to Eriksson et al, U.S. Patent 4,265,927, issued on May 5, 1981, teaches reacting a charged surface with a colloidal aqueous solution of a cationic surface active agent and heparin. The surface actlve agent of choice is specifically mentioned as one of a primary amine type.
While such medical research has resulted in improved stabilization of the heparinized surface, the covalent bonding which takes place with the stabilizing dialdehyde results in reductlon of the physiologlcal activity of the heparln.
Additionally, such a procedure is complicated in that many steps are involved and, consequently, ~s relatively costly.
206~247 One presently available heparin complex used to treat blood contacting surfaces is formed from benzalkonium chloride. This available complex ~s actually a m~xture of alkylben~yldimethylammonium chloride of the general formula, [C6H5CH2 N (CH3)2 R] Cl, in which R represents a mixture of alkyls, including all or some of the groups comprising Cg and greater, with Cl2, Cl4 and Cl6 compr~sing the major portion.
Generally, the composition breaks down to more than 20% Cl4, more than 40%, Cl2 and a less than 30X mixture of C8, Clo and Cl6. The use of benzalkonium chloride is taught in U.S. Patent 3,522,346, issued to Chang on July 28, 1970; and in the articles "Semipermeable AqueQus Microcapsules", Chang et al, Canadian Journal of Physiology and Pharmacology, Vol. 45, 1967, Pages 705-715; and "A Simple Non-thrombogenic Coating", Amplatz, MD, Investigative Radiology, Vol. 6, No. 4, July-August 1971, Pages 280-289. While the use of benzalkonium chlor~de/heparin complex coatings on medical art1cles has been effective, esp~cially for short duration applications, they still demonstrate limited stability.
The binding of hepar~n onto a plastlc polymer surface in a fully stable way has presented cons~derable diff~culties. One ma~or disadvantage w~th plastic materials coated with currently available heparin-benzalkonium complexes is that these coatlng complexes are unstable and sub~ect to desorption or leaching.
Consequent1y, ~n contact with biological fluids such coating can lose up to one half of the heparin content in a period of 20 minutes. The offered explanat~on for this phenomena is that the ~onic bonding of the an~onic heparin to the cationic organic quaternary ammon~um groups ~n the plastic surface ~s so unstable that heparin is continuously lost with fluid flow. Only short term appl~cations involv~ng blood contact of short duration can be carried out with such unstable heparinized surfaces.
Other ~nvestigators have suggested us~ng additional types of ammon~um salts which are complexed with heparin. A group of 20S~2~7 surface active agents was suggested ~n U.S. Patent No.
3,717,502, ~ssued to Masuhara et al on February 20~ lg73. This list broadly includes dimethyl alkylbenzyl ammonium chloride, benzyldimethyl-2-~2-(p-1,1,3,4-tetramethylbutyl phenoxy) ethoxy]
ammon~um chloride, alkyl-tr~methylammon~um chloride, dilauryldimethyammonium chloride or the l~ke. Alkyl-ammonium salts were suggested ~n U.S. Patent Nos. 4,302,368, issued to Dudley, deceased et al on November 24, 1981; and 3,634,1239 and in article "A Thrombogen~c Index For Blood Contacting Mater~als", Roohk et al, Amer~can Society Artificial Internal Organs, Vol. XXIII, 1977, page 152-161.
As demonstrated above, benzalkonium chloride/hepar~n complex coatings, while providing adequate biocompatibility, were not sufficiently stable in sal~ne. Other investigators have demonstrated that some alkyl ammonium salts, e.g.
tr~dodecylmethyl ammon~um salts, do not ~nh~bit thromb~gensis.
St~ll other ~nvest~gators have complexed hepar~n with esters, see U.S. Patent No. 3,835,112, ~ssued to Mand~gu~an et al on September 10, 1974: U.S. Patent No. 4,440,926, ~ssued to Mand~gu~an on Apr~l 3, 1984 and French Patent No. 010792 ~ssued on November 20, 1981, to Pharm~ndustr~e. In U.S. Patent No.
4,326,532, ~ssued to Hammar on Apr~l 27, 1982, heparin and ch~tosan were reacted together to form a non-thrombogen~c coat~ng.
Still further invest~gators have suggested attach~ng heparin covalently or ~onically to polymers, see U.S. Patent Nos.
4,415,490, ~ssued to Joh on November 15, 1983; 3,853,804, ~ssued to Yen et al on December 10, 1974, 4,350,806, ~ssued to Wagener on September 21, 1982 and Japanese Patent 043041, ~ssued to Toray Industr~es Inc. on November 4, 1979.
206~2~7 Other attempts of attach~ng heparin to device surfaces have ~nvoled prepar~ng the substrate surface to react with cationic or anionic compounds, e.g. heparin. In U.S. Patent 4,565,740, ~ssued to Golander et al on January 21, 1986 a complex formed by treating the substrate surface with a polymeric cation~c surfactant and a dialdehyde could then be subsequently reacted wlth cat~onic or an~onic compounds, including heparin. U.S.
Patent No. 4,254,180, ~ssued to Kline on March 3, 1981, disclosed a mixture of a resin and colloidal graphite used to form objects. The exposed surface was made heparin recieptive by treatment w~th a cationic surface act~ve agent.
Derivatlves of heparin have also been suggested as providing ant~-thrombogenlc properties. For example, ~n U.S. Patent 4,331,697, issued to Kudo et al on May 25, 19~2, a spec~fic derivative of heparin was disclosed which in the presence of actinic light was applied to the surface of medical devices.
The above references demonstrate the keen ~nterest ~n developing a hepar~n, or s~m~lar type reagent, b~ocompatible coat~ng.
However, ava~lable heparin coatings do not prov~de adequate sal~ne stab11~ty or non-thrombogen~c propertles. Aga~nst th~s background ~t ~s 1mportant to find new hepar~n coating compos~t~ons which optimize stability, part~cularly ~n saline, and provide assured protect~on aga~nst thrombogens~s. These compositions should be capable of being applied sat~sfactorily and consistently to a variety of materials such as natural polymers and synthetic plastics and will result ~n complete coverage of a med~cal art~cle substrate surface with an adhes~ve film coating.
In co-pending appl~cat~on U.S. Ser~al Number 097,295, f~led on September 14, 1987, which is a continuation of U.S. Ser~al Number 820,670 non-thrombogen~c quaternary ammon~um/heparin complexes were disclosed. These complexes were demonstrated as providing ~mproved sal~ne stab~lity and biolog~cal act~vity over 20~42~7 previously disclosed heparin materials. These disclosed complexes were alkylbenzyldimethyl ammon;um cat~on~c ~ons having the formula:
, R--N-CH
Where R is a un~form a1kyl group conta~n~ng between 16 to 18 carbon atoms.
