U.S. patent application number 10/768335 was filed with the patent office on 2006-01-26 for hemostatic compositions and devices.
Invention is credited to Thomas L. Craven, Anne J. Gorman, Sanyog M. Pendharkar.
Application Number | 20060019868 10/768335 |
Document ID | / |
Family ID | 35658026 |
Filed Date | 2006-01-26 |
United States Patent
Application |
20060019868 |
Kind Code |
A1 |
Pendharkar; Sanyog M. ; et
al. |
January 26, 2006 |
Hemostatic compositions and devices
Abstract
The present invention includes both sterilized and unsterilized
hemostatic compositions that contain a continuous, biocompatible
liquid phase having a solid phase of particles of a biocompatible
polymer suitable for use in hemostasis and which is substantially
insoluble in the liquid phase, and a discontinuous, biocompatible
gaseous phase, each of which is substantially homogenously
dispersed throughout the continuous liquid phase, methods for
making such compositions, medical devices that contain sterilized
hemostatic compositions disposed therein and methods of making such
devices.
Inventors: |
Pendharkar; Sanyog M.; (Old
Bridge, NJ) ; Gorman; Anne J.; (Hightstown, NJ)
; Craven; Thomas L.; (Bridgewater, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
35658026 |
Appl. No.: |
10/768335 |
Filed: |
January 30, 2004 |
Current U.S.
Class: |
514/200 ;
514/13.6; 514/13.7; 514/17.2; 514/54; 514/9.3 |
Current CPC
Class: |
A61L 26/0061 20130101;
A61L 26/0095 20130101; A61P 7/04 20180101; A61K 2300/00 20130101;
A61K 31/715 20130101; A61L 2400/04 20130101; A61K 38/39 20130101;
A61L 26/0038 20130101; A61K 38/363 20130101; A61K 38/36 20130101;
A61K 38/36 20130101 |
Class at
Publication: |
514/002 ;
514/054 |
International
Class: |
A61K 38/39 20060101
A61K038/39; A61K 31/715 20060101 A61K031/715 |
Claims
1. A hemostatic composition, comprising: a continuous,
biocompatible liquid phase, a solid phase comprising particles of a
biocompatible polymer suitable for use in hemostasis and which is
substantially insoluble in said liquid phase; and a discontinuous
gaseous phase comprising a biocompatible gas, said continuous
liquid phase comprising said solid phase and said discontinuous
gaseous phase substantially homogenously dispersed there through,
wherein the ratio of said liquid phase, said solid phase and said
gaseous phase is effective to provide said composition with
hemostatic properties.
2. The composition of claim 1 wherein said liquid phase is
aqueous.
3. The composition of claim 2 wherein said liquid phase comprises
saline.
4. The composition of claim 3 wherein said biocompatible polymer is
selected from the group consisting of proteins and
polysaccharides.
5. The composition of claim 4 wherein said protein is selected from
the group consisting of gelatin, collagen, fibrinogen and
fibronectin.
6. The composition of claim 5 wherein said protein comprises
gelatin.
7. The composition of claim 6 wherein the average diameter of said
particle is from about 40 to about 1200 microns.
8. The composition of claim 7 wherein said particles, said liquid
phase and said gaseous phase are present in said hemostatic
composition at a ratio of from about 1:2:1 to about 1:12:13, based
on g:ml:ml.
9. The composition of claim 8 wherein said particles, said liquid
phase and said gaseous phase are present in said hemostatic
composition at a ratio of from about 1:4:1 to about 1:8:9, based on
g:ml:ml.
10. The composition of claim 8 wherein the density of said
composition is from about 0.9 g/ml to about 0.3 g/ml.
11. The composition of claim 9 wherein the density of said
composition is from about 0.8 g/ml to about 0.6 g/ml.
12. The composition of claim 1 wherein said gas is selected from
the group consisting of air, nitrogen, carbon dioxide, xenon and
argon.
13. The composition of claim 1 further comprising a functionally
effective amount of an additive selected from the group consisting
of antimicrobial agents, foaming agents, foam stabilizers,
surfactants, antioxidants, humectants, thickeners, diluents,
lubricants, wetting agents, irradiation stabilizers, plasticizers,
heparin neutralizers, procoagulants and hemostatic agents.
14. The composition of claim 13 comprising up to about 20 percent
by weight of glycerol, based on the weight of said liquid
phase.
15. The composition of claim 13 comprising up to about 1 percent by
weight of a quaternary amine, based on the weight of said liquid
phase.
16. The composition of claim 15 comprising from about 0.001% to
about 0.01% by weight of benzalkonium chloride, based on the weight
of said liquid phase
17. The composition of claim 1 wherein said composition is
sterile.
18. The composition of claim 13 wherein said composition is
sterile.
19. The composition of claim 18 wherein said functional additive is
selected from the group consisting of fibrinogen and thrombin.
20. A method for making a substantially homogenous hemostatic
composition suitable for use in hemostatic devices suitable for
applying a flowable hemostatic composition to a site requiring
hemostatis, said method comprising: providing a biocompatible
liquid, particles of a biocompatible polymer suitable for use in
hemostasis and which is substantially insoluble in said liquid, and
a biocompatible gas, combining said liquid, said particles and said
gas; and mixing said liquid, said particles and said gas under
conditions effective to form a continuous liquid phase comprising
said particles and a discontinuous gaseous phase substantially
homogenously dispersed there through, thereby forming said
substantially homogeneous hemostatic composition, wherein the ratio
of said continuous liquid phase, said particles and said gaseous
phase is effective to provide said composition with hemostatic
properties.
