Note: Descriptions are shown in the official language in which they were submitted.
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The invention relates to a paste for haemostasis and temporary bridging
of defects in cases of bone trauma.
Since 1892 the bone wax first described by Horsley and later on modified in
various ways has been used as a means of mechanically stopping the bleeding
of bones. Its original composition was 7 parts of bees wax, 1 part of almond
oil, and 1 part of almond oil, and 1 part of salicyclic acid. The bone wax
most frequently used today consists of 89 parts of bees wax and 11 parts of
isopropyl palmitate. This preparation causes strong foreign-substance
reactions and chronic inflammation reactions. A minor portion only is re-
sorbed within 12 weeks, while at the same time the osteo-anagenesis is
delayed considerably. From the clinical point of view, the possible
formation of pseudo arthroses must be watched.
.
It is the ob~ect of the invention to provide a paste for haemostasis and
temporary bridging of defects in cases of bone trauma, which paste will
safely stop bleeding of the traumatized bone and not impede the osteogenesis
but rather act osteoinductively. The solution of the problem posed is on
the surprising finding that a paste containing 8 prolamin and finely dis-
persed tricalcium phosphate or hydroxyl apatite and a physiologically com-
patible diluent provides optimum haemostasis of the traumatized bone and is
an excellent means for the temporary bridging of defects.
In accordance with the present teachings, a paste is provided for haemo-
stasis and temporary bridging of defects in cases of bone trauma character-
ized in that it contains from 3 to 60% by weight of prolamin and from 5 to
20% of tricalcium phosphate or hydroxyl apatite in finely dispersed form
and a physiologically compatible diluent.
The diluent used preferably is a mixture of an aliphatic alcohol having
from 2 to 5 carbon atoms, particularly ethanol and water at a volumetric
ratio of approximately 1:1 to 10:0.5.
Prolamins are the major protein constituents of cereal grains or meal.
Contrary to all other proteins they can be extracted from flour by the
use of 80% alcohol, yet they are not soluble in anhydrous alcohol or
water. The most important prolamins are zein, gliadin, and hordein.
Zein is preferred in accordance with the invention. The prolamin,
preferably zein is used in
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the paste in a quantity of from about 3 to 60, preferably 5 to
45% by weight.
Contrary to all other proteins, the prolamins are soluble in
diluted alcohols and other solvents, but are not soluble in
water. A mixture of ethanol and water is the preferred solvent
and diluent, the water content ranging between 4 and 50%, depend-
ing on how quickly the prolamin is desired to precipitate. In
ethanol prolamins yield viscous, slightly thixotropic solutions.
The viscosity of the solutions rises as the concentration of
ethanol rises, at the same prolamin content. On the other hand,
the viscosity increases as the concPntration of prolamin in-
creases, at a given concentration of ethanol.
The prolamins are resorbable so pseudoarthrosis cannot develop
which is conceivable as a consequence of bone wax not being re-
sorbed or being resorbed too slowly, e.g. in case of sternum
closure.
The contents of finely dispersed hydroxyl apatite or tricalcium
phosphate promote the regeneration of the bone. The particle
size of the hydroxyl apatite or tricalcium phosphate in general
lies within a range of from approximately 3 to 20 ~m, particu-
larly from approximately 10 to 15 ~m.
The addition of methyl cellulose or carboxymethyl cell~lose in
an amount of from 2 to 10% by weight provides optimum consisten-
cy of the paste, thus yielding a preparation to stop bleeding
of the bone when applied easily as a thin film. Also greater
bone defects ca~ be filled and bridged by applying the paste.
Furthermore, it is possible to repair comminuted fractures.
An antibiotic may be added to the paste for use in prophylaxis
and therapy of infections. Specific examples of useful anti-
biotics are tobramycin, gentamycin, cefotaxim, and mixtures
thereof. The antibiotic is used in suffici~ntly great quantity
to obtain the complete inhibition of growth of the germs to be
killed.
Instead of or in addition to the antibiotic the paste may con-
tain a cytostatic drug. Specific examples of cytostatic sub-
stances are mitomycin, dichlorene, decarbacin, or cisplatin.
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The cytostatic drug is used in an amount sufficient to retard
the growth of the tumor.
