U.S. patent application number 13/438371 was filed with the patent office on 2012-10-11 for malleable, biodegradable hemostatic agent.
This patent application is currently assigned to HERAEUS MEDICAL GMBH. Invention is credited to Sebastian VOGT.
Application Number | 20120258159 13/438371 |
Document ID | / |
Family ID | 45887872 |
Filed Date | 2012-10-11 |
United States Patent
Application |
20120258159 |
Kind Code |
A1 |
VOGT; Sebastian |
October 11, 2012 |
MALLEABLE, BIODEGRADABLE HEMOSTATIC AGENT
Abstract
A malleable, biodegradable hemostatic agent is provided that can
be used for mechanical sealing of bleeding bone tissue, as well as
a method for forming a malleable, biodegradable hemostatic agent of
this type, and a medical implant having a coating that includes a
malleable, biodegradable hemostatic agent of this type. The
malleable, biodegradable hemostatic agent contains (a) at least one
saturated glycerol-1,2,3-tri-fatty acid ester having a melting
temperature above 37.degree. C., (b) at least one filling agent
present in particulate form, at least in part, and having a melting
temperature above 37.degree. C., and (c) at least one compound
having a melting temperature not above 37.degree. C. and a
solubility at a temperature of 25.degree. C. of less than 50 grams
per liter of water.
Inventors: |
VOGT; Sebastian; (Erfurt,
DE) |
Assignee: |
HERAEUS MEDICAL GMBH
Wehrheim
DE
|
Family ID: |
45887872 |
Appl. No.: |
13/438371 |
Filed: |
April 3, 2012 |
Current U.S.
Class: |
424/422 ;
514/547 |
Current CPC
Class: |
A61L 24/046 20130101;
A61L 27/28 20130101; A61L 2300/45 20130101; A61P 41/00 20180101;
A61L 2400/04 20130101; A61L 2300/404 20130101; A61L 24/0015
20130101; A61P 43/00 20180101; A61P 7/04 20180101; A61L 2300/418
20130101; A61L 2300/406 20130101; A61L 2430/02 20130101; A61L
24/0042 20130101; A61L 2300/606 20130101 |
Class at
Publication: |
424/422 ;
514/547 |
International
Class: |
A61K 31/23 20060101
A61K031/23; A61P 7/04 20060101 A61P007/04; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 6, 2011 |
DE |
10 2011 016 277.1 |
Claims
1. A malleable, biodegradable hemostatic agent containing the
following components: (a) at least one saturated
glycerol-1,2,3-tri-fatty acid ester having a melting temperature
above 37.degree. C.; (b) at least one filling agent at least
partially present in particulate form and having a melting
temperature above 37.degree. C.; and (c) at least one compound
having a melting temperature not above 37.degree. C. and a
solubility at a temperature of 25.degree. C. of less than 50 grams
per liter of water.
2. The malleable, biodegradable hemostatic agent according to claim
1, wherein the hemostatic agent has a pH in water at a temperature
of 25.degree. C. in a range of 5.0-9.0.
3. The malleable, biodegradable hemostatic agent according to claim
1, wherein the hemostatic agent has a pH in water at a temperature
of 25.degree. C. in a range of 5.5-8.5.
4. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (b) has a solubility at a temperature of
25.degree. C. of less than 50 grams per liter of component (c).
5. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (a) is selected from the group consisting of
saturated glycerol-1,2,3-tri-fatty acid esters comprising at least
one fatty acid residue of 12-28 carbon atoms.
6. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (a) is selected from the group consisting of
saturated glycerol-1,2,3-tri-fatty acid esters comprising at least
one fatty acid residue of 14-24 carbon atoms.
7. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (a) is selected from the group consisting of
glycerol-1,2,3-tribehenic acid ester, glycerol-1,2,3-tristearic
acid ester, and glycerol-1,2,3-tripalmitic acid ester.
8. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (b) has a solubility at a temperature of
25.degree. C. of at least 100 grams per liter of water.
9. The malleable, biodegradable hemostatic agent according to claim
1, wherein component (b) is selected from the group consisting of
polymers of at least one alkylene oxide, copolymers of at least one
alkylene oxide, and at lest one calcium compound.
10. The malleable, biodegradable hemostatic agent according to
claim 9, wherein component (b) is selected from the group
consisting of poloxamers, polyethylene glycols, and poly(propylene
glycol-co-ethylene glycol).
11. The malleable, biodegradable hemostatic agent according to
claim 9, wherein the calcium compound is selected from the group
consisting of calcium carbonate, dolomite, .alpha.-tricalcium
carbonate, .beta.-tricalcium carbonate, hydroxylapatite, carbonate
apatite, octacalcium phosphate, calcium phosphate made amorphous,
calcium sulfate dihydrate, and calcium sulfate hemihydrate.
12. The malleable, biodegradable hemostatic agent according to
claim 1, wherein component (c) is a saturated fatty acid ester.
13. The malleable, biodegradable hemostatic agent according to
claim 12, wherein the saturated fatty acid ester is selected from
the group consisting of (i) esters of polyols and at least one
fatty acid, (ii) alkyl fatty acid esters, and (iii) esters of
polyethers and fatty acids.
14. The malleable, biodegradable hemostatic agent according to
claim 13, wherein the saturated fatty acid ester is selected from
the group consisting of glycerol-1,2,3-trioctylester, mixed esters
of glycerol and caprylic acid and lauric acid,
propane-1,2-diol-di-fatty acid esters, and fatty acid esters of
1,3-dihydroxy-2,2-di(hydroxymethyl)propane, lauric acid ethylester,
myristic acid methylester, myristic acid ethylester, myristic acid
isopropylester, palmitic acid methylester, palmitic acid
ethylester, palmitic acid isopropylester, and ethylene glycol fatty
acid esters.
15. The malleable, biodegradable hemostatic agent according to
claim 1, containing 3-50% by weight of the at least one component
(a), 10-80% by weight of the at least one component (b), and 10-50%
by weight of the at least one component (c), all % by weight being
relative to the total weight of the hemostatic agent.
16. The malleable, biodegradable hemostatic agent according to
claim 1, further comprising at least one fibrinolysis inhibitor
selected from the group of .epsilon.-aminocarbonic acids.
17. The malleable, biodegradable hemostatic agent according to
claim 1, further comprising at least one substance selected from
the group consisting of antibiotics and antiseptic agents.
18. A method for forming a malleable, biodegradable hemostatic
agent, the method comprising the steps of: (a) providing a
malleable, biodegradable hemostatic agent according to claim 1; (b)
heating the malleable, biodegradable hemostatic agent to a
temperature in a range of 35-40.degree. C.; and (c) forming the
heated malleable, biodegradable hemostatic agent.
19. The method according to claim 18, wherein at least one of the
heating and the forming is effected by a hand of a user of the
malleable, biodegradable hemostatic agent.
20. A medical implant having a coating comprising the malleable,
biodegradable hemostatic agent according to claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] The invention relates to a malleable, biodegradable
hemostatic agent that can be used for mechanical sealing of
bleeding bone tissue, a method for forming a malleable,
biodegradable hemostatic agent of this type, and a medical implant
having a coating that comprises a malleable, biodegradable
hemostatic agent of this type.