21. The method of claim 20 wherein said liquid phase comprises
saline.
22. The method of claim 21 wherein said biocompatible polymer is
selected from the group consisting of proteins and
polysaccharides.
23. The method of claim 22 wherein said protein is selected from
the group consisting of gelatin, collagen, fibrinogen and
fibronectin.
24. The method of claim 23 wherein said protein comprises
gelatin.
25. The method of claim 24 wherein the average diameter of said
particle is from about 40 to about 1200 microns.
26. The method of claim 24 wherein said particles, said liquid
phase and said gaseous phase are combined at a ratio of from about
1:2:1 to about 1:12:13, based on g:ml:ml.
27. The method of claim 26 wherein the density of said
substantially homogenous hemostatic composition is from about 0.9
g/ml to about 0.3 g/ml.
28. The method of claim 20 wherein said gas is selected from the
group consisting of air, nitrogen, carbon dioxide, xenon and
argon.
29. The method of claim 20 further comprising adding to said liquid
phase a functionally effective amount of an additive selected from
the group consisting of antimicrobial agents, foaming agents, foam
stabilizers, surfactants, antioxidants, humectants, lubricants,
thickeners, diluents, wetting agents, irradiation stabilizers,
heparin neutralizers, procoagulants and hemostatic agents.
30. The method of claim 29 wherein up to about 20 weight percent of
glycerol are added to said liquid, based on the weight of said
liquid.
31. The method of claim 29 wherein up to about 1 weight percent of
a quaternary amine is added to said liquid, based on the weight of
said liquid.
32. The method of claim 20 further comprising irradiating said
substantially homogeneous composition with an amount of ionizing
irradiation and for a time effective to provide a sterile,
substantially homogeneous composition.
33. The method of claim 29 further comprising irradiating said
substantially homogeneous composition with an amount of ionizing
irradiation and for a time effective to provide a sterile,
substantially homogeneous composition.
34. The method of claim 33 wherein said additive is selected from
the group consisting of fibrinogen and thrombin.
35. A medical device suitable for applying a flowable hemostatic
composition to a site requiring hemostatis, said device having
disposed therein a substantially homogeneous hemostatic
composition, said substantially homogeneous hemostatic composition
comprising: a continuous, biocompatible liquid phase, a solid phase
comprising particles of a biocompatible polymer suitable for use in
hemostasis and which is substantially insoluble in said liquid
phase; and a discontinuous gaseous phase comprising a biocompatible
gas, said continuous liquid phase comprising said solid phase and
said discontinuous gaseous phase substantially homogenously
dispersed there through, wherein the ratio of said liquid phase,
said solid phase and said gaseous phase is effective to provide
said composition with hemostatic properties.
36. The device of claim 35 wherein said liquid phase comprises
saline.
37. The device of claim 35 wherein said biocompatible polymer is
selected from the group consisting of proteins and
polysaccharides.
38. The device of claim 37 wherein said protein is selected from
the group consisting of gelatin, collagen, fibrinogen and
fibronectin.
39. The device of claim 38 wherein said protein comprises
gelatin.
40. The device of claim 39 wherein the average diameter of said
particle is from about 40 to about 1200 microns.
41. The device of claim 35 wherein said particles, said continuous
liquid phase and said gaseous phase are present in said
substantially homogeneous hemostatic composition at a ratio of from
about 1:2:1 to about 1:12:13, based on g:ml:ml.
42. The device of claim 41 wherein the density of said
substantially homogeneous hemostatic composition is from about 0.9
g/ml to about 0.3 g/ml.
43. The device of claim 35 wherein said gas is selected from the
group consisting of air, nitrogen, carbon dioxide, xenon and
argon.
44. The device of claim 35 wherein said composition further
comprises a functionally effective amount of an additive selected
from the group consisting of antimicrobial agents, foaming agents,
foam stabilizers, surfactants, antioxidants, humectants,
thickeners, lubricants, diluents, wetting agents, irradiation
stabilizers, plasticizers, heparin neutralizers, procoagulants and
hemostatic agents.
45. The device of claim 44 wherein said composition comprises up to
about 20 weight percent of glycerol, based on the weight of said
liquid phase.
46. The device of claim 44 wherein said composition comprises up to
about 1 weight percent of a quaternary amine, based on the weight
of said liquid phase.
47. The device of claim 35 wherein said composition and said device
are sterile.
48. The device of claim 44 wherein said composition and said device
are sterile.
49. The device of claim 48 wherein said functional additive is
selected from the group consisting of fibrinogen and thrombin.
50. A method for making a medical device suitable for applying a
flowable hemostatic composition to a site requiring hemostasis, the
method comprising: providing a substantially homogeneous hemostatic
composition, said composition comprising a continuous,
biocompatible liquid phase, a solid phase comprising particles of a
biocompatible polymer suitable for use in hemostasis and which is
substantially insoluble in said liquid phase, and a discontinuous
gaseous phase comprising a biocompatible gas, said continuous
liquid phase comprising said solid phase and said discontinuous
gaseous phase substantially homogenously dispersed there through,
wherein the ratio of said liquid phase, said solid phase and said
gaseous phase is effective to provide said composition with
hemostatic properties; and dispensing said substantially
homogeneous hemostatic composition into said medical device.
51. The method of claim 50 wherein said liquid phases comprises
saline.