The present invention relates to add~tional alkylbenzyl ammonium/heparin complexes useful as coat~ng composit~on having improved surface adhesion and ant~-thrombogen~c than heparin composit~ons heretofore known. These compositions have the d~st~nct advantages of being relatively simple to prepare and easily applied as coatings to medical article surfaces.
SUMMARY OF THE INVENTION
In accordance w~th the present ~nvent~on non-thrombogenic quaternary ammonium/heparin complexes are provided having ~n excess of fifty percent by we~ght of one or more alkylbenzyl ammon~um cation~c ~ons having the formula:
Rl-- N~ --R3 Wherein Rl ls an alkyl group having from about 14, 15 or l9 to about 22 carbons;
R2 ~s an alkyl group having from about l to about five carbons; and ~ 7 -2a6~2~7 R3 is an alkyl group having from about l to about five carbons;
Additionally, methods are provided for preparing the present complex and rendering the surface of a medical article non-thrombogen~c. These processes e~ther ~nvolve coating the surface of such a device with the present trialkylbenzyl ammonium-heparin complex, or coating the surface with a representative trlalkylbenzyl ammonium salt and subsequently treating this surface with heparin salt.
As will be discussed ~n deta~l below, surfaces of medlcal articles so treated w~th the ~nstant heparin complex have prolonged non-thrombogenicity, improved adhesion to polymer surfaces, decreased desorption and improved biological compatibility.
DETAILED DESCRIPTION OF THE INVENTION
As ~ndicated above, the present ~nvent~on relates to a hydrophob~c, organ~c solvent soluble coat~ng complex compr~sing an~on~c hepar1n and at least 50X by we~ght of one or more alkylbenzyl ammon~um cat~on~c salts of the follow~ng formula:
Rl-- N+ --R3 Where~n Rl ~s an alkyl group hav~ng from about 14 to about 22 carbons;
R2 ~s an alkyl group hav~ng from about l to about five 3C carbons;and R3 ~s an alkyl group hav~ng from about l to about five carbons.
205~2~
In the above referred to co-pending application U.S. Serial Number-0~7~295, the alkylbenzyl ammonium cationic salts consisted of those wherein Rl is an alkyl group having from about 16 to about 18 carbons, while R2 and R3 are methyl groups. It has now been determined that additional trialkylbenzyl ammonium cat~onic salts are useful for the purposès of the present ~nvention. These cat~onic salts are of the formu1a:
Rl-- N+ --R3 Wherein Rl is an alkyl group having from about 14, 15 or l9 to about 22 carbons;
R2 is an alkyl group having from about l to about five carbons;and R3 is an alkyl group having from about l to about five carbons.
When medlcal art1cles are coated wlth the instant hepar1n complex they are found to have the following characteristics when compared with presently used heparin coatings:
(l) tmproved adhesion and surface retention:
(2) prolonged non-thrombogenicity and decreased desorption;
and (3) optimum hydrophobicity and solubility in organic solvents.
The ~nvention also prov~des a process for coating the surface of polymeric medical articles comprising:
206~2~7 (a) providing a medical article; and (b) coating the medical art~cle with a complex of anionic heparin and at least 50X by weight of one or more alkylbenzyl ammonium cationic salts of the following formula:
Rl-- N+ _-R3 Where~n Rl ~s an alkyl group having from about 14 to about 22 carbons;
R2 ~s an alkyl group having from about 1 to about five carbons;and R3 ~s an alkyl group hav~ng from about 1 to about five carbons.
With a first group of such cation~c salts being those wherein R
~s an alkyl group hav~ng from 16 to 18 carbons, w~th R2 and R3 be~ng methyl groups, and a second group of such cat~on~c salts be~ng those where~n Rl ~s an alkyl group hav~ng from about 14, 15 or 19 to about 22 carbons; R2 ~s an alkyl group hav~ng from about 1 to about f~ve carbons; and R3 ~s an alkyl group hav~ng from about 1 to about f~ve carbons.
In accordance w~th another embod~ment the process ~s carried out by treat~ng the med~cal art~cle wlth a solution of at least 50X
by we~ght of one or more cation~c quaternary ammonium organ~c salts hav~ng the follow~ng formula:
X
Rl-- N~ --R3 Wherein Rl ~s an alkyl group hav~ng from about 14, 15 or 19 to , .. .
,. . .
- lo~ 247 about 22 carbons;
R2 is an alkyl group having from about l to about five carbons;
R3 is an alkyl group having from about l to about five carbons; and X is a halogen; and applying a heparin sa1t to such treated surface.
The process of the instant invention further includes direct coating means of the heparin complex by straight application means as in the case of dip coating and indirect coating means as in the case of sequential appllcations of a cation~c salt surfactant and the ~onic heparln.
As is evident from the above descr~pt~on, there is provided a particular heparin/quaternary ammonium complex which when applied to the surface of medical articles results in a markedly improved heparinized coating. Of critical ~mportance is the discovery herein of particular alkylbenzyl dimethyl ammonium cat~onic salts which can be used in high 10ading concentrations with heparin to form coat1ngs having the stated beneficial features. It has been found that the present hepar1n/quaternary ammonium complex must have at least 50 weight percent of the organic cationic salt and preferably from 60 to 70 weight percent to achieve medical article coatings of optimum quality.
Weight percent as used herein means the ratios of the quaternary ammonium moieties to the total weight of the complex. These weight percentages relate to, but are not limited by, the degrees of substitution of the heparin molecule by the cationic quaternary ammonium salt.
~hile all the present hepar~ complexes and mixtures thereof have the desired non-thrombogenic and stability characteristics, , ~ .
optimum and preferred results have been achieved with compl ~ ~s5 ~ ~ ~ 7 consisting of cetalkonium heparin and/or stearylkonium heparin and mixtures thereof. It appears that the homogeneous nature of the organic cationic salt gives optimum stability and uniformity to the ultimate coating.
~hile not to be construed as limiting, it is speculated that the unexpected results achieved with the instant heparin/quaternary ammonium complex in conjunction with organic substrate surfaces result from the use of the particular organic salts at high concentrations. Therefore it is theorized that the longer organic chains of the cationic salt cause greater affinity to the organic substrate surface and their high concentration enhances the adhesion of the complex thereby stabilizing the heparin on the organic surface. Consequently the instant complex coating has vastly superior hydrophobicity and surface adhesion over the presently and most commonly used complexes of hepar~n and benzalkonium chloride.
