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Patent 2218103 Summary

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(12) Patent Application: (11) CA 2218103
(54) English Title: COATING FOR BIOMATERIAL WHICH CAN BE INTRODUCED INTO THE BLOODSTREAM OR INTO THE TISSUE OF THE HUMAN BODY
(54) French Title: REVETEMENT DESTINE A UNE MATIERE BIOLOGIQUE POUVANT ETRE INTRODUITE DANS LE FLUX SANGUIN OU DANS LE TISSU DU CORPS HUMAIN
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61L 33/00 (2006.01)
(72) Inventors :
  • REERS, MARTIN (Germany)
  • STUBER, WERNER (Germany)
  • STEMBERGER, AXEL (Germany)
  • ALT, ECKHARD (Germany)
(73) Owners :
  • HOECHST AKTIENGESELLSCHAFT (Germany)
(71) Applicants :
  • BEHRINGWERKE AKTIENGESELLSCHAFT (Germany)
(74) Agent: BERESKIN & PARR LLP/S.E.N.C.R.L.,S.R.L.
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1996-02-06
(87) Open to Public Inspection: 1996-10-17
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/EP1996/000471
(87) International Publication Number: WO1996/032143
(85) National Entry: 1997-10-10

(30) Application Priority Data:
Application No. Country/Territory Date
195 14 104.0 Germany 1995-04-13

Abstracts

English Abstract

The coating consists of a composition, the components of which are soluble in a solvent, preferably chloroform. In detail, they are a medicament carrier like poly-D, L-lactide, serine protease inhibitors, advantageously thrombin inhibitors and prostaglandines or prostacyclines or derivatives thereof. With such a coating, coated bio-material in the tissue or in the bloodstream are continuously slowly decomposed and the formation of thromboses is prevented.


French Abstract

L'invention concerne un revêtement contenant une composition dont les constituants sont solubles dans un solvant, de préférence dans le chloroforme. Cette composition comprend un excipient de médicament, par exemple poly-D, L-lactide, des inhibiteurs de la sérine protéase, de préférence des inhibiteurs de la thrombine, ainsi que de la prostaglandine ou de la prostacycline ou leurs dérivés. Ce revêtement permet à la matière biologique revêtue de se décomposer lentement dans le tissu ou le flux sanguin et d'empêcher la formation de thromboses.

Claims

Note: Claims are shown in the official language in which they were submitted.


- 6 -
Claims

1. A coating for biomaterial which can be introduced
into the bloodstream or into the tissue of the
human body, such as infusion, cardiac or balloon
catheters, electrodes for heart pacemakers and
defibrillators, suture material, oxygenators,
support constructions for vessels (stents) or the
like, this coating preventing in particular blood
coagulating on the biomaterial due to adhesion of
plasmatic or cellular constituents, and the coating
having a blood- and tissue-compatible medicinal
substance carrier which is dissolved in an
organic solvent, and in which at least one medicament
is incorporated and which, after application
to the biomaterial and evaporation of the solvent,
is permanently biodegraded in the body, wherein an
inhibitor of serine proteases is present in
homogeneously dispersed dissolved form in the
medicinal substance carrier, this inhibitor being
soluble together with the medicinal substance
carrier in the same organic solvent, so that
application to the biomaterial and evaporation of
the solvent result in a homogeneous coating which
is composed of medicinal substance carrier and
inhibitor and has a function comparable to that of
endothelium.

2. A coating as claimed in claim 1, wherein the
inhibitor is a directly acting thrombin inhibitor.

3. A coating as claimed in claim 2, wherein the
thrombin inhibitor suppresses contact activation
of blood coagulation.

4. A coating as claimed in any of the preceding
claims, wherein, to achieve an endothelium-like

- 7 -
action, furthermore a prostaglandin or
prosta-cycline or a corresponding derivative is added
together with the medicinal substance carrier and
the inhibitor to the solvent and is contained in
dissolved form in the medicinal substance carrier.