52. The method of claim 51 wherein said biocompatible polymer
comprises a protein selected from the group consisting of gelatin,
collagen, fibrinogen and fibronectin.
53. The method of claim 52 wherein said protein comprises
gelatin.
54. The method of claim 53 wherein the average diameter of said
particle is from about 40 to about 1200 microns.
55. The method of claim 54 wherein said particles, said liquid
phase and said gaseous phase are combined at a ratio of from about
1:2:1 to about 1:12:13, based on g:ml:ml.
56. The method of claim 55 wherein the density of said
substantially homogenous hemostatic composition is from about 0.9
g/ml to about 0.3 g/ml.
57. The method of claim 50 wherein said gas is selected from the
group consisting of air, nitrogen, carbon dioxide, xenon and
argon.
58. The method of claim 50 further comprising adding to said liquid
phase a functionally effective amount of an additive selected from
the group consisting of antimicrobial agents, foaming agents, foam
stabilizers, surfactants, antioxidants, humectants, lubricants,
thickeners, diluents, wetting agents, irradiation stabilizers,
heparin neutralizers, procoagulants and hemostatic agents.
59. The method of claim 58 wherein up to about 20 weight percent of
glycerol are added to said liquid, based on the weight of said
liquid.
60. The method of claim 58 wherein up to about 1 weight percent of
a quaternary amine is added to said liquid, based on the weight of
said liquid.
61. The method of claim 50 further comprising irradiating said
device having said substantially homogeneous composition dispensed
therein with an amount of ionizing irradiation and for a time
effective to provide a sterile device having a sterile,
substantially homogeneous hemostatic composition disposed
therein.
62. The method of claim 58 further comprising irradiating said
device having said substantially homogeneous composition dispensed
therein with an amount of ionizing irradiation and for a time
effective to provide a sterile device having a sterile,
substantially homogeneous hemostatic composition disposed
therein.
63. The method of claim 62 wherein said additive is selected from
the group consisting of fibrinogen and thrombin.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to hemostatic compositions
suitable for use in hemostatic devices that in turn are suitable
for applying flowable hemostatic compositions to a site requiring
hemostasis, to such hemostatic devices containing such compositions
disposed therein and to methods of making such hemostatic
compositions and devices.
BACKGROUND OF THE INVENTION
[0002] Gelatin-based hemostats, both in solid sponge or powder
form, are commercially available and are used in surgical
procedures. Gelatin powder, when mixed with fluid, can form a paste
or slurry that is useful as a flowable, extrudable and injectable
hemostat for diffuse bleeding, particularly from uneven surfaces or
hard to reach areas. The conventional slurry is prepared at the
point of use by mechanical agitation and mixing of the powder and
liquid to provide uniformity of the composition. The paste then is
placed into a delivery means or applicator, e.g. a syringe, and
applied to the wound.
[0003] The main disadvantage of this approach is the need to mix
the powder with the liquid, knead it into a paste and back-fill it
into the delivery device of choice, all at the time of need and at
the point of use. The manipulations are time consuming and
potentially can compromise the sterility of the delivered product.
Thus, a need exists for a sterile, flowable, moldable hemostatic
composition that is ready to use at the point of use or can be
prepared with minimal manipulation and without risk of compromising
the sterility of the product.
[0004] It would be desirable if a hemostatic device, e.g. a
delivery means such as a syringe or other applicator, would be
pre-filled with a hemostatic composition and instantly available to
the surgeon at the point of use without need for further
manipulation. The hemostatic composition pre-filled in the device
or applicator should be sterile and flowable and should require
minimum preparation time and minimal force when extruded or
injected through the delivery means at the point of use. The
compositions of the present invention provide such properties and
pre-filled devices.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to hemostatic compositions
suitable for use in preparing hemostatic devices that in turn are
suitable for use in applying flowable hemostatic compositions and
comprising a substantially homogenous, sterilized hemostatic
composition disposed therein, where the composition comprises a
continuous, biocompatible liquid phase, a solid phase comprising
porous or non-porous particles of a biocompatible polymer suitable
for use in hemostasis and which are substantially insoluble in the
liquid phase, and a discontinuous gaseous phase comprising a
biocompatible gas. The continuous liquid phase comprises the solid
particulate phase and the discontinuous gaseous phase substantially
homogenously dispersed there through. The ratio of the liquid
phase, the solid particulate phase and the discontinuous gaseous
phase is effective to provide the composition with hemostatic
properties, both prior to and after sterilization. Compositions of
the present invention may be prepared well in advance of the time
of use and need not be prepared at the point of use, yet they
maintain physical properties effective to provide flowability,
extrudability or injectability at the point and time of use. The
present invention also includes methods of making the hemostatic
compositions, medical devices containing the compositions disposed
therein and methods of making such devices.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Both sterilized and unsterilized compositions of the present
invention contain solid, porous or non-porous particles of a
biocompatible polymer suitable for use in hemostasis, a
biocompatible liquid and a biocompatible gas as its three necessary
components. The particles, liquid and gas are combined and mixed
under conditions effective to provide a substantially homogeneous
hemostatic composition comprising a continuous liquid phase having
the solid polymer particles and a discontinuous gas phase
homogenously dispersed there through. The amount and average
diameter of particles contained in the composition and the relative
amounts of the solid, liquid and gaseous phases is effective to
provide the composition with hemostatic and physical properties, as
described herein below.