Commerc1ally available Benzalkonium Chloride is a mixture of alkylbenzyld1methylammonium chloride of the general formula, ~C6HsCH2 N (CH3)2 R~ Cl, ln wh~ch R represents a mixture of alkyls, includ~ng all or some of the groups comprising C8 and greater, with Cl2, Cl4 and C16 comprising the ma~or portion.
Generally, the composition breaks down to more than 20X Cl4, more than 40X, Cl2 and a less than 30X mlxture of Cg, Clo and Cl6. While the use of benzalkonium chloride/heparin complex coatings on medical art~cles has been effective, especially for short duration applications, they still demonstrate limited stability which is probably due to the heterogeneous nature of the mixture.
Any conventional material which makes direct contact with the blood such as glass, metals, and resins may be used as 2Q~2~7 substrates within the purv~ew of the present ~nvention. The polymeric res~n mater~als which serve as the substrate to be treated by the composition and processes of this invention may be any polymeric res~n, natural or synthetic, conventionally used to fabricate articles commonly used in contact with blood.
For example, catheters, artificial blood vessels, valves and like prosthetics are frequently fabricated from a polyethylene, polyacrylic, polypropylene, polyvinyl chloride, polyam~de, polyurethane, polyvinylpyrrolidone, polyv~nyl alcohol, cellulose acetate, polystyrene, polytetrafluoroethylene, polyester such as polyethylene terephthalate, silicone rubber, natural rubber, polycarbonate and llke polymeric resins and hydrogels, thereof.
The resin substrate may be rig~d or flex~ble ln character, cellular or non-cellular, porous or non-porous. Also within the scope of the invent~on is the treatment of a coating of such a polymer res~n on a metal or ceram~c material.
The follow~ng examples g~ve greater ~llustrat~on and understand~ng of the invention.
In the first set of examples (Examples 1-3) are directed to the alkylbenzyl d~methyl ammon~um cat~onic salts where~n Rl ~s an alkyl group having from about 16 to 18 carbons, with R2 and R3 being methyl groups. These examples demonstrate the ~mproved stab~lity and b~ocompat~bil~ty of th~s case of compounds, of whlch ammonium cat~onic salts of the instant ~nvention are a part, ~n comparlson to presently ava~lable compounds and compositions.
A Stearyl d~methyl benzyl ammonium Hepar~n complex was prepared as follows: ~7 grams of heparin was dissolved in 215 milliliters of distilled water. The solution was m~xed with a 420 m~ ter of a water solut~on containing 63 grams of purified 2. ~ 7 Stearyl dimethyl benzyl ammonium chloride. This mixing was performed by stirring the heparin solution and adding the stearylkonlum chloride solution to lt in a drop wise manner whereby an insoluble complex of heparin and the stearylkonium chloride was formed as a precipitate. This complex compound was separated from solùtion by means of filtration and found to contain about 63X stearylkonium cation. The complex was found to be h~ghly hydrophobic and had limited solubilit~es in polar organic solvents such as methanol, ethanol and isopropyl alcohol.
To illustrate the comparat~ve character~st~cs of the heparin complex prepared in Example l and benzalkonium heparin, which is a presently available compound, the following example and tests were carried out.
Six polyester cores generally used in arterial filters known as AF 1025 and manufactured by American Hospital Supply Corporation were prov~ded. Two are dip coated in a 0.2X, by weight of tommercially available benzalkonium heparin ("BKH") dissolved in isopropyl alcohol. Two other cores were dip coated in a 0.2X, by weight solution of stearylkonium heparin ("SKH") dissolved in a m~xture of trifluro trichloro ethane and ethanol. The two remaining cores were tested as controls.
The prepared filters along with the controls were subjected to a leaching or desorption test to determ~ne the amount of heparin loss experienced with circulating sal1ne liquid. The amounts and the biological activities of the respective heparln complexes on each filter were determinPd. The quantity of the heparin complex was ascertained by extraction w~th an organic solvent and the extract subjected to ultraviolet spectrophotcmetric analysis. The heparin biological activity test was performed utilizing a different portion of the same 2 ~ ~
extracts in accordance with the Propopath Proteolytic Enzyme Detection System of American Hospital Supply Corporation.
The ~eaching test was carr~ed out as follows. The saline circulation text utilized 3/8" x 3/32" PVC tubing of three meters in length, a total saline volume of 1.5 l~ters. and the test was run at a temperature of 37C. The saline solution was continuously circulated through the test circuit and saline samples were removed at predeterm~ned intervals. These samples were analyzed for heparin content and activ~ties as indicated above.
After 4 hours of sallne c~rculation, each filter was removed and dissected. 250mls. of ethyl alcohol was then used to extract any organic coatings on the core of each filter including the control. The alcohol extract was then sub~ected to the UV
spectrophotometric test to determine the amount of heparin complex as well as the biological activity test indicated above. The amounts and activities of heparin complexes remaining on the two sets of filters before and after saline leaching are tabulated ~n Tables 1 and 2. The intermittent activities of the respect~ve saline solutions are outlined in Table 3.
Turning to Tables 1 and 2, it is evident that the Stearylkonium Heparin coating is more stable than the Benzalkonium Heparir, because in excess of 80% of the orig~nal SKH coating composition survives the saline leaching in both sets of tests whereas there is a loss of at least 85% of the BKH coatings. Th~s is confirmed by the Heparin Activity test of the residual coatlngs ~hich indicates that BKH loses a minimum of 75X of its heparin activity over the four hours of saline leaching.
The test date of Tables 1 and 2 are also important because .
_ 15 -2~2~7 medical devlces used for blood flow are generally primed or stored ~n saline solutions.
Consequently desorption character~stlcs in this medium are ~mportant in and of themselves. As one example, blood gas sensor dev~ces used for determin~ng types and amounts of blood gases are generally coated wlth hepar~n complexes and stored ~n saline. It can be apprec~ated from the test data that such devices eoated with benzalkon~um heparin will not have the requisite anti-thrombogenic qual~ty after significant saline storage.