[0002] Hemostasis is attained during surgeries by different
procedures depending on the anatomical situation, e.g.
electrocoagulation (cauterization) of the blood vessels. In a
number of surgeries in the region of the skull and, predominantly,
at the sternum, bone wax is used to seal the capillary vessels and
thus to achieve hemostasis, because of the strong bleeding that
occurs in these locations due to the anatomical situation. In the
process, the bone wax is first kneaded to be soft by the surgeon
and then pressed directly onto and/or into the bleeding bone areas.
This blocks the flow of blood, which causes hematomas to arise and
the supply vessels to ultimately become closed by fibrin.
[0003] Bone wax has been known since the 19th century and generally
contains bleached bees wax and a plasticizer. Substances including
almond oil, Vaseline, palmitic acid, isopropyl ester, and myristic
acid isopropyl ester, can be used as plasticizer. Conventional bone
waxes are viscous masses and relatively difficult to knead at room
temperature. The plasticizer contained in the bees wax serves to
soften the wax and make it malleable while the bone wax is being
kneaded owing to the warmth of the hand. Bone waxes based on bees
wax are considered to be non-degradable in the human body. Frequent
components of bees wax include esters of myristic acid and higher
alcohols, e.g. myristic acid myricyl ester. Presumably, the human
body has no suitable enzymes for degradation of the very
hydrophobic esters in a reasonable amount of time. The bone waxes
that are currently commercially available have a very good
hemostatic effect, but lead not infrequently to damage in the human
body. See: S. E. Katz, J. Rotmann, "Adverse effects of bone wax in
surgery of the orbit," Ophthal. Plast. Reconstr., 12(2):121-126
(1996); M. Lavigne et al., "Bone-wax granuloma after femoral neck
osteoplasty," Can. J. Surg., 51(3):E58-60 (2008); R. T. Allison,
"Foreign body reactions and an associated histological artifact due
to bone wax," Br. J. Biomed. Sci., 51(1):14-17 (1994); O. Eser et
al., "Bone wax as a cause of foreign body reaction after lumbar
disc surgery: A case report" Adv. Ther., 24(3):594-7 (2007). The
very good adhesive effect on moist and also fatty bone tissue can
be seen as the main advantage of conventional bone waxes.
[0004] A number of alternatives to conventional bone wax are known
according to the prior art. European Patent Application Publication
EP 0 109 310 A2, for example, discloses a wax-like mass that is
based on calcium salts of fatty acids and oligomers of
hydroxycarbonic acids.
[0005] From U.S. Pat. No. 4,595,713, German published patent
application DE 32 29 540 A1, DE Utility Model 1 985 889, and
European Patent Application Publication EP 1 142 597 A1 are known
wax-like compositions that contain oligoesters of hydroxycarbonic
acids, for example lactic acid and 6-hydroxycarbonic acid. It has
been evident that acidic degradation products, which adversely
affect the bone tissue due to local lowering of the pH value, are
generated during hydrolytic degradation upon use of these wax-like
compositions.
[0006] Compositions based on polyethers are a promising development
(see U.S. Patent Application Publication Nos. US 2009/0286886 and
US 2011/0002974). For example, poly(propylene glycol-co-ethylene
glycols) can be used as polyethers. These compositions are
kneadable and spreadable when exposed to the warmth of a hand.
However, the good solubility of the polyethers in aqueous media
must be seen as a disadvantage. This leads to adhesion of the
compositions being more difficult in the presence of strongly
bleeding bone tissue due to beginning dissolution of the wax-like
composition. This may possibly lead to secondary bleeding which in
turn causes the seal to begin to be dissolved or be fully
dissolved. However, it is a particular advantage of the mixtures
that they possess no barrier function for bone healing whatsoever
and are completely eliminated through the renal pathway, see A.
Suwan et al., "Controversial role of two different local hemostatic
agents on bone healing," J. Am. Sci., 6(12):15-163 (2010).
[0007] Accordingly, there still is a need for a malleable,
biodegradable hemostatic agent that is not associated with the
disadvantages described above. The hemostatic agent should be a
mass, which is kneadable and malleable at body temperature, similar
to the bone wax that is commercially available thus far. The
viscosity of the hemostatic agent should be high enough for the
mass to withstand the pressure of bleeding. Furthermore, the
hemostatic agent should have sufficient cohesion, such that it does
not disintegrate or dissolve within few minutes upon contact with
blood or other aqueous media. Moreover, the hemostatic agent should
not release any substantial quantities of acidic or alkaline
components, in order to not damage the bone tissue by a
non-physiological pH. Moreover, the material should be
biodegradable or it should be subject to renal elimination, such
that there is no permanent barrier effect of the material that
might impair the healing process of the bone tissue. In addition,
the mass should not stick to rubber gloves when it is being kneaded
or applied.
BRIEF SUMMARY OF THE INVENTION
[0008] Therefore, according to the invention, an object is to
provide an advantageous malleable, biodegradable hemostatic agent
that can be used for mechanical sealing of bleeding bone tissue.
Another object according to the invention is to provide a method
for forming a malleable, biodegradable hemostatic agent of this
type. Another object of the invention is to provide a medical
implant having a coating that comprises a malleable, biodegradable
hemostatic agent of this type.
[0009] Accordingly, the invention provides a malleable,
biodegradable hemostatic agent that comprises (a) at least one
saturated glycerol-1,2,3-tri-fatty acid ester having a melting
temperature above 37.degree. C., (b) at least one filling agent
present in particulate form, at least in part, and having a melting
temperature above 37.degree. C., and (c) at least one compound
having a melting temperature not above 37.degree. C. and a
solubility at a temperature of 25.degree. C. of less than 50 grams
per liter of water.
[0010] The invention also provides a method for forming a
malleable, biodegradable hemostatic agent of this type, comprising
the steps: (a) providing a malleable, biodegradable hemostatic
agent according to the above description, (b) heating the
malleable, biodegradable hemostatic agent to a temperature in the
range of 35-40.degree. C., and (c) forming the heated malleable,
biodegradable hemostatic agent.
[0011] Moreover, the invention provides a medical implant having a
coating that comprises a malleable, biodegradable hemostatic agent
of this type.
[0012] The invention is based on the surprising finding that
interaction of components (a), (b), and (c) allows a mixture to be
provided that acts effectively as a hemostatic agent and can be
used to seal bleeding bone tissue. It is particularly surprising in
this context that the hemostatic agent according to the invention
based on components (a) by (c) is present as a wax-like, kneadable
mass that adheres both to dry and wet surfaces. The viscosity and
mechanical stability of the mixture are surprisingly sufficiently
high to allow it to be used to arrest bleeding as an effective
hemostatic agent and to withstand the bleeding pressures that occur
in the case of injury. Although the mixture is biodegradable, it
surprisingly has sufficient mechanical stability not to
disintegrate upon contact with blood.