[0007] The hemostatic composition so formed is a hemostatic paste,
or slurry, that exhibits improved properties of flowability,
extrudability and/or injectability when compared to flowable
hemostatic compositions of similar liquid/particle composition but
that do not contain a gaseous phase. Compositions of the present
invention may be prepared, filled into a medical device, such as a
syringe or other known applicators used to dispense flowable
hemostatic compositions, and sterilized by ionizing irradiation,
well in advance of the time of their intended use. The compositions
further may include additives to facilitate the preparation of the
composition, enhance physical and mechanical properties, enhance
the hemostatic properties of the composition or provide
antimicrobial properties.
[0008] As used herein, "continuous" and "discontinuous" are used in
the ordinary meaning of those words in the context of standard
nomenclature used to define and describe dispersions. For example,
when combined and mixed with the continuous liquid phase, the
volume of biocompatible gas added to the liquid phase is disrupted
by mixing so as to form the discontinuous, i.e. dispersed, gaseous
phase comprising pockets or isolated bodies of gas.
[0009] As used herein, "substantially homogenous" denotes that
physical state of the compositions or pastes where the solid and/or
gaseous phases are uniformly dispersed throughout the continuous
liquid phase such that the ratio of solid:gas:liquid and the
density of any portion or cross-section of the composition or paste
are substantially the same.
[0010] As used herein, "sterile" means substantially free of living
germs and/or microorganisms and as further recognized and described
by governmental standards pertaining to compositions and medical
devices described and claimed herein.
[0011] As used herein, "hemostatic", or "hemostatic properties",
means the ability to stop or minimize bleeding, as one skilled in
the art of hemostasis would understand those terms to mean, as
further exemplified in the examples of the specification.
[0012] As used herein, "Peak Expression Force" is the peak force
value required to extrude compositions from a pre-filled 10 cc
Becton Dickinson (BD) luer syringe fitted with a 14 gauge
angiocatheter tip, as described in the examples of the
specification.
[0013] A variety of biocompatible natural, semi-synthetic or
synthetic polymers may be used to prepare the solid particles used
in compositions of the present invention. The polymer selected must
be substantially insoluble in the liquid chosen for the particular
composition. Preferably, water-insoluble biodegradable polymers
that provide mechanical, chemical and/or biological hemostatic
activity are used. Polymers that may be used include, without
limitation, proteins and polysaccharides. Polysaccharides that may
be used include oxidized cellulose, chitosan, chitin, alginate,
oxidized alginate and oxidized starch. The biocompatible polymer
used to prepare the particles preferably is a cross-linked or
denatured protein, such as gelatin, collagen, fibrinogen or
fibronectin. A preferred gelatin powder is Surgifoam.RTM.
hemostatic gelatin powder, available from Johnson & Johnson
Wound Management, a division of Ethicon, Inc. Surgifoam.RTM. powder
is a partially cross-linked gelatin powder prepared by milling
gelatin sponge into particles having an average diameter of from
about 40 microns to about 1200 microns, more preferably from about
100 microns to about 1000 microns, as determined by laser
diffraction.
[0014] Compositions of the present invention comprise a continuous
liquid phase in which the solid particles and gaseous phase are
dispersed. Depending upon the particular medical device and use
thereof, the liquid may be aqueous or non-aqueous. Preferably, the
liquid phase is aqueous. Aqueous liquids may include, without
limitation, biocompatible aqueous solutions, such as calcium
chloride and saline. More preferably, the liquid phase comprises
saline. The liquid phase and solid particulate phase are present in
relative amounts effective to provide a paste, or slurry, suitable
for use in providing hemostasis. Excessive dilution of the solid
particulate phase, although beneficial to further reduce the peak
expression force, will detrimentally affect the hemostatic
properties of the material and therefore is not desired. The weight
ratio of solid particles to liquid generally is from about 1:2 to
about 1:12. A preferred weight ratio of the solid gelatin particles
to saline is from about 1:3 to about 1:6. A more preferred weight
ratio of the solid gelatin particles to saline is about 1:5.
[0015] Any biocompatible gas may be used to prepare compositions of
the present invention including, but not limited to, air, carbon
dioxide, nitrogen, xenon or argon. Preferably an inert gas such as
argon or nitrogen is used. Air, nitrogen and argon are sensitive to
ultrasound and may provide a means to locate the composition once
injected in the body. Similarly, as xenon is radio-opaque, using
xenon also may provide a means to locate the composition once
placed in the body. In addition, as carbon dioxide lowers pH,
selection of carbon dioxide may enhance antimicrobial properties of
the compositions. The gas must be combined and mixed with the
continuous liquid phase until it is uniformly dispersed throughout
the liquid phase so as to form a discontinuous, gaseous phase
substantially homogenously dispersed in the continuous liquid
phase. The homogenous dispersion of the gas phase in the liquid
phase provides the composition with improved physical properties
relating to flowability, extrudability and injectability, as
described herein. Such improved properties are characterized by way
of physical measurements of the compositions, including density and
peak expression force, both prior to and after irradiation of the
compositions during sterilization.
[0016] The relative concentration of the three major components of
the compositions of the present invention and the substantially
homogenous nature of such compositions are key in providing both
hemostatic and physical properties to the compositions. The solid
particles, liquid phase and gaseous phase generally will be present
in compositions of the present invention at a ratio of from about
1:2:1 to about 1:12:13, based on weight:volume:volume (g:ml:ml).
Preferably the ratio will be from about 1:4:1 to about 1:8:9. More
preferably the ratio will be about 1:5:3. The density of
compositions of the present invention will be from about 0.9 g/ml
to about 0.3 g/ml, more preferably from about 0.8 g/ml to about 0.6
g/ml.