TABLE l-FIRST SET
BEFORE SALINE RECIRCULATION AFTER 4 HRS. OF
SALINE RECIRCULATION
mg BKH HEPARIN mg BKH HEPARIN
or SKH ACTIVITY or SKH ACTIVITY
0.2X BKH 19 1140 0 122 COATED (OX OF (10.7% OF
FILTER ORIGINAL) ORIGINAL) 0.2X SKH 19 875 16.3 750 COATED (85.7X OF (85.7X OF
FILTER ORIGINAL) (ORIGINAL) BEFORE SALINE RECIRCULATION AFTER 4 HRS. OF SALINE
RECIRCULATION
mg BKH HEPARIN mg BKH HEPARIN
or SKH ACTIVITY or SKH ACTIYITY
0.2X BKH 19 1140 2.3 271 COATED (12.1X OF (23.8X OF
FILTER ORIGINAL) ORIGINAL) 0.2X SKH 19 875 16.0 750 COATED (84.2X OF (85.7Z OF
FILTER ORIGINAL) ORIGINAL) Table 3 outlines the t~me ~nterval readings of the hepar~n 2 '1 7 activities of the circulating solutions. There is no detect~on (ND) of biological heparin actlvity dur1ng the SKH test while the BKH demonstrates an accelerated desorpt~on w~thin the f~rst hour and v1rtual deact~vat~on over the four hour period. This data confirms the conclusions reached w~th respect to Tables l and 2.
s TOTAL HEPARIN ACTIVITY DETECTED IN CIRCULATING SALINE
0.2X BKH COATED 0.2X SKH COATED
FILTER FILTER
(AFTER PRIMING) l HOUR 698 ND
3 l/4 HOURS 788 ND
and (3) optimum hydrophobicity and solubility in organic solvents.
The ~nvention also prov~des a process for coating the surface of polymeric medical articles comprising:
206~2~7 (a) providing a medical article; and (b) coating the medical art~cle with a complex of anionic heparin and at least 50X by weight of one or more alkylbenzyl ammonium cationic salts of the following formula:
Rl-- N+ _-R3 Where~n Rl ~s an alkyl group having from about 14 to about 22 carbons;
R2 ~s an alkyl group having from about 1 to about five carbons;and R3 ~s an alkyl group hav~ng from about 1 to about five carbons.
With a first group of such cation~c salts being those wherein R
~s an alkyl group hav~ng from 16 to 18 carbons, w~th R2 and R3 be~ng methyl groups, and a second group of such cat~on~c salts be~ng those where~n Rl ~s an alkyl group hav~ng from about 14, 15 or 19 to about 22 carbons; R2 ~s an alkyl group hav~ng from about 1 to about f~ve carbons; and R3 ~s an alkyl group hav~ng from about 1 to about f~ve carbons.
In accordance w~th another embod~ment the process ~s carried out by treat~ng the med~cal art~cle wlth a solution of at least 50X
by we~ght of one or more cation~c quaternary ammonium organ~c salts hav~ng the follow~ng formula:
X
Rl-- N~ --R3 Wherein Rl ~s an alkyl group hav~ng from about 14, 15 or 19 to , .. .
,. . .
- lo~ 247 about 22 carbons;
R2 is an alkyl group having from about l to about five carbons;
R3 is an alkyl group having from about l to about five carbons; and X is a halogen; and applying a heparin sa1t to such treated surface.
The process of the instant invention further includes direct coating means of the heparin complex by straight application means as in the case of dip coating and indirect coating means as in the case of sequential appllcations of a cation~c salt surfactant and the ~onic heparln.
As is evident from the above descr~pt~on, there is provided a particular heparin/quaternary ammonium complex which when applied to the surface of medical articles results in a markedly improved heparinized coating. Of critical ~mportance is the discovery herein of particular alkylbenzyl dimethyl ammonium cat~onic salts which can be used in high 10ading concentrations with heparin to form coat1ngs having the stated beneficial features. It has been found that the present hepar1n/quaternary ammonium complex must have at least 50 weight percent of the organic cationic salt and preferably from 60 to 70 weight percent to achieve medical article coatings of optimum quality.
Weight percent as used herein means the ratios of the quaternary ammonium moieties to the total weight of the complex. These weight percentages relate to, but are not limited by, the degrees of substitution of the heparin molecule by the cationic quaternary ammonium salt.
~hile all the present hepar~ complexes and mixtures thereof have the desired non-thrombogenic and stability characteristics, , ~ .
optimum and preferred results have been achieved with compl ~ ~s5 ~ ~ ~ 7 consisting of cetalkonium heparin and/or stearylkonium heparin and mixtures thereof. It appears that the homogeneous nature of the organic cationic salt gives optimum stability and uniformity to the ultimate coating.
~hile not to be construed as limiting, it is speculated that the unexpected results achieved with the instant heparin/quaternary ammonium complex in conjunction with organic substrate surfaces result from the use of the particular organic salts at high concentrations. Therefore it is theorized that the longer organic chains of the cationic salt cause greater affinity to the organic substrate surface and their high concentration enhances the adhesion of the complex thereby stabilizing the heparin on the organic surface. Consequently the instant complex coating has vastly superior hydrophobicity and surface adhesion over the presently and most commonly used complexes of hepar~n and benzalkonium chloride.
Commerc1ally available Benzalkonium Chloride is a mixture of alkylbenzyld1methylammonium chloride of the general formula, ~C6HsCH2 N (CH3)2 R~ Cl, ln wh~ch R represents a mixture of alkyls, includ~ng all or some of the groups comprising C8 and greater, with Cl2, Cl4 and C16 comprising the ma~or portion.
Generally, the composition breaks down to more than 20X Cl4, more than 40X, Cl2 and a less than 30X mlxture of Cg, Clo and Cl6. While the use of benzalkonium chloride/heparin complex coatings on medical art~cles has been effective, especially for short duration applications, they still demonstrate limited stability which is probably due to the heterogeneous nature of the mixture.
Any conventional material which makes direct contact with the blood such as glass, metals, and resins may be used as 2Q~2~7 substrates within the purv~ew of the present ~nvention. The polymeric res~n mater~als which serve as the substrate to be treated by the composition and processes of this invention may be any polymeric res~n, natural or synthetic, conventionally used to fabricate articles commonly used in contact with blood.
For example, catheters, artificial blood vessels, valves and like prosthetics are frequently fabricated from a polyethylene, polyacrylic, polypropylene, polyvinyl chloride, polyam~de, polyurethane, polyvinylpyrrolidone, polyv~nyl alcohol, cellulose acetate, polystyrene, polytetrafluoroethylene, polyester such as polyethylene terephthalate, silicone rubber, natural rubber, polycarbonate and llke polymeric resins and hydrogels, thereof.