[0013] Without wishing to be limited by theoretical considerations,
the advantageous properties appear to be based on the formation of
a stable matrix in which the filling agents, which are present in
particulate form, are bonded to each other by the at least one
saturated glycerol-1,2,3-tri-fatty acid ester having a melting
temperature above 37.degree. C. The additional use of at least one
compound having a melting temperature not above 37.degree. C. and a
solubility at a temperature of 25.degree. C. of less than 50 grams
per liter of water ensures that the mixture formed as such is
malleable. Surprisingly, this does not impair the mechanical
stability of the hemostatic agent thus generated. In this context,
it is particularly surprising that the compound having a melting
temperature not above 37.degree. C. and a solubility at a
temperature of 25.degree. C. of less than 50 grams per liter of
water, does not exit or is not released from the hemostatic agent,
but rather remains firmly enclosed in the system that presumably is
based on the formation of a matrix.
DETAILED DESCRIPTION OF THE INVENTION
[0014] According to the invention, a hemostatic agent is provided.
According to the invention, a hemostatic agent shall be understood
to be compositions having hemostatic properties.
[0015] The hemostatic agent according to the invention is malleable
or plastically workable. Herein, malleability shall be understood
to be the property of the hemostatic agent to change shape
irreversibly when exposed to a force and to maintain the shape
after being exposed to a force.
[0016] Furthermore, the hemostatic agent according to the invention
is biodegradable. Herein, substances shall be called biodegradable
if they can be degraded by the human body.
[0017] The hemostatic agent of the present invention preferably has
a pH in water in the range of 5.0 to 9.0, more preferably a pH in
the range of 5.5 to 8.5, even more preferably a pH in the range of
6.0 to 8.0, and particularly preferably a pH in the range of 6.5 to
7.5, at room temperature of 25.degree. C.
[0018] According to a preferred embodiment, the hemostatic agent
according to the invention contains no oligoesters of
hydroxycarbonic acids and in particular no oligoesters of lactic
acid or 6-hydroxycaproic acid.
[0019] The biodegradable hemostatic agent according to the
invention contains, as component (a), at least one saturated
glycerol-1,2,3-tri-fatty acid ester having a melting temperature
above 37.degree. C. According to general usage, saturated
glycerol-1,2,3-tri-fatty acid ester shall be understood to be a
glycerol ester having three fatty acid residues which each have no
carbon-carbon multiple bonds.
[0020] The melting temperature of the at least one saturated
glycerol-1,2,3-tri-fatty acid ester used as component (a) is above
37.degree. C., preferably above 40.degree. C., more preferably
above 42.degree. C., and even more preferably above 45.degree.
C.
[0021] In the scope of the entire present invention, melting
temperature shall be understood to be the temperature at which the
respective substance transitions from the solid to the liquid state
of aggregation. If the transition of a substance from the solid to
the liquid state of aggregation does not occur at a certain
temperature, but rather in a melting range, the scope of the
invention has the melting temperature understood to be the lower of
the two limit temperatures of the melting range.
[0022] A melting temperature being in the specified range ensures
that the saturated glycerol-1,2,3-tri-fatty acid ester does not
melt and the hemostatic agent is not softened at body temperature
of 37.degree. C.
[0023] The at least one component (a) is preferably selected from
the group consisting of saturated glycerol-1,2,3-tri-fatty acid
esters that comprise at least one fatty acid residue of 12-28
carbon atoms, more preferably of 14-24 carbon atoms, and even more
preferably of 12-22 carbon atoms. According to a particularly
preferred embodiment, component (a) is preferably selected from the
group consisting of saturated glycerol-1,2,3-tri-fatty acid esters
that have three fatty acid residues of 12-28 carbon atoms,
preferably of 14-24 carbon atoms, and even more preferably of 12-22
carbon atoms. The fatty acid residues can be branched, but are
preferably non-branched. Moreover, the fatty acid residues can be
substituted, optionally. However, the fatty acid residues
preferably are non-substituted. The fatty acid residues are
preferably selected from the group consisting of fatty acid
residues of lauric acid, myristic acid, palmitic acid, margaric
acid, stearic acid, arachic acid, and behenic acid.
[0024] The esters used as component (a) can have identical
residues. On the other hand, component (a) can just as well be a
mixed ester. Herein, mixed esters shall be understood to be esters
that comprise at least two different fatty acid residues. In
particular, three different fatty acid residues can be present in
the mixed esters.
[0025] According to a preferred embodiment, component (a) is
selected from the group consisting of glycerol-1,2,3-behenic acid
ester, glycerol-1,2,3-tristearic acid ester, and
glycerol-1,2,3-tripalmitic acid ester.
[0026] Component (a) appears to work as a matrix forming substance
in the hemostatic agent according to the invention. In this
context, it appears to assume the role of a binding agent that
provides for extraordinarily high mechanical stability of the
hemostatic agent through strong cohesion to the remaining
components, in particular to the filling agent that is present as
component (b).
[0027] The at least one component (b) is at least one filling
agent, which is at least in partly present in particulate form and
has a melting temperature above 37.degree. C. The melting
temperature of the filling agent used as component (b) preferably
is above 40.degree. C., more preferably is above 42.degree. C., and
even more preferably is above 45.degree. C. This ensures that the
filling agent does not melt and that the hemostatic agent is not
softened at body temperature of 37.degree. C.
[0028] Preferably, the filling agent used as component (b) is
hydrophilic. According to a preferred embodiment, the filling agent
has a solubility at a temperature of 25.degree. C. of at last 70
grams per liter of water, more preferably a solubility of at least
100 grams per liter of water, and even more preferably a solubility
of at least 130 grams per liter of water.
[0029] The filling agent is at least in partly present in
particulate form. Preferably at least 30 percent, more preferably
at least 50 percent, even more preferably at least 70 percent,
particularly preferably at least 90 percent, even more particularly
preferably at least 95 percent, and in particular at least 99
percent of the filling agent are present in particulate form.
[0030] The particles of the filling agent that are present may
differ in shape. For example, the particles of the filling agent
can be spherical, cubic or irregular in shape. The particles of the
filling agent preferably have a mean particle diameter in the range
of 50 nm to 500 .mu.m, more preferably in the range of 100 nm to
100 .mu.m, and even more preferably in the range of 500 nm to 100
.mu.m. Herein, the mean particle diameter shall be understood to
mean that at least 50% of the particles have the specified particle
diameter.
[0031] According to a preferred embodiment, component (b) is a
hydrophilic filling agent. Filling agents with a pH value in the
range of 6-8 in the presence of water have proven to be
particularly advantageous.
[0032] Component (b) is preferably selected from the group
consisting of polyethers and calcium compounds.
[0033] According to an embodiment of the invention, the polyether
that is suitable as component (b) is selected from the group
consisting of polymers of at least ethylene oxide, polymers of at
least propylene oxide, copolymers of at least ethylene oxide,
copolymers of at least propylene oxide, and copolymers of at least
ethylene oxide and propylene oxide. The copolymers of ethylene
oxide and propylene oxide can just as well be block copolymers, in
particular poloxamers.
[0034] In this context, the use of polyalkylethers, for example
poloxamers, polyethylene glycols or poly(propylene
glycol-co-ethylene glycol) has proven to be particularly
advantageous.