[0017] Compositions of the present invention include compositions
described herein that are sterile, in that they have been
irradiated with a level of, e.g. ionizing irradiation. Such
irradiation may include e-beam or gamma irradiation. The level of
irradiation and conditions of sterilization, including the time
that the compositions are irradiated, are those that provide
sterile compositions, as defined herein. Once having the benefit of
this disclosure, one skilled in the art will be able to readily
determine the level of irradiation necessary to provide sterile
compositions.
[0018] The hemostatic compositions may further comprise effective
amounts of one or more additives or compounds including, but not
limited to, antimicrobial agents, foaming agents, foam stabilizers,
surfactants, antioxidants, humectants, wetting agents, lubricants,
thickeners, diluents, irradiation stabilizers, e.g. radical
scavengers, plasticizers, and stabilizers. For example, glycerol
may be added to enhance the extrudability or injectability of the
composition. When utilized, glycerol may be present in the
compositions at from about 0% to about 20% by weight, based on the
weight of the liquid phase. Preferably, the composition may
comprise from about 1% to about 10% by weight of glycerol, based on
the weight of the liquid phase. More preferably, the compositions
may comprise from about 1% to about 5% by weight of glycerol, based
on the weight of the liquid phase.
[0019] In addition, quaternary amines may be used to provide
enhanced properties to the compositions. For example, benzalkonium
chloride, Polybrene or Onamer M may be used at levels up to about 1
percent by weight, based on the weight of the liquid phase.
Preferably, benzalkonium chloride is used at levels of from about
0.001% to about 0.01% by weight, based on the weight of the liquid
phase. More preferably, the compositions may comprise from about
0.002 to about 0.006% by weight benzalkonium chloride, based on the
weight of the liquid phase. It is believed that the quaternary
amines may serve multiple functions, acting as an antimicrobial
agent, a foaming agent, a radical scavenger and as a heparin
neutralizer.
[0020] Such hemostatic compositions may further comprise heparin
neutralizers, procoagulants or hemostatic agents, such as thrombin,
fibrinogen, fibrin, Factor Xa, or Factor VIIa. By "effective
amount", it is meant that amount necessary to provide to the
compositions those properties for which the additive is being
added. The effective amount also is limited by the maximum amount
that may be added without causing detrimental biological
affects.
[0021] Compositions of the present invention are particularly
advantageous for use in hemostatic compositions where additives
that are sensitive to irradiation, are utilized. For example,
thrombin, in an aqueous solution, has been found to lose all
procoagulant activity when exposed to sterilization irradiation. In
contrast, thrombin retained approximately 40% of its original
enzymatic activity and all of its hemostatic activity after
sterilization when formulated in compositions according to this
invention, as shown in Example 9. While bovine thrombin is
exemplified herein, human-derived thrombin also may be used in
compositions of the present invention.
[0022] Medical devices in which the hemostatic compositions of the
present invention may be utilized include any device currently
being used to apply a flowable or injectable hemostatic paste or
slurry to a site, or wound, requiring hemostasis. The site
requiring hemostasis may be the result of an injury or a surgical
procedure. Examples of devices or applicators include syringes such
as Becton Dickinson or Monoject luer syringes. Other devices are
disclosed in detail in U.S. Pat. No. 6,045,570, the contents of
which are incorporated by reference in their entirety.
[0023] In one embodiment for making compositions of the invention,
a substantially homogenous paste is prepared by first mixing the
particles with the liquid to form a uniform paste. The liquid may
include effective amounts of additives dissolved therein as
described above. The gas then is incorporated into the paste and
mixed until it is homogenously dispersed throughout the paste, thus
providing a discontinuous gaseous phase dispersed throughout the
continuous liquid phase. Mixing may be accomplished by extrusion or
by mixing in a confined space under conditions effective to provide
a uniform dispersion of the solid particles and gas into the liquid
phase. Substantially homogeneous dispersion of the gas into the
paste or slurry is important in providing the compositions with
their desired properties. If the gaseous phase is not homogeneously
dispersed through out the paste, the density of the combined
gaseous phase and paste will not be effective to provide the
compositions with adequate peak expression force both prior to and
after sterilization of the composition. When prepared in this
manner, a preferred volume ratio of gas to paste is from about 1:10
to about 2:1. A more preferred volume ratio of gas to paste is from
about 1:5 to about 1:1. An even more preferred volume ratio of gas
to paste is from about 1:2 to about 1:1.
[0024] Alternately, a mixer, e.g. a double planetary mixer, may be
utilized in making compositions of the present invention. The
liquid is added to the mixer. The liquid may include effective
amounts of additives dissolved therein prior to addition of
particles or the gas to the solution. For example, a saline
solution containing glycerol and benzalkonium chloride may be
prepared and then added to the mixer. A source of gas is provided
to the mixer whereby a first portion of the gas may be added to the
liquid solution. The mixture of gas and liquid is mixed to disperse
the gas in the liquid phase, forming a foam-like consistency. The
balance of the gas and the solid particles are added to the mixer
over time with continuous mixing until all ingredients have been
added. The mixing is continued until such time as a substantially
homogenous composition is formed containing the solid particles and
gaseous phase uniformly dispersed throughout the continuous liquid
phase.
[0025] The hemostatic compositions prepared as above are
transferred into a medical device as described above and the device
containing the hemostatic composition is sterilized, preferably by
ionizing radiation. More preferably, sterilization is by gamma
irradiation as exemplified herein.