The resin substrate may be rig~d or flex~ble ln character, cellular or non-cellular, porous or non-porous. Also within the scope of the invent~on is the treatment of a coating of such a polymer res~n on a metal or ceram~c material.
The follow~ng examples g~ve greater ~llustrat~on and understand~ng of the invention.
In the first set of examples (Examples 1-3) are directed to the alkylbenzyl d~methyl ammon~um cat~onic salts where~n Rl ~s an alkyl group having from about 16 to 18 carbons, with R2 and R3 being methyl groups. These examples demonstrate the ~mproved stab~lity and b~ocompat~bil~ty of th~s case of compounds, of whlch ammonium cat~onic salts of the instant ~nvention are a part, ~n comparlson to presently ava~lable compounds and compositions.
A Stearyl d~methyl benzyl ammonium Hepar~n complex was prepared as follows: ~7 grams of heparin was dissolved in 215 milliliters of distilled water. The solution was m~xed with a 420 m~ ter of a water solut~on containing 63 grams of purified 2. ~ 7 Stearyl dimethyl benzyl ammonium chloride. This mixing was performed by stirring the heparin solution and adding the stearylkonlum chloride solution to lt in a drop wise manner whereby an insoluble complex of heparin and the stearylkonium chloride was formed as a precipitate. This complex compound was separated from solùtion by means of filtration and found to contain about 63X stearylkonium cation. The complex was found to be h~ghly hydrophobic and had limited solubilit~es in polar organic solvents such as methanol, ethanol and isopropyl alcohol.
To illustrate the comparat~ve character~st~cs of the heparin complex prepared in Example l and benzalkonium heparin, which is a presently available compound, the following example and tests were carried out.
Six polyester cores generally used in arterial filters known as AF 1025 and manufactured by American Hospital Supply Corporation were prov~ded. Two are dip coated in a 0.2X, by weight of tommercially available benzalkonium heparin ("BKH") dissolved in isopropyl alcohol. Two other cores were dip coated in a 0.2X, by weight solution of stearylkonium heparin ("SKH") dissolved in a m~xture of trifluro trichloro ethane and ethanol. The two remaining cores were tested as controls.
The prepared filters along with the controls were subjected to a leaching or desorption test to determ~ne the amount of heparin loss experienced with circulating sal1ne liquid. The amounts and the biological activities of the respective heparln complexes on each filter were determinPd. The quantity of the heparin complex was ascertained by extraction w~th an organic solvent and the extract subjected to ultraviolet spectrophotcmetric analysis. The heparin biological activity test was performed utilizing a different portion of the same 2 ~ ~
extracts in accordance with the Propopath Proteolytic Enzyme Detection System of American Hospital Supply Corporation.
The ~eaching test was carr~ed out as follows. The saline circulation text utilized 3/8" x 3/32" PVC tubing of three meters in length, a total saline volume of 1.5 l~ters. and the test was run at a temperature of 37C. The saline solution was continuously circulated through the test circuit and saline samples were removed at predeterm~ned intervals. These samples were analyzed for heparin content and activ~ties as indicated above.
After 4 hours of sallne c~rculation, each filter was removed and dissected. 250mls. of ethyl alcohol was then used to extract any organic coatings on the core of each filter including the control. The alcohol extract was then sub~ected to the UV
spectrophotometric test to determine the amount of heparin complex as well as the biological activity test indicated above. The amounts and activities of heparin complexes remaining on the two sets of filters before and after saline leaching are tabulated ~n Tables 1 and 2. The intermittent activities of the respect~ve saline solutions are outlined in Table 3.
Turning to Tables 1 and 2, it is evident that the Stearylkonium Heparin coating is more stable than the Benzalkonium Heparir, because in excess of 80% of the orig~nal SKH coating composition survives the saline leaching in both sets of tests whereas there is a loss of at least 85% of the BKH coatings. Th~s is confirmed by the Heparin Activity test of the residual coatlngs ~hich indicates that BKH loses a minimum of 75X of its heparin activity over the four hours of saline leaching.
The test date of Tables 1 and 2 are also important because .
_ 15 -2~2~7 medical devlces used for blood flow are generally primed or stored ~n saline solutions.
Consequently desorption character~stlcs in this medium are ~mportant in and of themselves. As one example, blood gas sensor dev~ces used for determin~ng types and amounts of blood gases are generally coated wlth hepar~n complexes and stored ~n saline. It can be apprec~ated from the test data that such devices eoated with benzalkon~um heparin will not have the requisite anti-thrombogenic qual~ty after significant saline storage.
TABLE l-FIRST SET
BEFORE SALINE RECIRCULATION AFTER 4 HRS. OF
SALINE RECIRCULATION
mg BKH HEPARIN mg BKH HEPARIN
or SKH ACTIVITY or SKH ACTIVITY
0.2X BKH 19 1140 0 122 COATED (OX OF (10.7% OF
FILTER ORIGINAL) ORIGINAL) 0.2X SKH 19 875 16.3 750 COATED (85.7X OF (85.7X OF
FILTER ORIGINAL) (ORIGINAL) BEFORE SALINE RECIRCULATION AFTER 4 HRS. OF SALINE
RECIRCULATION
mg BKH HEPARIN mg BKH HEPARIN
or SKH ACTIVITY or SKH ACTIYITY
0.2X BKH 19 1140 2.3 271 COATED (12.1X OF (23.8X OF
FILTER ORIGINAL) ORIGINAL) 0.2X SKH 19 875 16.0 750 COATED (84.2X OF (85.7Z OF
FILTER ORIGINAL) ORIGINAL) Table 3 outlines the t~me ~nterval readings of the hepar~n 2 '1 7 activities of the circulating solutions. There is no detect~on (ND) of biological heparin actlvity dur1ng the SKH test while the BKH demonstrates an accelerated desorpt~on w~thin the f~rst hour and v1rtual deact~vat~on over the four hour period. This data confirms the conclusions reached w~th respect to Tables l and 2.
s TOTAL HEPARIN ACTIVITY DETECTED IN CIRCULATING SALINE
0.2X BKH COATED 0.2X SKH COATED
FILTER FILTER
(AFTER PRIMING) l HOUR 698 ND
3 l/4 HOURS 788 ND
The following demonstrates the non-thrombogenic nature of SKH.
F~brinogen adsorption is a known precursor to thrombogenesis.