[0035] According to another preferred embodiment, the polyether
used as component (b) is selected from the group consisting of
polyethylene glycol 35,000, polyethylene oxide 100,000,
polyethylene oxide 300,000, polyethylene oxide 1,000,000, and
poly(propylene glycol-co-ethylene glycol) having a polyoxyethylene
content in the range of 50-80% by weight.
[0036] Moreover, it can be preferred to use a hydrophilic filling
agent having a softening temperature above 45.degree. C. as
component (b). It has been evident that hydrophilic filling agents
having a softening point of 45.degree. C. cause the hemostatic
agent according to the invention to show surprisingly high
mechanical stability.
[0037] According to another preferred embodiment, component (b) can
be a calcium compound. The calcium compound can be, for example, a
calcium salt.
[0038] According to the invention, a calcium salt shall be
understood to mean a salt that contains at least calcium ions as
the cationic component. Further cationic components can be present
in the salt aside from the calcium ions. The further cationic
components can be, for example, cations of elements of the first or
second main group of the Periodic Table of elements, in particular
of sodium, magnesium or strontium.
[0039] It has proven to be particularly advantageous that the
calcium compound used as component (b) is the salt of at least one
inorganic acid. The calcium compound may also contain further
anionic components aside from anions derived from an inorganic
acid. The further anionic components can be, for example,
halogenide anions or hydroxide anions. Preferably, the salt of at
least one inorganic acid is selected from the group consisting of
calcium salts of carbonic acid, phosphoric acids, and sulphuric
acid. Accordingly, the calcium salt can be, for example, calcium
carbonate, dolomite, .alpha.-tricalcium carbonate,
.beta.-tricalcium carbonate, hydroxylapatite, carbonate apatite,
octacalciumphosphate, calcium phosphate made amorphous,
.beta.-tricalcium sulfate, calcium sulfate dihydrate, and calcium
sulfate hemihydrate. The calcium salts are very biocompatible and
are degraded by the action of osteoclasts or also by simple
dissolution.
[0040] The use of calcium sulfate hemihydrate has proven to be
particularly advantageous. A hemostatic agent according to the
invention that contains calcium sulfate hemihydrate as component
(b) can surprisingly harden independently by the action of water or
aqueous liquids, such as blood, without the extraordinarily high
viscosity and mechanical stability of the hemostatic agent being
lost.
[0041] It has been evident that component (b) ensures strong
cohesion to the remaining components in the hemostatic agent
according to the invention, in particular to the saturated
glycerol-1,2,3-tri-fatty acid ester having a melting temperature
above 37.degree. C. used as component (a). Surprisingly, component
(b) appears to act also as volumizer. Accordingly, it has been
evident that component (b) can become dissolved from the hemostatic
agent according to the invention after prolonged exposure to water
or aqueous liquids, for example blood, though without the
mechanical stability of the hemostatic agent being impaired.
Surprisingly, the dissolution creates hollow spaces and then a pore
system in the hemostatic agent, which allows, for example, bone
tissue to penetrate into the hemostatic agent thus allowing the
healing process to be accelerated substantially as compared to
hemostatic agents with a barrier effect.
[0042] The hemostatic agent of the present invention contains as
component (c) at least one compound having a melting temperature
not above 37.degree. C. and a solubility at a temperature of
25.degree. C. of less than 50 grams per liter of water.
[0043] According to a preferred embodiment, the compound contained
in the hemostatic agent as component (c) has a melting temperature
not above 36.degree. C., more preferably a melting temperature not
above 35.degree. C., even more preferably a melting temperature not
above 34.degree. C., particularly preferably a melting temperature
not above 32.degree. C., and even more particularly preferably a
melting temperature not above 30.degree. C.
[0044] According to another preferred embodiment, the solubility of
component (c) at a temperature of 25.degree. C. is less than 40
grams per liter of water, more preferably is less than 30 grams per
liter of water, even more preferably is less than 25 grams per
liter of water, particularly preferably is less than 15 grams per
liter of water, even more particularly preferably is less than 10
grams per liter of water, and in particular is less than 5 grams
per liter of water.
[0045] Component (c) can be, for example, a saturated fatty acid
ester. According to general usage, a saturated fatty acid ester is
understood to be an ester compound having one or more fatty acid
residues, wherein the fatty acid residues each are free of
carbon-carbon multiple bonds.
[0046] The fatty acid residues of the saturated fatty acid esters
used as component (c) preferably have 8-28 carbon atoms, more
preferably 8-22 carbon atoms, and even more preferably 8-18 carbon
atoms. The fatty acid residues can be branched, but preferably are
non-branched. Moreover, the fatty acid residues can have
substituents, but preferably are non-substituted. Conceivable fatty
acid residues are, for example, caprylic acid residues, pelargonic
acid residues, capric acid residues, lauric acid residues, myristic
acid residues, palmitic acid residues, margaric acid residues,
stearic acid residues, arachic acid residues, and behenic acid
residues.
[0047] According to a preferred embodiment, the saturated fatty
acid ester is selected from the group consisting of (i) esters of
polyols and at least one fatty acid, (ii) alkyl fatty acid esters,
and (iii) esters of polyethers and fatty acids.
[0048] According to an embodiment of the invention, the saturated
fatty acid ester is an ester of a polyol and at least one fatty
acid. This can be, for example, the ester of a polyol having a
chain length of 2-4 carbon atoms and preferably the ester of a
polyol having a chain length of 3 carbon atoms. The polyol can be
substituted or non-substituted. Esters of glycerol,
1,2-propanediol, and 1,3-propanediol have proven to be particularly
preferred. Preferred esters of polyols and at least one fatty acid
are selected from the group consisting of glycerol monoesters,
glycerol diesters, glycerol triesters, 1,2-propanediol monoesters,
1,2-propanediol diesters, 1,3-propanediol monoesters, and
1,3-propanediol diesters. The fatty acid residues of the esters of
polyols and at least one fatty acid can be identical. However, the
esters can just as well be mixed esters of polyols and more than
one fatty acid. Examples of esters of polyols and at least one
fatty acid to be mentioned include glycerol-1,2,3-trioctylester,
mixed esters of glycerol and caprylic acid and lauric acid,
propane-1,2-diol-difatty acid esters, and fatty acid esters of
1,3-dihydroxy-2,2-di(hydroxymethyl)propane.
[0049] According to an alternative embodiment, the saturated fatty
acid ester can just as well be an alkyl fatty acid ester. The alkyl
residue of the alkyl fatty acid esters preferably has a chain
length of 1-8 carbon atoms, more preferably a chain length of 1-6
carbon atoms, even more preferably a chain length of 1-4 carbon
atoms, and particularly preferably a chain length of 1-3 carbon
atoms. The alkyl residue of the alkyl fatty acid esters can be
branched or non-branched. Moreover, the alkyl residue of the alkyl
fatty acid esters can be substituted, optionally. Preferably, the
alkyl fatty acid ester is selected from the group consisting of
methyl fatty acid esters, ethyl fatty acid esters, propyl fatty
acid esters, and isopropyl fatty acid esters. Preferably, the alkyl
fatty acid esters are selected from the group consisting of lauric
acid ethylester, myristic acid methylester, myristic acid
ethylester, myristic acid isopropylester, palmitic acid
methylester, palmitic acid ethylester, and palmitic acid
isopropylester.