Upon addition of fine fibers of resorbable polymer in an amount
of from 1 to 15% by weight the consistency is changed such that
the mass becomes kneadable and moldable so that it may be applied
as a temporary bridging means of defects on bones~
Poly-~lactide-co-glycolide) is an hydrolyzable aliphatic poly-
ester used to produce resorbable surgical suture material. Other
resorbable fibrous polymers which may be incorporated in the
paste according to the invention are polyglycolide, polylactide,
polyoxalate, polysuccinate, polydioxanone, and poly-(esteramides).
The paste may be prepared in a way as disclosed in US patent
4,268,495 from which injectable solutions containing prolamin
are known for embolization and occlusion.
It is easy to press the kneadable paste into bone defects and
mold it so as to adapt it to the desired shape The mass solidi-
fies within a period of from about 30 to 90 minutes.
The paste may be sterilized by gamma radiation, heat, or the
addition of propylene oxide in an amount of from about 0.25 to
0.5% by weight.
The examples will explain the invention.
Example 1
A paste is prepared from the following components:
ethanol 60% V/V 51.7 g
zein 19.4 g
methyl cellulose 5.0 g
tricalcium phosphate (particle
size about 10~m~ 15.0 g
propylene oxide 1.0 g
The zein is introduced into the 60% aqueous ethanol, while care-
fully stirring the mass. Upon complete dissolution (about 12 to
14 hours) pH adjustment is made to approximately 6.5 to 6.8,
with the aid of a physiologically compatible acid or base . The
ethyl cellulose and tricalcium phosphate then are introduced
into the viscous solution obtained. The resulting paste
finally is mixed in the cold with 1 g of propylene oxide and
immediately bottled. An additional 1 to 13 g of fine fibers of
a resorbable polymer, preferably polyglycolide or polylactide
may be incorporated in the paste.
Example 2
In accordance with example 1 a paste is prepared from the com-
ponents below:
ethanol 60% V~V 51.7 g
zein 19.4 g
carboxymethyl cellulose - 5.0 g
hydroxyl apatite (particle
size about 10 ~m) 20.0 g
propylene oxide 1.0 g
Upon longitudinal separation of the sternum of a dop the paste
prepared in accordance with examples 1 and 2 is applied on the
spongy part of the bone to stop the bleeding. The paste is
applicable well and smoothly penetrates into the tiny cavities
of the bone. Diffuse bleeding out of the bone is stopped at once.
Upon obduction after 28 days the partial bridging of the former
defect can be observed. Histological proof of the haemostatic
substance is no longer possible.
Example 3
In accordance with example l a paste is prepared from the
components listed below:
ethanol 60% V/V 51.7 g
zein 19.4 g
methyl cellulose 5.0 g
tricalcium phosphate (particle
size about 10 ~m) 15.0 g
tobramycin 0.7 g
propylene oxide 1.0 g
The paste according to the invention is used to fill an infect-
ed bone cavity. Bone cavities in the ehronically infected bone
marrow are a locus minoris resistentiae for recurring infections.
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Upon cleaning of the bone marrow space up to sound tissue the
paste is used to stop the bleeding which begins. At the same
time the cavity either is filled completely or lined along the
walls, depending on ~he size. The precipitation which initiates
at once stops the paste from flowing out.
In a bacteriological test the bone pieces withdrawn periodically
in the experiment demonstrated distinct inhibition of germ
growth heyond the 28th day, and then at a declining tendency.
Example 4
In accordance with example 1 a paste is prepared from the fol-
lowing components:
ethanol 60~ V/V 51.7 g
zein 19O4 g
carboxymethyl cellulose 5.0 g
hydroxyl apatite (particle
size about 10 ~m) 20.0 g
mitomycin 0.8 g
propylene oxide 1.0 g
The paste according to the invention is used to retard the growth
of malignant tumoxs of the bone or bone marrow which certainly
or perhaps are existing. In context with the cytostatic drug
mitomycin the paste either may be applied in a flowable consi-
stency or in the form of the finest solid particles upon preci-
pitation or evaporation of the solvent.
The flowable form wil~ be chosen if it is desired that the paste
stop heavy bleeding from the area of tumor. Again a bone tumor
may be treated which either is known and considered inoperable
or which has been operated on and requires measures to stop the
bleeding. The prophylactic introduction of a cytostatic drug to
the border of the excision is of great advantage because in
this way it can be guaranteed that the effectiveness of the cy-
tostatic substance will last long enough. The range of the ef-
fectiveness is to be assumed to reach about 1 cm away from the
paste. As a systemic effect here is given under certain condi-
tions only, the release of the cytostatic drug may be very high.
In fact it still amounts to several gamma up to a distance of