[0026] While the following examples demonstrate certain embodiments
of the invention, they are not to be interpreted as limiting the
scope of the invention, but rather as contributing to a complete
description of the invention.
EXAMPLES
[0027] Samples prepared in the Examples below were tested for peak
expression force as determined using a Chatillon TCD 200, using a
50-lb load cell [DFG 550] at a speed of 2 inches/min. An
in-dwelling catheter sheath (size 12-14 gauge) was attached to the
sample syringe to be tested. The syringe then was inserted into a
holding apparatus, which then was loaded onto the test instrument.
The peak expression force was noted.
Example 1
[0028] A total of ten samples were prepared as follows. One gram of
dry Surgifoam.RTM. powder was placed in a plastic container and
mixed with 4 ml of saline. The container was capped and the
contents were shaken until a substantially homogenous paste of
uniform consistency was obtained. The paste was formed into a
cylindrical shape and placed into a 10 cc BD polypropylene
disposable luer syringe. The syringes were then capped and five of
the filled syringes were sterilized by gamma irradiation at a dose
of 25 kGy. The Peak Expression Force was determined and presented
in Table 1. Unsterilized samples are designated as 1a and
sterilized samples are designated as 1b.
[0029] At total of 10 samples were prepared as follows. 1 gm of dry
Surgifoam.RTM. powder was placed in a plastic container and mixed
with 4 ml of saline. The container was capped and the contents were
shaken until a substantially homogenous paste of uniform
consistency was obtained. The paste was formed into a cylindrical
shape and placed into a 10 cc BD polypropylene disposable luer
syringe. A second 10 cc BD luer syringe containing 3 ml of nitrogen
then was connected to the syringe containing the paste such that
the paste could be passed from syringe to syringe. The paste and
gas were extruded back and forth between the syringes to thoroughly
mix and disperse the gas throughout the paste until a substantially
homogeneous foam-like composition of uniform consistency was
obtained. The syringes were then capped and five of the filled
syringes were sterilized by irradiation at a dose of 25 kGy. The
Peak Expression Force was determined and presented in Table 1.
Unsterilized samples are designated as 1a' and sterilized samples
are designated as 1b'.
Example 2
[0030] A total of ten samples were prepared as follows. A saline
solution containing 0.005% by weight of benzalkonium chloride and
5% weight of glycerol was prepared. This solution was used to
prepare homogenous gelatin-powder pastes as described in Example 1.
The paste was formed into a cylindrical shape and placed into a 10
cc BD polypropylene disposable luer syringe. The syringes were then
capped and five of the filled syringes were sterilized by
irradiation at a dose of 25 kGy. The Peak Expression Force was
determined and presented in Table 1. Unsterilized samples are
designated as 2a and sterilized samples are designated as 2b.
[0031] A total of ten samples were prepared as follows. A saline
solution containing 0.005% by weight of benzalkonium chloride and
5% by weight of glycerol was prepared. This solution was used to
prepare homogenous gelatin-powder pastes as described in Example 1.
A second 10 cc BD luer syringe containing 3 ml of nitrogen then was
connected to the syringe containing the paste such that the paste
could be passed from syringe to syringe. The paste and gas were
extruded back and forth between the syringes to thoroughly mix and
disperse the gas throughout the paste until a homogeneous foam-like
composition of uniform consistency was obtained. The syringes were
then capped and five of the filled syringes were sterilized by
irradiation at a dose of 25 kGy. The Peak Expression force was
determined and presented in Table 1. Unsterilized samples are
designated as sample 2a' and sterilized samples are designated as
2b'. TABLE-US-00001 TABLE 1 Peak Expression Force Samples lbs (n =
5) Samples 1a 21.8 Samples 1b 26.4 Samples 1'a 12.0 Samples 1'b
21.0 Samples 2a 17.2 Samples 2b 22.4 Samples 2'a 11.8 Samples 2'b
16.8
[0032] As the data in Table 1 indicates, the inclusion of the
gaseous phase homogenously dispersed throughout the paste
significantly reduces the peak expression force of the composition
prior to sterilization compared to pastes that do not include the
homogenously dispersed gaseous phase or other additives.
Consequently, the sterilized composition including the homogenously
dispersed gaseous phase exhibits an expression force significantly
less than that of a sterilized paste that does not include the
homogenously dispersed gaseous phase. In fact, the sterilized
composition including the gas phase approximates the expression
force of the pre-sterilized paste containing no gaseous phase or
additives. Thus, a fully sterilized composition may be provided
with flowability and/or injectability, as evidenced by peak
expression force, equal to or better than that of a unsterilized
paste containing no gaseous phase or additives, which is beneficial
to health care providers at the point of use. The use of additives,
e.g. benzalkonium chloride and glycerol, may be used to further
enhance the properties of the compositions of the present invention
upon sterilization.
Example 3
[0033] 25 grams of Surgifoam.RTM. gelatin powder were mixed with
125 ml of normal saline containing 0.005% benzalkonium chloride and
5% glycerol, based on weight of saline, until a uniform paste was
formed. The resulting paste was loaded into a 1/2 pint Donvier
mixer fitted with a mixing paddle. A tube connected to a nitrogen
source was fitted through the lid of the mixer and the system
"closed" to the environment by wrapping in a film. The system was
purged with nitrogen for 20 minutes. The paste was then mixed to
homogenously incorporate the nitrogen by rotating the paddle
rapidly by hand. Mixing was terminated when the composition filled
the available volume, indicating homogeneous distribution of the
gas phase. The composition was loaded into a 60 cc syringe and
subsequently dispensed into 10 cc BD luer syringes via a two-way
luer connector. The density of the composition was approximately
0.7-0.75 grams/ml. The syringes were then capped and some of the
filled syringes were sterilized by irradiation at a dose of 25
kGy.