[0050] According to another alternative embodiment, the saturated
fatty acid ester used as component (c) is the ester of a polyether
and a fatty acid. Preferably, the ester is selected from the group
consisting of esters of fatty acids and polymers of at least
ethylene oxide, esters of fatty acids and polymers of at least
propylene oxide, esters of fatty acids and copolymers of at least
ethylene oxide, and esters of fatty acids and copolymers of at
least propylene oxide. It has proven to be particularly
advantageous that the esters of polyethers and fatty acids used as
component (c) are selected from the group consisting of ethylene
glycol fatty acid esters.
[0051] The presence of component (c) in the hemostatic agent
according to the invention lowers the melting range and thus
ensures the malleability of the hemostatic agent. Moreover,
component (c) also acts as a lubricant in that it clearly lowers
the friction due to the remaining components. Moreover, it has
surprisingly been evident that component (c) is capable of reducing
the otherwise inevitable recrystallization of the
glycerol-1,2,3-tri-fatty acid ester used as component (a) in the
hemostatic agent.
[0052] The composition of the hemostatic agent according to the
invention with regard to components (a), (b), and (c) is not
particularly limited.
[0053] According to a preferred embodiment of the invention, the
hemostatic agent contains 3-50% by weight of the at least one
component (a), 10-80% by weight of the at least one component (b),
and 10-50% by weight of the at least one component (c), relative to
the total weight of the hemostatic agent. According to a
particularly preferred embodiment, the hemostatic agent of the
present invention contains 5-40% by weight of the at least one
component (a), 20-75% by weight of the at least one component (b),
and 20-40% by weight of the at least one component (c), relative to
the total weight of the hemostatic agent.
[0054] It has proven to be particularly advantageous for the
formation of a stable matrix that the solubility of component (b)
in component (c) be low. Accordingly, the solubility of component
(b) at a temperature of 25.degree. C. preferably is less than 50
grams per liter of component (c), more preferably is less than 20
grams per liter of component (c), even more preferably is less than
10 grams per liter of component (c), particularly preferably is
less than 5 grams per liter of component (c), and even more
particularly preferably is less than 3 grams per liter of component
(c).
[0055] Moreover, for formation of a stable matrix, it has been
found to be particularly advantageous that the solubility of
component (b) in components (a) and (c) of the hemostatic agent be
low. Accordingly, the solubility at a temperature of 25.degree. C.
of the at least one component (b) preferably is less than 5% by
weight, more preferably is less than 3% by weight, and even more
preferably is less than 1% by weight, relative to the total weight
of components (a) and (c).
[0056] The hemostatic agent according to the invention can
optionally comprise further components aside from components (a),
(b), and (c).
[0057] For example, at least one other calcium salt can be
contained in the hemostatic agent according to the invention.
Preferably, the calcium salt is selected from the group consisting
of calcium chloride, calcium acetate, and calcium lactate. It has
been evident that the calcium ions contained in the calcium salts
act on secondary blood coagulation as blood coagulation factor IV
and thus promote blood coagulation. Preferably, the fraction of the
further calcium salt is less than 2% by weight, relative to the
total weight of the hemostatic agent. Adding at least one easily
soluble calcium salt selected from the group consisting of calcium
chloride, calcium acetate, and calcium lactate or the at least one
fibrinolysis inhibitor allows the hemostatic agent according to the
invention to not only mechanical hemostasis, but also hemostasis by
a biochemical route.
[0058] According to another preferred embodiment, the hemostatic
agent according to the invention further contains at least one
fibrinolysis inhibitor. Conceivable fibrinolysis inhibitors are, in
particular, members of the group of .epsilon.-aminocarbonic acids.
.epsilon.-Aminocarbonic acids are lysine analogues and act on
plasminogen, a precursor of plasmin, in order to inhibit the
formation of plasmin, which normally effects enzymatic cleavage of
fibrin. As a result, this leads to stabilization of fibrin, which
promotes blood coagulation locally. The .epsilon.-aminocarbonic
acids, 6-aminocaproic acid, 4-(aminomethyl)benzoic acid, and
trans-4-(aminomethyl)cyclohexan-1-carbonic acid have proven to be
particularly advantageous for this purpose.
[0059] According to a further preferred embodiment, the hemostatic
agent according to the invention contains at least one substance
selected from the group consisting of antibiotics and antiseptic
agents. Members of the groups of aminoglycoside antibiotics,
glycopeptide antibiotics, lincosamide antibiotics, and peptide
antibiotics are preferred as antibiotics. Conceivable antiseptic
agents are, for example, polyhexanide, octenidine hydrochloride,
and chlorhexidine. The presence of the antibiotics and/or
antiseptic agents allows effective local infection protection to be
attained by means of the hemostatic agent.
[0060] The hemostatic agent according to the invention can be
manufactured by a variety of routes.
[0061] According to an embodiment of the invention, the hemostatic
agent is manufactured by first placing all components of the
hemostatic agent in a suitable mixing vessel. Subsequently, the
individual components can be mixed, for example by stirring.
[0062] Preferably, the mixture thus obtained is then heated. It has
proven to be advantageous to heat the mixture to a temperature
above the melting point of components (a), (b), and (c). For
example, the mixture can be heated to a temperature above
50.degree. C., preferably to a temperature above 60.degree. C., and
even more preferably to a temperature above 70.degree. C. In the
process, the mixture can be heated, for example, to a temperature
in the range of 50.degree. C.-100.degree. C., preferably to a
temperature in the range of 60.degree. C.-95.degree. C., and even
more preferably to a temperature in the range of 70.degree.
C.-90.degree. C. It can therefore be advantageous according to the
invention that a melted mass be formed during the heating of the
mixture.
[0063] Preferably, the heating can proceed for a period of time of
at least 5 minutes. For example, the mixture can be heated for a
period of time of 5 minutes-4 hours, preferably for a period of
time of 15 minutes-2 hours, and even more preferably for a period
of time of 30 minutes-60 minutes. It is preferable for the mixture
to be stirred in this context. Stirring the melted mass allows
simple homogenization of the mixture to be attained and the
formation of a matrix by components (a), (b), and (c) to be
simplified.
[0064] Subsequently, the heated mixture can be cooled down.
Preferably, the mixture is cooled down to a temperature in the
range of 15.degree. C.-30.degree. C., and more preferably to a
temperature in the range of 20.degree. C.-25.degree. C.
[0065] Subsequently, the cooled mixture can be further homogenized,
if required. Homogenization can be carried out, for example, by
means of kneading or triturating the mixture.
[0066] Components other than components (a), (b), and (c) can be
added to the mixture prior to components (a), (b) or (c),
concurrently with components (a), (b), and (c) or separate from
these in one or more of the further procedural steps.
