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
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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.
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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
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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.
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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.
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