Example 4
[0034] 2.5 liters of normal saline containing 0.005% benzalkonium
chloride and 5% glycerol dissolved therein, based on the weight of
saline, were added to a 2-gallon double planetary Ross mixer and
mixed at maximum speed with a first portion of nitrogen for 5
minutes to form a foamed liquid. 500 grams of Surgifoam gelatin
powder and the balance of nitrogen were added to the foamed liquid
over a 12-minute time period with continuous mixing. The
composition was mixed for a further 10 minutes after all of the
powder and gas was added. The density of the resulting composition
was 0.6 grams/ml. The composition was dispensed into 12 cc Monoject
syringes.
Example 5
[0035] One-gram samples of Surgifoam.RTM. gelatin powder each were
mixed with 5 ml of a saline solution containing 0.005% benzalkonium
chloride and 5% glycerol to form uniform pastes. The resulting
paste was back-loaded into 10 cc BD luer syringes. All air was
extnided from the syringes, leaving the paste packed in the
syringe. The first set of syringes was irradiated with no gas
incorporated therein and designated as sample 5a. A second set of
samples was prepared by dispensing 3 ml of nitrogen into the
syringes containing the uniform paste. The syringes were capped
without further mixing and then stored at 4.degree. C. The samples
were designated as samples 5b. The third set of samples were
prepared by extruding the paste back and forth between the first
syringe and a second syringe containing 3 ml of nitrogen until all
of the nitrogen was homogenously incorporated into the paste. The
fill-volume of the resulting homogeneous compositions was
approximately 9 ml and the density of the composition was
approximately 0.7 grams/ml. The syringes were then capped and some
of the pre-filled syringes were sterilized by irradiation at a dose
of 25 kGy. The Peak Expression Force of the three sets of samples
was determined and presented in Table 2. TABLE-US-00002 TABLE 2
Peak Expression Force Samples lbs (n = 5) Sample 5a 21.7 Sample 5b
20.7 Sample 5c 15.5
[0036] As the data in Table 2 indicates, homogeneous
distribution/dispersion of the gas throughout the paste is
essential to reduce the peak expression force of the composition
prior to irradiation and to maintain the lower peak expression
force of the composition after irradiation, compared to pastes
containing no gas or having gas poorly or partially dispersed there
through.
Example 6
[0037] One gram of Surgifoam.RTM. gelatin powder was mixed with 5
ml of normal saline to form a uniform paste. The resulting paste
was back-loaded into a 10 cc BD luer syringe. All air was extruded
from the syringe leaving the paste packed in the syringe.
[0038] A second set of 10 cc syringes containing nitrogen with
volume ranging from 1 ml to 4 ml, respectively, was fitted to the
first via a two-way luer connector. The paste was extruded into the
gas and then passed back and forth between the two syringes until
all of the gas was homogeneously incorporated into the paste. The
fill-volume of the resulting composition was approximately 6-10 ml
and the density was approximately 0.60 to 1.0 grams/ml, each
depending on the volume of gas introduced into the paste. The
syringes were then capped and some of the pre-filled syringes were
sterilized by irradiation at a dose of 25 kGy. Sterilized samples
were noted as samples 6a through 6e, respectively. The Peak
Expression Force of the sterilized samples was determined and
presented in Table 3. TABLE-US-00003 TABLE 3 Density (g/ml) Peak
Expression Force Samples Gas Volume (ml) (Pre-sterilized) lbs n = 5
Sample 6a 0 1.00 14.8 Sample 6b 1 0.86 12.9 Sample 6c 2 0.75 10.6
Sample 6d 3 0.66 8.6 Sample 6e 4 0.60 8.0
Example 7
[0039] One gram of Surgifoam gelatin powder was mixed with 5 ml of
normal saline to form a uniform paste. The resulting paste was
back-loaded into a 10 cc BD luer syringe. All air was extruded from
the syringe, leaving the paste packed in the syringe. A second set
of 10 cc syringes containing air with volume ranging from 0 ml to 4
ml, respectively, were fitted to the first syringe via a two-way
luer connector. The paste was extruded into the gas and then passed
back and forth between the two syringes until all of the gas was
homogenously incorporated into the paste. The fill-volume of the
resulting composition was approximately 6-10 ml and the density was
approximately 0.60 to 1.0 grams/ml, each depending on the volume of
gas introduced into the paste. The syringes were then capped and
some of the filled syringes were sterilized by irradiation at a
dose of 25 kGy. Sterilized samples were noted as samples 7a through
7e, respectively. The Peak Expression Force of the sterilized
samples was determined and presented in Table 4. TABLE-US-00004
TABLE 4 Density (g/ml) Peak Expression Force Samples Gas Volume
(ml) (Pre-sterilized) lbs n = 5 Sample 7a 0 1.00 14.8 Sample 7b 1
0.86 11.0 Sample 7c 2 0.75 10.9 Sample 7d 3 0.66 10.1 Sample 7e 4
0.60 10.0
Example 8
Hemostatic Performance of Different Materials in Porcine Splenic
Biopsy Punch Model
[0040] A porcine spleen biopsy punch model was used for evaluation
of the hemostatic properties of samples prepared in Examples 1
through 7 and 9. A 6-mm biopsy punch was used to cut a tissue flap
3 mm deep. The tissue flap was cut out and 0.4 ml of the test
materials was applied to the wound site. Manual compression was
held over the wound site for 2 minutes. The wound site was then
observed for up to 3 minutes for signs of bleeding. If bleeding was
observed, additional applications of manual compression for 30
seconds each time were used until complete hemostasis was achieved.