Therefore by comparing relative amounts of Fibrinogen bound by different surfaces, pred~ctions can be formulated on the relative thromboginicity of an artif kial blood contact material. This methodology util~zes a radiolabeled Fibrinogen which is dynamically exposed to a surface with a phosphate buffer carrier. Then by determining the radioactiYity of the test samples, a relative amount of bound Fibrinogen can be determined. The Fibrinogen Adsorption Test is outlined by H.V.
.
- 17 - 2 ~6 ~2 47 Roohk et al, Vol. XXIII Tran. Am. Soc. Art. Interm Organs, 1977, pg. 157 herein incorporated by reference. Th~s method can be ut~ ed as an ~ndex to evaluate and screen artific1al blood contact surfaces for blood compatibility.
A medical grade PVC tubing ~s dip coated ~n 0.4X (WT/volume) SKH
~n a mixture of Tr~chloro-trifluro ethane and ethanol, subsequently drled, and ster~l~zed by gamma radlat~on. The tubing sample and a control PVC tub~ng sample ~s then subjected to the F~br~nogen Adsorpt~on Test of Roohk et al and the results set forth 1n Table 4. As can be appreclated there 1s ~ncreasing fibr~nogen adsorpt~on on the control over time and m~nimal Fibr~nogen adsorpt~on on the SKH coated PVC thereby demonstratlng the excellent anti-thrombogenlc nature of the SKH
coatings of the present ~nvention.
PERCENTAGE OF FIBRINOGEN ADSORPTION
TIME CONTROL PVC TUBING SKH COATED PVC
TUBING
0 0.00 0.00 20 30 m~n 0.48 0.22 60 m~n 0.69 0.20 90 m~n 0.74 0.22 In summary, the results of the examples and the data of tables 1-4, ~nd~cate that stearylkon1um/hepar~n (SKH) complex coat~ngs have the follow1ng properties:
1. Superior surface adhesion in that SKH is 10 ff mes less soluble ~n saline than benzalkon~um hepar~n complex and ls more hydrophobic and has h1gher affinity to plast~c surfaces than benzalkon~um hepar~n complex.
- _ 18 ~ ~ 247 2. Nonflammable solvent solubility (e.g. freon TE-35), because of the high loading of detergent thereby rendering the complex virtually non polar.
3. Improved anti-thrombogenic performance to that of BKH.
Example 4 demonstrates the stab~l~ty of the group of trialkylbenzyl ammonium heparin wherein Rl is an alkyl ~roup having from about 14, 15 or 19 to 22 carbons; R2 is an alkyl group having from about 1 to five carbons; and R3 ~s an alkyl group having from about 1 to five carbons. of the invention on artificial surfaces. As stated above, the abillty of the heparin salts of the invention to provide an improved biocompatible surface is dependent upon the capability of the salt to remain on the surface. This capability is demonstrated by the following example.
Six quaternary ammonium salts were used in preparation of the heparin complexes. These complexes were prepared ~n accordance with those procedures described for the preparation of the stearyl d~methyl benzyl ammonium heparin complex in Example 1.
The ammonium salts used ~n the preparation of the heparin complexes were:
Myristyl d~methyl (Rl . C14, and R2 and R3 ~ are Cl) benzyl ammonium chloride;
Eicosane dimethyl (Rl . C20, and R2 and R3 ~ are Cl) benzyl ammonium chloride;
Docosane dimethyl (Rl ~ C22, and R2 and R3 . are Cl) benzyl ammonium chloride;
Stearyl dipentyl (Rl ~ Clg, and R2 and R3 ~ are Cs) benzyl ~mmon~um chloride;
Stearyl dibutyl (Rl . Clg, and R2 and R3 . are C4) benzyl ammonium chlorlde; and ~,.. . .
19- ~42~7 Stearyl methyl butyl (Rl ~ C18, R2 - Cl and R3 , C4) benzyl ammonium chloride.
The blood contacting surfaces of an arterial blood filter were flashed coated by pass~ng a 0.25% weight/volume solution of the prepared quaternary ammon~um heparin complexes dissolved 1n a m~xture of tr~fluorotr~chloroethane and ethanol or toluene through the ~lter. The filter was then air dried. The filter used was an arter~al f~lter known as AF 1040 or 540 sold and manufactured by Baxter Healthcare Corporat~on of Deerfield, Ill~no~s. F~lters were also coated with a 0.25X we~ght/volume solut~on of Benzalkon~um heparin complex ~n ~sopropyl alcohol.
Th~s later complex ~s, as already stated, a commercially available complex. The results of a compar~son of the stability of this later complex with those of the invention demonstrate the unexpected benefits of the ~nvention.
The coated f~lters were subjected to a saline rec~rculation procedure s~m~lar to that descr~bed ~n Example 2. The sal~ne rec~rculation cond~t~ons var~ed by flow~ng the sal~ne through the f~lters at a rate of 4 l~ters/mlnute, under amb~ent temperature for a total of 2 hours.
After tomplet~on of the sal~ne rec~rculat~on the concentration of the hepar~n on the blood contact~ng surfaces was determ~ned by a Factor Xa Inh~b~tion Assay. Th~s assay ~s descr~bed ~n greater deta~l ~n U.S. Pharmacope~a Nat~onal Formulary, 1985 Ed~t~on (21st Rev~s~on of U.S. Pharmacopeia, 16th Ed~t~on Nat~onal Formulary) at page 482 of the Offic~al Monographs under the sub~ect head~ng "Hepar~n Sod~um", wh~ch ~s ~ncorporated ~n ~ts ent~rety here~n. The descr~bed assay procedure requ~res the use of a chromophore substrate. The assays performed ~n th~s Example used a chromogen~c substrate, model number F-2222 manufactured by the Kab~ V~trum A.B., D~agnost~ca Company of Sweden.
