Note: Descriptions are shown in the official language in which they were submitted.
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Collagen Implant Containing Active Ingredient(s) for
Implantation in Bones or Soft Tissues and Process for its
Manufacture
The invention concerns an implant resorbable in the body and
5 containing active ingredients, for implantation in bones and
soft tissues. It especially relates to a collagen implant ln
the form of a sheet containing active ingredient(s), which
optionally c~n be rolled into a rod and which after implan-
tation in the bone or tissue gradually releases the ingre-
10 dient(s).
It is known that collagen can be used as material which isbioresorbable in the body, for filling defects in bones
or in soft tissues.
The use of polyhydroxy acetic acid ester for the manufacture
15 of antibiotic-containing resorbable surgical materials, e.g.
tubes, is known from DE-PS 12 93 396. DE-OS 20 51 ~ des-
cribes a combination of an active ingredient with a polylac-
tide or of a copolymer of lactide and glycolide units.
The above-mentioned materials are synthetic polymers or co-
20 polymers which are decomposed in the body. Such polymers
and copolymers have increasingly gained in significance
because as fully synthetic products they have readilly re-
producible properties and can be prepared in high purity.
;.... .
Materials of the above-mentioned polymers and copolymers are
also used as synthetic resorbable suture materials.
For many years collagen has been known as a resorbable ma-
terial and has been used hemostatically, especially during
5 and a~ter surgical operations or to fill body cavities or to
cover wounds. There have always been certain problems con-
cerning the degree of purity of collagen, since it is ex-
tracted from natural products, and is difficult to produce
in high purity. However, collagen can be made with a high
10 degree of purity, so that complications can be avoided when
using it for surgical purposes.
DE-OS 28 43 963 describes a shaped mass resorbable in the
body, on the basis of collagen. This shaped mass contains,
in addition to denatured collagen, a bioresorbable binding
15 agent as well as optionally an active ingredient. The above-
mentioned polymers and copolymers o-F glvcolic acid or of lac-
tide and glycolide are especially s~itable as the bioresor-
bable binding agents.
It is the object of this invention to provide a bioresorbable
20 implant containing an active ingredient for im~lantation in
bones or soft tissues.
This object has been attained by providing a very ~ure nati-`
ve collagen containing an acti~e ingredient, and having a
factor nitrogen:hydroxyproline~ 3 to 5 in the form of a sheet
25 or rod, the rod beinq made by rolling the collagen sheet.
(By the term "native collagen" is ment collagen which is
purified but not changed in its structure.)
-
The rod-shaped collaaen product has about the same thickness
as a pencil. It can be conveniently made by adding a solu-
30 tion of the active ingredient to a collagen solution; after
.,
drying, e.g. with hot air or by lyo~hilization, the colla-
gen is first prepared in sheet Eorm ~as a so-called fascia).
Also the reverse route, depending on the stability of the
active ingredient, can be undertaken, by first preparing
the collagen fascia and then charginy it with the active
ingredient. This can be done e.g. by spraying an aqueous so-
lution of an active ingredient, e.g. an antibiotic in the
iorm of a salt on the collagen sheet and allowing it
to dry there. Equally it is possible to apply the antibio-
tic or another pharmacologically e~fective compound, bypainting, rolling, dipping or sprinkling with an active in-
gredient in powder form or in a similar manner. The so ob-
tained collagen sheet charged with the acti~e ingredient
can then be rolled into a rod-shaped product of about pencil
thickness. In this form it can be cut into anv desired
length depending on the desired dose and can be packed to
remain sterile until used.
Especially suitable active ingredients in combination with
collagen are aminoglycoside antibiotics, such as gentamycin. In
salt form, e.g. as sulfate, gentamycin is water-soluble and can
be added to the collagen in a wide ran~e from about 1 to about
100 mg/cm2 fascia or it can ~e sprayed on. The collagen sheet
(collagen fascia) containing the gentamycin can then be rolled
and dried and thereafter it maintains its rod-shape.
Other active ingredients such as sulfonamides, antise~tics,
or corticosteroids can be added instead of or in addition
to the antibiotic.
The collagen used has a purity expressed by the factor nit-
rogen:hydroxyproline ~ 3 to 5. Such a collagen can be pre-
pared in the manner described in the example.
Using the rod-sha~ed collagen charaed with an active in-
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gredient of the invention is of special a~vantaye in -tha-t
the active lngredlent adheres very well to the collagen
and optionally can even be bonded to it. To the extent that
the collagen decomposes over a period of time, the active
ingredient is released~ so tha-t there is a sustained re-
lease A further advantage is that the carrier
matrix collagen serves as a guide for proliferating con-
nective tissue cells and thus promotes the healing of the
wound in a known manner.
~xample
The following highly pure native collagen is prepared as
follows:
Fresh beef tendons freed from all pigment layers and res-
idues of muscle were homogenised and an amount correspon-
ding to 100 g dry weight was extracted with 3 liters 0.05 Mcitrate buffer (pH 3.7) for 24 hours and then dialysed~for
12 hours against 1% acetic acid. Ihe tissue, suspended in
3 liters 1% acetic acid, was incubated with constant stir-
ring for 48 hours at 15C with pepsin in a ratio of collagen
to pepsin of 50 : 1.
The preparation was diluted with 1% acetic acid to 5 liters
and then freed from undissolved tendon fragments by centri-
fugation.
The viscous collagen solution was diaIysed against alkalised
tap water (p~ 8.0) and wasthen vigorously centrifuged. The
residue was again dissolved in 5 liters 1% acetic acid and
dialysed. This process was repeated until the factor nitro-
gen:hydroxv~roline was ~ 3. After the last dialysis a 1.5%
collagen solution in 0.05% acetic acid was prepared.
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Preparation of the Collagen Implant containing Active In-
gredient
10 ml of the 1.5~ collagen solution obtained as above are
placed in a dish of 10 x 10 cm. 100 ma gentamycin tin the
5 form of its sulfate) were added thereto. The solution was
then lyophilized in the dish to yield a sponge-like mass
having the shape of the dish. This sponge was then pressed
into a fascia or sheet and optionally rolled into a rod-
shaped product of pencil thickness.
10 The gentamycin-containing implant ohtained in this way was
sterile-packed and sterilised with ethylene oxide in known
manner.
Use
If the above-mentioned collagen implant containing 100 mg
15 c,tentamycin is introduced into the tibia, it is completely
resorbed there within 3 weeks. During this time the genta-
mvcin is released.
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