Table 5 lists the results of the evaluation. Results for
unsterilized or sterilized samples are represented as an average
values for all samples tested. TABLE-US-00005 TABLE 5 In vivo
Hemostasis Performance Time to Hemostasis Samples Number of
Compressions (mins:seconds) Samples 1a 3 3:35 (n = 2) Samples 2a 3
3:33 (n = 2) Samples 1b 1 2:00 (n = 3) Samples 2b 2 3:00 (n =
6)
Example 9
[0041] Two vials of lyophilized Bovine thrombin (20,000 units
Thrombogen JJMI) were reconstituted in 20 ml of saline to provide a
working solution of 1000 u/ml. Clotting activity was measured in an
in vitro test as described in Example 10. One vial of this material
was stored at 4-8.degree. C. and the clotting activity measured at
day 1, day 8 and day 30, respectively. The second vial was
sterilized by gamma irradiation (25 kGy) and the clotting activity
measured as above. The unsterilized and sterilized samples were
designated samples 9a and 9b, respectively. Both sterilized and
unsterilized samples were stored at 4-8.degree. C. between
measurements.
[0042] Another 2 vials of 20,000 units of lyophilized bovine
thrombin were reconstituted in saline containing 0.005%
benzalkonium chloride and 5% glycerol. One vial was stored at.
4-8.degree. C. and the clotting activity was measured at day 0, day
1, day 8 and day 30. The second vial was sterilized by gamma
irradiation (25 kGy) and the clotting activity measured as above.
In between measurements both the sterilized and unsterilized
samples were stored at 4-8.degree. C. The unsterilized and
sterilized samples were designated samples 9c and 9d,
respectively.
[0043] Several samples of gelatin paste containing the thrombin
noted above were prepared by mixing 1 gram of Surgifoam gelatin
powder with 5 ml of thrombin solution. The resulting paste was
loaded into a 10 cc syringe. Samples were then either sterilized at
25 kGy followed by storage at 4-8.degree. C., or stored
unsterilized at 4-8.degree. C. Samples so prepared are designated
and identified below. [0044] Sample 9e=1 g Surgifoam.RTM. powder
plus 5 ml of sample 9a; Sterilized [0045] Sample 9f=1 g
Surgifoam.RTM. powder plus 5 ml of sample 9a plus 3 ml Nitrogen:
Foamed and Sterilized [0046] Sample 9g=1 g Surgifoam.RTM. powder
plus 5 ml of sample 9c; Unsterilized [0047] Sample 9h=1 g
Surgifoam.RTM. powder plus 5 ml of sample 9c; Sterilized [0048]
Sample 9i=1 g Surgifoam.RTM. powder plus 5 ml of sample 9c plus 3
ml Nitrogen; Foamed and Sterilized
Example 10
[0049] Measurement of Thrombin Activity by an in Vitro Coagulation
Test in a Fibrometer Instrument (BBL)
[0050] Method: Serial dilutions of test sample containing thrombin
were prepared in Veronal buffer pH 7.2. 0.2 ml of pooled normal
plasma (Citrol Level 1 control plasma-Dade Diagnostics) was warmed
to 37.degree. C. in the fibrometer incubator block. 0.1 ml of
pre-warmed sample dilution was added to the plasma and the timer
started simultaneously. The time to clot formation was recorded.
All samples were tested in duplicate and an average clotting time
calculated. Data was graphed as the log.sub.10 dilution vs.
log.sub.10 clotting time and a regression analysis performed.
Freshly prepared thrombin was considered to have 100% activity and
all other samples were calculated as a percentage of the activity
relative to the freshly prepared thrombin. Results are presented in
Table 6 and Table 7. TABLE-US-00006 TABLE 6 Effect of Storage time
on Thrombin Activity: Stabilization by Formulated Gelatin Paste
Storage Solution Percent Loss in Thrombin Activity (Stored at
6.degree. C.) Time 0 Day 1 Day 8 Day 30 9a 0 0 53.3 90.8 9c 0 NA
41.1 82.9 9g 0 0 0.8 0
[0051] TABLE-US-00007 TABLE 7 Effect of Gamma Irradiation on
Thrombin Activity: Stabilization by Formulated Gelatin paste Media
for Sterilized Thrombin * Samples % Loss in Thrombin Activity (5
ml/g gelatin powder - 25 kGy Dose) Day 6 Day 20 9b 100 100 9d 96.0
100 9e 72.6 NA 9f 66.8 56-72 9h 79.2 ND 9i 63.8 61-73
[0052] TABLE-US-00008 TABLE 8 In vivo Hemostasis Performance of
Pre-filled Thrombin/Gelatin Paste Time to Hemostasis TIME: SAMPLE
Number of Compressions (mins:secs) Day 0: 9 g 1 0:30 Day 42: 9 g 1
0:30 Day 42: 9 g 1 0:30 Day 42: 9 h 1 0:30 Day 42: 9 h 1 0:30
* * * * *