2~42~7 The results of this assay are l~sted below ~n Table 5 HEPARIN COMPLEX AMOUNT OF HEPARIN AMOUNT OF HEPARIN
BEFORE SALINE RETAINED AFTER
LEACHINGl SALINE LEACHINGl Myristyl dimethyl 479 499 benzyl hepar~n (lOOX retention) n.2 n.2 Eicosane dimethyl 779 877 benzyl heparin (lOOX retention) n~2 n.2 Docosane dimethyl 800 716 benzyl heparin n.2 (90~ retention) Stearyl dipentyl 238 308 benzyl heparin (100 retention) n~2 n,2 Stearyl d~butyl 363 360 benzyl heparin (lOOZ retention) n.2 n~
Stearyl methyl 527 523 butyl benzyl (lOOX retent~on) hepar~n n.2 n.2 Benzalkonium 951 210 heparin (22X retention) n.2 n.2 1 (Units . As spec1fied ~n the 1ncorporated herein reference for measuring Heparin Activity) (n . # filters tested) In summary, the results of Example 4, as demonstrated by the data in table 5 indicates that alkyl benzyl ammonium/heparin complex coatlngs of this ~nvention are substantially the same as those described ~n the co-pending appl k ation, and exemplified by the above examples 1-4 In particular the results of Example 4 demonstrate that the complexes of the invent~on have superior - 21 - 2~ 2 ~ 7 surface adhesion and are less soluble in saline than Benzalkonium heparin complex. The complexes of the invent;on are also more hydrophobic and have a higher affinity to plastic surfaces than Benzalkonium heparin complexes.
It w111 be understood that the embodiments described herein are merely exemplary and that a person skilled in the art may make many variations and modifications without departing from the splrit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention as defined ln the appended claims.
F~brinogen adsorption is a known precursor to thrombogenesis.
Therefore by comparing relative amounts of Fibrinogen bound by different surfaces, pred~ctions can be formulated on the relative thromboginicity of an artif kial blood contact material. This methodology util~zes a radiolabeled Fibrinogen which is dynamically exposed to a surface with a phosphate buffer carrier. Then by determining the radioactiYity of the test samples, a relative amount of bound Fibrinogen can be determined. The Fibrinogen Adsorption Test is outlined by H.V.
.
- 17 - 2 ~6 ~2 47 Roohk et al, Vol. XXIII Tran. Am. Soc. Art. Interm Organs, 1977, pg. 157 herein incorporated by reference. Th~s method can be ut~ ed as an ~ndex to evaluate and screen artific1al blood contact surfaces for blood compatibility.
A medical grade PVC tubing ~s dip coated ~n 0.4X (WT/volume) SKH
~n a mixture of Tr~chloro-trifluro ethane and ethanol, subsequently drled, and ster~l~zed by gamma radlat~on. The tubing sample and a control PVC tub~ng sample ~s then subjected to the F~br~nogen Adsorpt~on Test of Roohk et al and the results set forth 1n Table 4. As can be appreclated there 1s ~ncreasing fibr~nogen adsorpt~on on the control over time and m~nimal Fibr~nogen adsorpt~on on the SKH coated PVC thereby demonstratlng the excellent anti-thrombogenlc nature of the SKH
coatings of the present ~nvention.
PERCENTAGE OF FIBRINOGEN ADSORPTION
TIME CONTROL PVC TUBING SKH COATED PVC
TUBING
0 0.00 0.00 20 30 m~n 0.48 0.22 60 m~n 0.69 0.20 90 m~n 0.74 0.22 In summary, the results of the examples and the data of tables 1-4, ~nd~cate that stearylkon1um/hepar~n (SKH) complex coat~ngs have the follow1ng properties:
1. Superior surface adhesion in that SKH is 10 ff mes less soluble ~n saline than benzalkon~um hepar~n complex and ls more hydrophobic and has h1gher affinity to plast~c surfaces than benzalkon~um hepar~n complex.
- _ 18 ~ ~ 247 2. Nonflammable solvent solubility (e.g. freon TE-35), because of the high loading of detergent thereby rendering the complex virtually non polar.
3. Improved anti-thrombogenic performance to that of BKH.
Example 4 demonstrates the stab~l~ty of the group of trialkylbenzyl ammonium heparin wherein Rl is an alkyl ~roup having from about 14, 15 or 19 to 22 carbons; R2 is an alkyl group having from about 1 to five carbons; and R3 ~s an alkyl group having from about 1 to five carbons. of the invention on artificial surfaces. As stated above, the abillty of the heparin salts of the invention to provide an improved biocompatible surface is dependent upon the capability of the salt to remain on the surface. This capability is demonstrated by the following example.
Six quaternary ammonium salts were used in preparation of the heparin complexes. These complexes were prepared ~n accordance with those procedures described for the preparation of the stearyl d~methyl benzyl ammonium heparin complex in Example 1.
The ammonium salts used ~n the preparation of the heparin complexes were:
Myristyl d~methyl (Rl . C14, and R2 and R3 ~ are Cl) benzyl ammonium chloride;
Eicosane dimethyl (Rl . C20, and R2 and R3 ~ are Cl) benzyl ammonium chloride;
Docosane dimethyl (Rl ~ C22, and R2 and R3 . are Cl) benzyl ammonium chloride;
Stearyl dipentyl (Rl ~ Clg, and R2 and R3 ~ are Cs) benzyl ~mmon~um chloride;
Stearyl dibutyl (Rl . Clg, and R2 and R3 . are C4) benzyl ammonium chlorlde; and ~,.. . .
19- ~42~7 Stearyl methyl butyl (Rl ~ C18, R2 - Cl and R3 , C4) benzyl ammonium chloride.
The blood contacting surfaces of an arterial blood filter were flashed coated by pass~ng a 0.25% weight/volume solution of the prepared quaternary ammon~um heparin complexes dissolved 1n a m~xture of tr~fluorotr~chloroethane and ethanol or toluene through the ~lter. The filter was then air dried. The filter used was an arter~al f~lter known as AF 1040 or 540 sold and manufactured by Baxter Healthcare Corporat~on of Deerfield, Ill~no~s. F~lters were also coated with a 0.25X we~ght/volume solut~on of Benzalkon~um heparin complex ~n ~sopropyl alcohol.
Th~s later complex ~s, as already stated, a commercially available complex. The results of a compar~son of the stability of this later complex with those of the invention demonstrate the unexpected benefits of the ~nvention.
The coated f~lters were subjected to a saline rec~rculation procedure s~m~lar to that descr~bed ~n Example 2. The sal~ne rec~rculation cond~t~ons var~ed by flow~ng the sal~ne through the f~lters at a rate of 4 l~ters/mlnute, under amb~ent temperature for a total of 2 hours.