5. A coating as claimed in any of the preceding
claims, wherein additionally an antithrombin which
can be rapidly released, such as hirudin, is
incorporated into the medicinal substance carrier.

6. A coating as claimed in any of the preceding
claims, wherein a poly-D,L-lactide is used as
medicinal substance carrier.

7. A coating as claimed in any of the preceding
claims, wherein the individual components of the
coating are dissolved in chloroform.

8. A coating as claimed in any of the preceding
claims, wherein the coating forms on the biomaterial
a paint-like adhesive layer with layer
thicknesses of less than 100 micrometers, preferably
less than 50 micrometers or 10 micrometers.

9. A coating as claimed in any of the preceding
claims, wherein a compound of the following structure
is used as soluble antithrombin:

- 8 -




Image




in which R' is a naphthalene ring which is bonded
in the alpha or beta position and is optionally
derivatized with alkyl groups which contain up to
3 carbon atoms, and/or alkoxy groups with in each
case up to 3 carbon atoms, or is a tetralin ring
or indane ring which is bonded in the alpha or
beta position and which is optionally derivatized
with alkyl groups which comprise up to 3 carbon
atoms, and/or else alkoxy groups with in each case
up to 3 carbon atoms, or is a phenyl ring which is
optionally derivatized with alkyl groups which
contain up to 4 carbon atoms, and/or with up to
three groups of the structure O-X in which O is
oxygen and X is hydrogen, methyl, ethyl, n-propyl,
i-propyl or tert-butyl, and/or with a group of the
structure -COOY in which Y is hydrogen, methyl,
ethyl, n-propyl, i-propyl, tert-butyl, i-butyl,
i-pentyl or neo-pentyl, or is a chroman system
which is preferably derivatized with up to 5 alkyl
groups which contain up to 3 carbon atoms, is a
qroup of the structure A-B where A = -(CH2) n- and
n = 1-4 and B is an acid functionality selected
from the group consisting of carboxyl
functionality which can optionally be esterified or be
in an amide form, where the esters contain an
alcohol with up to 17 carbon atoms, sulfonic acid
functionality, a functionality of a phosphorus

- 9 -

acid, a boronic acid functionality and tetrazole
group, or R1 is a group of the structure A-B-C
where A has the above meaning, B is carbonyl or
sulfonyl, and the group C is derived from an
N-bonded alpha, beta, gamma or delta amino acid or
from the group of N-glycosidically linked uronic
acids, and R2 and R3 can be identical or different
and are alkyl groups with up to 4 carbon atoms or
together form a heterocyclic ring which has up to
8 ring members and can be derivatized with a
hydroxyl group or a hydroxyalkyl group with up to
3 carbon atoms, and this hydroxyl group is optionally
in esterified form, where the corresponding
acids are carboxylic acids which contain up to 17
carbon atoms, and in which the carbon atom labeled
with * has the R or S structure, but preferably
the R structure (CRC220).

10. A coating as claimed in claim 9, wherein R' is
4-methoxy-2,3,6-trimethylphenyl, R1 is -CH2-COOX
with X equal to hydrogen and R2 and R3 together are
piperidine.

11. A coating as claimed in any of the preceding
claims, wherein the components of the coating are
present dissolved in a solvent, preferably chloroform,
where the contents of the individual components
per milliliter of the solvent have the
following values:

100 to 300, preferably 150 to 160, milligrams of
medicinal substance carrier;

0.5 to 20% by weight, preferably up to 10% by
weight, of a directly acting antithrombin
(CRC220);

- 10 -

0.3 to 2% by weight, preferably 0.5-1% by weight,
of a prostaglandin derivative or of a
corresponding analog;

0.5 to 10% hirudin.

12. A coating as claimed in claim 10, wherein the mixture
preferably comprises 5% by weight of each
individual substance.

Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 022l8l03 lgg7-lO-lO

WO 96/32143 - 1 - PCT/EP96/00471

Coating for biomaterial which can be introduced into
the bloodstream or into the tissue of the human body

The invention relates to a coating for biomaterial
which can be introduced into the bloodstream or into
the tissue of the human body. This term is used to
designate, for example, infusion catheters, cardiac
catheters, balloon catheters, electrodes, suture mate-
rials for vessel anastomoses, oxygenators, vessel pros-
theses or supports for vessels, called stents, etc.,which remain for a short time or else for a long time
directly in arteries and velns and in body tissue or
come into contact with blood. The hazards for the
patients, for example due to thrombosis formation and
inflammations, are known and have to be considered with
regard to the success of therapy and severity of the
disorder.

EP-A1-0578998 discloses the production of such bio-
material with a covering of a biodegradable material,for example poly-D,L-lactide, with medicaments then
also being incorporated into this biodegradable mate-
rial and, on degradation of the biomaterial in the
implanted state, being gradually released at, prefer-
ably, a constant rate to the patient. Heparin is men-
tioned, for example, as medicament which, incorporated
in dispersed form, then specifically reaches the blood
circulation and speeds up the action of plasmatic
inhibitors such as antithrombin III and heparin
cofactor II as catalyst thereof.

It has furthermore been proposed, in German Patent
Applications P 43 34 272.8 and P 44 35 652.8, to coat
biomaterial with a biodegradable material, with the
coating being very thin with layer thicknesses of less
than 100 micrometers so that only the primary structure
of the biomaterial is covered. If, for example, the

REPT~Cr ~NT SHEET (RULE 26)

CA 02218103 1997-10-10

-- 2

primary structure is a network structure as is the case
with said vessel prostheses or stents, only the indi-
vidual strands of the prosthesis are coated; in no case
is the prosthesis enveloped by a complete casing. It
has emerged with a paint-like coating of this type that
an antithrombogenic effect is achieved merely by the
slow biological microdegradation of the coating mate-
rial. The coating material used in this case comprises
biodegradable synthetic polymers such as polyglycols
and polylactides, and corresponding copolymers or mix-
tures etc., which are dissolved in an organic solvent,
preferably chloroform, which evaporates after applica-
tion to the biomaterial.

It is also proposed in these patent applications to
incorporate medicinal substances into the coating mate-
rial, using as medicinal substances both anticoagulant
and antiinflammatory medicinal substances. The incorpo-
ration of antibiotics is also possible. However, in
contrast to the abovementioned process, these medicinal
substances are intended not to be released to a large
extent into the bloodstream but to act essentially
locally.

It has emerged from experiments that the formation of
thrombi can be prevented to a large extent with a
paint-like coating of this type, where appropriate in
combination with incorporated medicinal substances, so
that the surgical risks which are always a worry other-
wise can be greatly reduced.

The invention is based on the object of indicating acoating material in which the advantageous effects can
be further increased.
This object is achieved according to the invention by
the features of claim 1.

REPT-~M~T SHEET (RULE 26)

- CA 02218103 1997-10-10


According to this, at least one inhibitor of serine
proteases which, just like the medicinal substance car-
rier itself, is it itself able to dissolve in the
organic solvent necessary for preparation of the coat-
ing material, preferably chloroform, is used. Thlsresults in a homogeneous solution, which is applied to
the biomaterial, after which the solvent is subse-
quently evaporated off so that a dissolved homogeneous
mixture is then present as coating on the biomaterial.
The inhibitor is a directly acting thrombin inhibitor,
i.e. acts without the involvement of an endogenous
cofactor or the like.

Another homogeneously dissolved medicament which can
also be present is a prostaglandin or prostacycline, it
additionally being possible to incorporate fast-acting
antithrombogenic agents such as hirudin.

The medicinal substance carrier preferably used is a
poly-D,L-lactide which can be bought as R203 from
Boehringer, Ingelheim; the antithrombin preferably used
is an amidinophenylalanine derivative as claimed in
claims 9 and 10, which is marketed by Behring-Werken AG
under the name CRC220 and is described in detail in
EP-A1-0513543.

The provision of a coating material according to the
present invention was based on the idea that endothe-
lial cells have, as inner linings of blood vessels,
mechanisms which prevent adhesion of cells and plasma
proteins. In this connection, released substances such
as prostaglandins in particular prevent the deposition
of blood plateletsi in addition, substances which coun-
teract thrombin formation are produced on the surface.
It has now emerged from the experiments for the present
invention that so-called self-cleaning surfaces, i.e.
permanently biodegradable materials, in combination
REPT-~M~NT SHEET (RULE 26)

CA 02218103 1997-10-10


with homogeneously dispersed inhibitors of thrombin and
serine proteases, and, where appropriate, prostaglan-
dins or prostacycline derivatives or appropriate
analogs, which are incorporated in dissolved form into
the coating materials, have an endothelium-like action.
The result of this is, while there is only low systemic
availability of the incorporated dissolved medicaments,
by combination with the self-cleaning surface coating
there is prevention of deposition, of activation of
plasma coagulation and of blood platelet aggregation.
The coating material can be referred to, as it were, as
long-term depot, the aim being to keep the release of
the medicaments, in particular of the antithrombins, as
low as possible in order not to result in the known
disadvantages of systemic dosage.

A so-called triple combination consisting of thrombin
inhibitors such as hirudin and said CRC220 with a syn-
thetic prostaglandin derivative (iloprost) has proven
useful on introduction into the blood circulation of
implants or prostheses which are associated with a par-
ticularly high risk of activating coagulation. In this
case, the hirudin acts as thrombin inhibitor which is
rapidly available directly in the surgical phase and by
which the complication of the surgical intervention is
reduced. The inhibitors which are also homogeneously
dispersed in the medicinal substance carrier then bring
about the necessary long-term compatibility.

The coating material according to the invention is pro-
duced by initially preparing a basic solution of a
medicinal substance carrier, preferably poly-D,L-
lactide, and a solvent, preferably chloroform. For the
solution, 50 to 300 milligrams, preferably 150 to
160 milligrams, of a medicinal substance carrier are
dissolved in one milliliter of solvent, preferably
chloroform.

REPT-~C~M~T SHEET (RULE 26)

CA 02218103 1997-10-10


Said antithrombin CRC220 is dissolved in this basic
solution to result in a content of between 0.5 and
about 20% by weight, preferably up to 10% by weight, in
the final mixture based on the medicinal substance
carrier. Furthermore, said prostaglandin derivative
Iloprost is also dissolved in a content between 0.5 and
7% by weight, preferably 1 to 5% by weight, and finally
hirudin is added in a content between 2 and 10% by
weight of the complete solution, preferably about 5% by
weight.

After application of this solution to biomaterial, the
chloroform evaporates so that a homogeneous mixture of
medicinal substance carrier and added medicaments is
then present as coating.




REPT-~M~NT SHEET (RULE 26)

Representative Drawing

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Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1996-02-06
(87) PCT Publication Date 1996-10-17
(85) National Entry 1997-10-10
Dead Application 2001-02-06

Abandonment History

Abandonment Date Reason Reinstatement Date
2000-02-07 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $300.00 1997-10-10
Maintenance Fee - Application - New Act 2 1998-02-06 $100.00 1997-10-10
Registration of a document - section 124 $100.00 1998-02-12
Registration of a document - section 124 $100.00 1998-04-14
Maintenance Fee - Application - New Act 3 1999-02-08 $100.00 1999-02-01
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
HOECHST AKTIENGESELLSCHAFT
Past Owners on Record
ALT, ECKHARD
BEHRINGWERKE AKTIENGESELLSCHAFT
REERS, MARTIN
STEMBERGER, AXEL
STUBER, WERNER
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 1998-02-10 1 38
Description 1997-10-10 5 194
Claims 1997-10-10 5 144
Abstract 1997-10-10 1 53
PCT 1997-10-10 15 445
Assignment 1998-02-12 4 154
PCT 1998-03-18 7 181
Assignment 1998-04-14 2 80
Assignment 1997-10-10 3 135
Correspondence 1997-12-30 1 31