[0067] According to an alternative embodiment of the invention,
only one or two, but not all, of components (a), (b), and (c) are
placed in a suitable mixing vessel. Usually, it is not critical
which of the components is placed in the mixing vessel first. If
one component is to be placed in the mixing vessel first, the
component preferably is component (a) or component (c). If two of
the components are placed in the mixing vessel, the components
preferably are components (a) and (c). The remaining component or
remaining components not placed in the mixing vessel initially can
be added at a later point in time. The addition of the component(s)
can proceed, for example, after heating or cooling down of the
component(s) already placed in the mixing vessel.
[0068] The hemostatic agent of the present invention described
herein is structured such that it is malleable and easily kneadable
and strongly adheres to dry and wet surfaces at a temperature of
37.degree. C. Therefore, the invention also relates to a method for
forming the hemostatic agent according to the invention.
[0069] In this method, the hemostatic agent described above is
initially provided. The form, in which it is provided, is not
limited. However, usually the hemostatic agent is provided in a
container. The container is preferably structured such that it can
be opened easily by a user. Conceivable suitable containers are,
for example, tins, bottles, bags or cartridges, each of which can
be provided with suitable closures. The hemostatic agent is usually
removed from the bag by the user after opening the container.
[0070] After it has been provided, the hemostatic agent is heated.
Heating preferably is carried out to a temperature in the range of
35-40.degree. C. The hemostatic agent is easy to shape at this
temperature.
[0071] According to a preferred embodiment, the heating is effected
by at least one of the user's hands. The heating of the hemostatic
agent according to the invention by the user can proceed, for
example, by means of kneading the hemostatic agent. Since the
hemostatic agent of the present invention does not adhere to the
gloves of the user, the user can wear gloves while heating the
hemostatic agent with at least one of the user's hands. However, in
this context, the gloves should preferably be selected in such a
manner that the warmth of the hand of the user can be transmitted
via the glove to the hemostatic agent. Gloves made of materials
with correspondingly suitable thermal conductivity are well-known
according to the prior art and are usually sold as gloves suitable
for laboratory activities or medical activities.
[0072] According to an alternative embodiment, it is feasible just
as well to heat the hemostatic agent by other means, preferably by
the addition of external heat, for example by irradiating it.
Accordingly, the heating is not effected by one of the user's hands
according to this embodiment. However, heating by at least one of
the user's hands has proven to be particularly preferred.
[0073] Moreover, the hemostatic agent of the present invention is
formed. Preferably, forming is understood to be any change of the
shape or geometry of the hemostatic agent provided.
[0074] The forming is preferably effected by at least one of the
user's hands. The forming can also be carried out while the user
wears gloves. Forming of the hemostatic agent according to the
invention can already lead to heating of the hemostatic agent, for
example by kneading of the hemostatic agent by a user. Accordingly,
the scope of the invention includes the step of heating the
hemostatic agent and the step of forming the hemostatic agent are
effected by a continuous action of the user. Moreover or instead,
the forming can be effected after heating the hemostatic agent to a
temperature in the range of 35-40.degree. C. The forming can serve,
for example, to give the hemostatic agent a shape that is suitable
for mechanical sealing of bleeding bone tissue during a subsequent
surgery. After forming, the hemostatic agent can be used
instantaneously by the user in a surgery.
[0075] The hemostatic agent of the present invention can be used
for different medical purposes. According to an embodiment, the
hemostatic agent is used for mechanical closure of bleeding bone
wounds. For this purpose, the hemostatic agent serves as a bone
sealing agent. It can be pressed onto or into bleeding bone areas
by the user for this purpose.
[0076] Moreover, it is also feasible to use the hemostatic agent of
the invention as bone replacement material. It can be of advantage
in this process, in particular, to replace parts of damaged bones
with the hemostatic agent according to the invention.
[0077] The invention also relates to a medical implant having a
coating comprising the hemostatic agent according to the invention.
The hemostatic agent according to the invention can therefore be
used for the coating of medical implants. In this context, medical
implants shall be understood to mean materials and devices that are
inserted into the body, at least in part, in the course of a
surgical intervention.
[0078] The medical implants can be manufactured, for example, from
metal or plastic material. The medical implants preferably are
articular endoprostheses, osteosynthesis materials, vascular
prostheses, or hernial meshes. Conceivable articular endoprostheses
are, e.g., knee endoprostheses and hip endoprostheses. For example,
plates, marrow nails, and screws can serve as osteosynthesis
materials.
[0079] According to the invention, a coating of a medical implant
shall be understood to mean a layer that covers and adheres to at
least a part of a surface of the medical implant. The coating of
the medical implant comprises the hemostatic agent according to the
invention. Accordingly, the invention can provide the coating to be
formed fully by the hemostatic agent according to the invention or
optionally that the coating contains further components.
[0080] For coating, it is preferable to apply the hemostatic agent
of the present invention, which has been heated and formed
appropriately, to at least one surface of the medical implant, at
least in part. The application can be carried out, for example, in
that at least a part of the heated and formed hemostatic agent is
pressed onto the at least one surface of the medical implant, or at
least part of the hemostatic agent is applied by a relative motion
of the hemostatic agent with respect to the medical implant surface
to be coated, during which the hemostatic agent contacts the
medical implant surface to be coated (for example by spreading
it).
EXAMPLES
[0081] The invention is illustrated by the following examples,
though these may not be construed such as to limit the invention in
any way or form.
[0082] The following chemicals were used in the examples described
below: [0083] Glycerol-1,2,3-tristearate; [0084]
Glycerol-1,2,3-tripalmitate; [0085] Glycerol-1,2,3-trimyristate,
[0086] Glycerol-1,2,3-tristearate; [0087]
Glycerol-1,2,3-triarachinate; [0088] Glycerol-1,2,3-trioctanoate;
[0089] Glycerol-1,2,3-tripelargonate; [0090]
Glycerol-1,2,3-triheptanoate (Fluka); [0091] Mygliol 812 (saturated
glycerol-1,2,3-tri-fatty acid ester that is liquid at room
temperature and has fatty acids with medium chain length, mainly
glycerol-1,2,3-tri-fatty acid esters of caprylic acid and capric
acid); [0092] Calcium carbonate (precipitated, conforming to Ph.
Eur., Fluka); [0093] .beta.-tricalcium carbonate (in-house
synthesis); [0094] Calcium sulfate dihydrate (Fluka, conforming to
Ph. Eur., Fluka); [0095] Calcium sulfate hemihydrate (in-house
synthesis by thermal dehydration using Fluka calcium sulfate
dihydrate); [0096] 6-Aminocaproic acid (Fluka); [0097]
4-(Aminomethyl)benzoic acid (Aldrich); [0098]
trans-4-(Aminomethyl)cyclohexan-1-carbonic acid (tranexamic acid);
[0099] L.mu.trol.RTM. micro 127 (poly(propylene glycol-co-ethylene
glycol, Aldrich); [0100] Gentamicin sulfate (activity coefficient
600).
Examples 1-6
[0101] Hemostatic agents according to the invention comprising the
compositions and properties according to Table 1 below were
produced in Examples 1-6.