After tomplet~on of the sal~ne rec~rculat~on the concentration of the hepar~n on the blood contact~ng surfaces was determ~ned by a Factor Xa Inh~b~tion Assay. Th~s assay ~s descr~bed ~n greater deta~l ~n U.S. Pharmacope~a Nat~onal Formulary, 1985 Ed~t~on (21st Rev~s~on of U.S. Pharmacopeia, 16th Ed~t~on Nat~onal Formulary) at page 482 of the Offic~al Monographs under the sub~ect head~ng "Hepar~n Sod~um", wh~ch ~s ~ncorporated ~n ~ts ent~rety here~n. The descr~bed assay procedure requ~res the use of a chromophore substrate. The assays performed ~n th~s Example used a chromogen~c substrate, model number F-2222 manufactured by the Kab~ V~trum A.B., D~agnost~ca Company of Sweden.
2~42~7 The results of this assay are l~sted below ~n Table 5 HEPARIN COMPLEX AMOUNT OF HEPARIN AMOUNT OF HEPARIN
BEFORE SALINE RETAINED AFTER
LEACHINGl SALINE LEACHINGl Myristyl dimethyl 479 499 benzyl hepar~n (lOOX retention) n.2 n.2 Eicosane dimethyl 779 877 benzyl heparin (lOOX retention) n~2 n.2 Docosane dimethyl 800 716 benzyl heparin n.2 (90~ retention) Stearyl dipentyl 238 308 benzyl heparin (100 retention) n~2 n,2 Stearyl d~butyl 363 360 benzyl heparin (lOOZ retention) n.2 n~
Stearyl methyl 527 523 butyl benzyl (lOOX retent~on) hepar~n n.2 n.2 Benzalkonium 951 210 heparin (22X retention) n.2 n.2 1 (Units . As spec1fied ~n the 1ncorporated herein reference for measuring Heparin Activity) (n . # filters tested) In summary, the results of Example 4, as demonstrated by the data in table 5 indicates that alkyl benzyl ammonium/heparin complex coatlngs of this ~nvention are substantially the same as those described ~n the co-pending appl k ation, and exemplified by the above examples 1-4 In particular the results of Example 4 demonstrate that the complexes of the invent~on have superior - 21 - 2~ 2 ~ 7 surface adhesion and are less soluble in saline than Benzalkonium heparin complex. The complexes of the invent;on are also more hydrophobic and have a higher affinity to plastic surfaces than Benzalkonium heparin complexes.
It w111 be understood that the embodiments described herein are merely exemplary and that a person skilled in the art may make many variations and modifications without departing from the splrit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention as defined ln the appended claims.
Claims (14)
- What is claimed:
l. A blood contacting medical article comprising:
a. a substrate surface; and b. an anti-thrombogenic surface coating of a complex of heparin and at least 50% by weight of a cationic trialkylbenzyl ammonium salt having the following formula:
R1-- N+ --R3 Wherein R1 is an alkyl group having from about 14, 15 or l9 to about 22 carbons;
R2 is an alkyl group hav1ng from about 1 to about five carbons;and R3 is an alkyl group hav1ng from about 1 to about five carbons. - 2. The medical article of Claim 1 wherein the complex is Myristyl dimethyl benzyl ammonium/heparin.
- 3. The medical article of Claim 1 wherein the complex is Eicosane dimethyl benzyl ammonium/heparin.
- 4. The medical article of Claim l wherein the complex is Docosane dimethyl benzyl ammonium/heparin.
- 5. The medical article of Claim l wherein the complex is Stearyl dipentyl benzyl ammonium/heparin.
- 6. The medical article of Claim 1 wherein the complex is Stearyl dibutyl benzyl ammonium/heparin.
- 7. The medical article of Claim 1 wherein the complex is Stearyl methyl butyl benzyl ammonium/heparin.
- 8. The medical article of Claim 1 wherein the substrate surface comprises a polymeric resin.
- 9. The medical article of Claim 1 wherein the organic cationic salt is present in an amount of 60 to 70% by weight of the complex composition.
- 10. A process for rendering the surfaces of blood contacting medical articles non-thrombogenic comprising:
a.providing a medical article; and b.coating the medical article with a complex of heparin and at least 50% by weight of one or more trialkylbenzyl dimethyl ammonium cationic salt of the formula:
R1-- N+ --R3 Wherein R1 is an alkyl group having from about 14, 15 or 19 to about 22 carbons;
R2 is an alkyl group having from about 1 to about five carbons;and R3 is an alkyl group having from about 1 to about five carbons; - 11. The process of Claim 10 wherein the coating step comprises:
a. providing an organic solution of the heparin complex;
b. applying the solution to the surface of a medical article;
and c.drying the medical article to form an integral adhesive coating thereon. - 12. A process for rendering the surfaces of blood contacting medical articles non-thrombogenic comprising:
a providing a medical article; and b treating the medical article with a solution of at least 50% by weight of one or more trialkylbenzyl cationic quaternary ammonium organic salts having the following formula:
R1-- N+ -- R3 Wherein R1 is an alkyl group having from about 14, 15 or 19 to about 22 carbons;
R2 is an alkyl group having from about 1 to about five carbons;
R3 is an alkyl group having from about 1 to about five carbons; and X is a halogen; and c.subsequently treating the medical article with an aqueous solution of heparin salt. - 13. The process of Claim 6 wherein the organic cationic salt consists of an alkyl R1 group of 16 carbon atoms.
- 14. The process of Claim 6 wherein the organic cationic salt consists of an alkyl R group of 18 carbon atoms.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/387,728 US5047020A (en) | 1987-09-14 | 1989-07-31 | Ionic heparin coating |
US387,728 | 1989-07-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2064247A1 true CA2064247A1 (en) | 1991-02-01 |
Family
ID=23531132
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002064247A Abandoned CA2064247A1 (en) | 1989-07-31 | 1990-07-23 | Ionic heparin coating |
Country Status (5)
Country | Link |
---|---|
US (1) | US5047020A (en) |
EP (1) | EP0484393A1 (en) |
JP (1) | JPH05500314A (en) |
CA (1) | CA2064247A1 (en) |
WO (1) | WO1991001767A1 (en) |
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- 1989-07-31 US US07/387,728 patent/US5047020A/en not_active Expired - Lifetime
-
1990
- 1990-07-23 EP EP90911372A patent/EP0484393A1/en not_active Withdrawn
- 1990-07-23 WO PCT/US1990/004134 patent/WO1991001767A1/en not_active Application Discontinuation
- 1990-07-23 JP JP2510615A patent/JPH05500314A/en active Pending
- 1990-07-23 CA CA002064247A patent/CA2064247A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO1991001767A1 (en) | 1991-02-21 |
JPH05500314A (en) | 1993-01-28 |
EP0484393A1 (en) | 1992-05-13 |
US5047020A (en) | 1991-09-10 |
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