[0102] For this purpose, first, the quantities of
glycerol-1,2,3-tripalmitate and glycerol-1,2,3-trioctanoate were
weighed into a beaker. Then, the resulting mixtures were heated for
30 minutes to 80.degree. C. while stirring, leading to the
generation of a homogeneous melted mass. After the melted mass had
cooled to room temperature, L.mu.trol.RTM. micro 127 and,
optionally, gentamicin sulfate were added. The mixtures were
homogenized by kneading or triturating until a homogeneous,
colorless mass had been generated in each case.
TABLE-US-00001 TABLE 1 Compositions and properties of the
hemostatic agents according to Examples 1-6. Glycerol- Glycerol-
1,2,3- L.mu.trol .RTM. 1,2,3- Gentamicin Example tripalmitate micro
127 trioctanoate sulfate Assessment 1 7.0 g 9.5 g 7.0 g --
Kneadable, solid 2 3.5 g 9.5 g 7.0 g -- Kneadable, very soft 3 3.5
g 9.5 g 6.0 g -- Kneadable, solid 4 7.0 g 9.5 g 7.0 g 0.38 g
Kneadable, solid 5 3.5 g 9.5 g 7.0 g 0.33 g Kneadable, very soft 6
3.5 g 9.5 g 6.0 g 0.31 g Kneadable, solid
Examples 7-24
[0103] Hemostatic agents according to the invention comprising the
compositions and properties according to Table 2 below were
produced in Examples 7-24.
[0104] For this purpose, first, the specified quantities of the
respective glycerol-1,2,3-tri-fatty acid esters were weighed into a
beaker. Then, the resulting mixtures were heated for 30 minutes to
80.degree. C. while stirring, leading to the generation of a
homogeneous melted mass. After the melted mass had cooled to room
temperature, L.mu.trol.RTM. micro 127 and, optionally, gentamicin
sulfate were added. The mixtures were homogenized by kneading or
triturating until a homogeneous, colorless mass had been generated
in each case.
TABLE-US-00002 TABLE 2 Compositions and properties of the
hemostatic agents according to Examples 7-24. Liquid
Glycerol-1,2,3- L.mu.trol .RTM. glycerol-1,2,3- tri-fatty acid
micro tri-fatty acid Gentamicin Example ester 127 ester sulfate
Assessment 7 3.5 g glycerol- 9.5 g 7.0 g glycerol- -- Kneadable,
1,2,3-trimyristate 1,2,3- very soft trioctanoate 8 3.5 g glycerol-
9.5 g 7.0 g glycerol- -- Kneadable, 1,2,3-tristearate 1,2,3- soft
trioctanoate 9 3.5 g glycerol- 9.5 g 7.0 g glycerol- -- Kneadable,
1,2,3- 1,2,3- soft triarachinate trioctanoate 10 3.5 g glycerol-
9.5 g 7.0 g Mygliol -- Kneadable, 1,2,3-trimyristate 812 soft 11
3.5 g glycerol- 9.5 g 7.0 g Mygliol -- Kneadable, 1,2,3-tristearate
812 soft 12 3.5 g glycerol- 9.5 g 7.0 g Mygliol -- Kneadable,
1,2,3- 812 triarachinate 13 3.5 g glycerol- 9.5 g 7.0 g glycerol-
-- Kneadable, 1,2,3-tripalmitate 1,2,3- soft triheptanoate 14 3.5 g
glycerol- 9.5 g 7.0 g glycerol- -- Kneadable, 1,2,3-stearate 1,2,3-
very soft triheptanoate 15 3.5 g glycerol- 9.5 g 7.0 g glycerol- --
Kneadable, 1,2,3-tripalmitate 1,2,3- very soft tripelargonate 16
3.5 g glycerol- 9.5 g 7.0 g glycerol- 0.31 g Kneadable,
1,2,3-trimyristate 1,2,3- very soft trioctanoate 17 3.5 g glycerol-
9.5 g 7.0 g glycerol- 0.31 g Kneadable, 1,2,3-tristearate 1,2,3-
soft trioctanoate 18 3.5 g glycerol- 9.5 g 7.0 g glycerol- 0.31 g
Kneadable, 1,2,3- 1,2,3- soft triarachinate trioctanoate 19 3.5 g
glycerol- 9.5 g 7.0 g Mygliol 0.31 g Kneadable, 1,2,3-trimyristate
812 very soft 20 3.5 g glycerol- 9.5 g 7.0 g Mygliol 0.31 g
Kneadable, 1,2,3-tristearate 812 soft 21 3.5 g glycerol- 9.5 g 7.0
g Mygliol 0.31 g Kneadable, 1,2,3- 812 triarachinate 22 3.5 g
glycerol- 9.5 g 7.0 g glycerol- 0.31 g Kneadable,
1,2,3-tripalmitate 1,2,3- soft triheptanoate 23 3.5 g glycerol- 9.5
g 7.0 g glycerol- 0.31 g Kneadable, 1,2,3-stearate 1,2,3- very soft
triheptanoate 24 3.5 g glycerol- 9.5 g 7.0 g glycerol- 0.31 g
Kneadable, 1,2,3-tripalmitate 1,2,3- very soft tripelargonate
Examples 25-58
[0105] Hemostatic agents according to the invention comprising the
compositions and properties according to Tables 3 to 7 below were
produced in Examples 25-58.
[0106] For this purpose, first, the quantities of the ingredients
specified in Tables 3 to 7 were weighed into a beaker and mixed
with each other by stirring. Then, the resulting mixtures were
heated to 80.degree. C. for 30 to 60 minutes. After the melted mass
had cooled to room temperature, the material was homogenized by
kneading or triturating until a homogeneous, colorless mass was
produced in each case.
TABLE-US-00003 TABLE 3 Compositions and properties of the
hemostatic agents according to Examples 25-31. Liquid
Glycerol-1,2,3- Calcium glycerol-1,2,3- Example tri-fatty acid
ester carbonate fatty acid ester Assessment 25 7.0 g glycerol- 9.5
g 7.0 g glycerol- Wax-like, 1,2,3-tristearate 1,2,3- malleable
trioctanoate 26 7.0 g glycerol- 9.0 g 7.0 g glycerol- Wax-like,
1,2,3-tristearate 1,2,3- malleable trioctanoate 27 7.0 g glycerol-
8.0 g 7.0 g glycerol- Wax-like, 1,2,3-tristearate 1,2,3- malleable
trioctanoate 28 7.0 g glycerol- 9.0 g 7.0 g glycerol- Wax-like,
1,2,3-trimyristate 1,2,3- malleable trioctanoate 29 7.0 g glycerol-
9.0 g 7.0 g glycerol- Wax-like, 1,2,3-tripalmitate 1,2,3- malleable
trioctanoate 30 7.0 g glycerol- 9.0 g 7.0 g glycerol- Wax-like,
1,2,3- 1,2,3- viscous, trisarachinate trioctanoate malleable 28 7.0
g glycerol- 9.0 g 7.0 g Mygliol Wax-like, 1,2,3-trimyristate 812
malleable 29 7.0 g glycerol- 9.0 g 7.0 g Mygliol Wax-like,
1,2,3-tripalmitate 812 malleable 30 7.0 g glycerol- 9.0 g 7.0 g
Mygliol Wax-like, 1,2,3-tristearate 812 malleable 31 7.0 g
glycerol- 9.0 g 7.0 g Mygliol Wax-like, 1,2,3- 812 viscous,
trisarachinate malleable
TABLE-US-00004 TABLE 4 Compositions and properties of the
hemostatic agents according to Examples 32 to 40. Liquid
Glycerol-1,2,3- Calcium glycerol-1,2,3- tri-fatty acid sulfate
Calcium tri-fatty acid Example ester hemihydrate carbonate ester
Assessment 32 6.5 g glycerol- 52.8 13.2 g 27.5 g Malleable
1,2,3-tripalmitate glycerol-1,2,3- without trioctanoate heating 33
6.8 g glycerol- 54.6 g 13.6 g 25.0 g Malleable 1,2,3-tripalmitate
glycerol-1,2,3- without trioctanoate heating, somewhat more solid
than in example 32 34 6.5 g glycerol- 52.8 13.2 g 27.5 g Malleable
1,2,3-trimyristate glycerol-1,2,3- without trioctanoate heating 35
6.5 g glycerol- 52.8 13.2 g 27.5 g Malleable 1,2,3-stearate
glycerol-1,2,3- without trioctanoate heating 36 6.5 g 6.5 g 52.8
13.2 g 27.5 g Malleable glycerol-1,2,3- glycerol-1,2,3- without
arachinate trioctanoate heating 37 6.5 g glycerol- 52.8 13.2 g 27.5
g Mygliol Malleable 1,2,3-tripalmitate 812 without heating 38 6.5 g
glycerol- 52.8 13.2 g 27.5 g Malleable 1,2,3-trimyristate
glycerol-1,2,3- without trioctanoate heating 39 6.5 g glycerol-
52.8 13.2 g 27.5 g Malleable 1,2,3-stearate glycerol-1,2,3- without
trioctanoate heating 40 6.5 g 6.5 g 52.8 13.2 g 27.5 g Malleable
glycerol-1,2,3- glycerol-1,2,3- without arachinate trioctanoate
heating
TABLE-US-00005 TABLE 5 Compositions and properties of the
hemostatic agents according to Examples 41 and 44. Liquid glycerol-
Calcium 1,2,3-tri- Glycerol-1,2,3- sulfate Calcium fatty acid
Gentamicin Example tripalmitate dihydrate carbonate ester sulfate
Assessment 41 6.4 g 51.9 g 13.0 g 27.1 g 1.6 g Malleable glycerol-
without 1,2,3- heating trioctanoate 42 6.7 g 53.7 g 13.4 g 24.6 g
1.6 g Malleable glycerol- without 1,2,3- heating trioctanoate 43
6.4 g 51.9 g 13.0 g 27.1 g 1.6 g Malleable Mygliol without 812
heating 44 6.7 g 53.7 g 13.4 g 24.6 g 1.6 g Malleable Mygliol
without 812 heating
TABLE-US-00006 TABLE 6 Compositions and properties of the
hemostatic agents according to Examples 45-50. Glycerol-
.beta.-Tri- Glycerol- 1,2,3- calcium Calcium 1,2,3-
.epsilon.-Amino- Example tristearate sulfate carbonate trioctanoate
carbonic acid Assessment 45 7.0 g 3.5 g 6.5 g 7.0 g 0.2 g 6-Amino-
Malleable glycerol- caproic acid without 1,2,3- heating
trioctanoate 46 7.0 g 3.5 g 6.5 g 7.0 g 0.2 g trans-4- Malleable
glycerol- (Aminomethyl)- without 1,2,3- cyclohexan-1- heating
trioctanoate carbonic acid 47 7.0 g -- 9.5 g 7.0 g 0.2 g 4-
Malleable glycerol- (Aminomethyl) without 1,2,3- benzoic acid
heating trioctanoate 48 7.0 g 3.5 g 6.5 g 7.0 g 0.2 g 6-Amino-
Malleable Mygliol caproic acid without 812 heating 49 7.0 g 3.5 g
6.5 g 7.0 g 0.2 g trans-4- Malleable Mygliol (Aminomethyl)- without
812 cyclohexan-1- heating carbonic acid 50 7.0 g -- 9.5 g 7.0 g 0.2
g 4- Malleable Mygliol (Aminomethyl) without 812 benzoic acid
heating
TABLE-US-00007 TABLE 7 Compositions and properties of the
hemostatic agents according to Examples 51-58. Liquid glycerol-
Glycerol- 1,2,3-tri- 1,2,3-tri-fatty Calcium fatty acid Calcium
.epsilon.-Aminocarbonic Example acid ester carbonate ester chloride
acid Assessment 51 7.0 g 9.5 g 7.0 g 0.3 g 0.2 g 6-Amino- Malleable
glycerol- glycerol- caproic acid without 1,2,3- 1,2,3- heating
tristearate trioctanoate 52 7.0 g 9.5 g 7.0 g 0.3 g 0.2 g trans-4-
Malleable glycerol- glycerol- (Aminomethyl)- without 1,2,3- 1,2,3-
cyclohexan-1- heating tristearate trioctanoate carbonic acid 53 7.0
g 9.5 g 7.0 g 0.2 g 0.2 g 4- Malleable glycerol- glycerol-
(Aminomethyl)ben- without 1,2,3- 1,2,3- zoic acid heating
tristearate trioctanoate 54 7.0 g 9.5 g 7.0 g 0.3 g 0.2 g 6-Amino-
Malleable glycerol- Mygliol caproic acid without 1,2,3- 812 heating
tristearate 55 7.0 g 9.5 g 7.0 g 0.3 g 0.2 g trans-4- Malleable
glycerol- Mygliol (Aminomethyl)- without 1,2,3- 812 cyclohexan-1-
heating tristearate carbonic acid 56 7.0 g 9.5 g 7.0 g 0.2 g 0.2 g
4- Malleable glycerol- Mygliol (Aminomethyl) without 1,2,3- 812
benzoic acid heating tristearate 57 7.0 g 9.5 g 7.0 g 0.2 g 0.2 g
4- Malleable glycerol- Mygliol (Aminomethyl)ben- without 1,2,3- 812
zoic acid heating trimyristate 58 7.0 g 9.5 g 7.0 g 0.2 g 0.2 g 4-
Malleable glycerol- Mygliol (Aminomethyl) without 1,2,3- 812
benzoic acid heating tripalmitate
[0107] A total of 5 g each of the kneadable masses produced in
Examples 1-58 were placed in 20 ml deionized water. The pH was
tested after 24 hours of storage at room temperature. In all cases,
no changes of the pH value as compared to the pH value of deionized
water of 6.5 were measured.
[0108] Moreover, a Zweymuller hip prosthesis was coated with the
mixtures of Examples 1-6 by forming the mixtures into cylinders and
subsequently spreading the cylinders over the cylinder surface. The
relative motion of the structured surface of the prosthesis with
respect to the cylinder caused material to be transferred from the
cylinder to the surface of the prosthesis. Depending on the
pressure of application and the number of repetitions of the
transfer processes, between 80 and 150 mg of the material of the
mixtures from Examples 1-6 were transferred.
[0109] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *