U.S. patent application number 12/956709 was filed with the patent office on 2011-03-24 for method of making flexible bioresorbable hemostatic packing and stent having a preselectable in-vivo residence time.
This patent application is currently assigned to MEDTRONIC XOMED, INC.. Invention is credited to Matthew J. Halvorsen, Leah Kavanagh, Dana A. Oliver.
Application Number | 20110070285 12/956709 |
Document ID | / |
Family ID | 36034279 |
Filed Date | 2011-03-24 |
United States Patent
Application |
20110070285 |
Kind Code |
A1 |
Oliver; Dana A. ; et
al. |
March 24, 2011 |
METHOD OF MAKING FLEXIBLE BIORESORBABLE HEMOSTATIC PACKING AND
STENT HAVING A PRESELECTABLE IN-VIVO RESIDENCE TIME
Abstract
The invention provides a method of making flexible bioresorbable
foam having hemostatic properties and a preselectable in-vivo
residence time. A blend of crosslinked collagen blended and a
hyaluronic acid component is prepared. The blend is mixed with
water to form a suspension. The blend is freezed and lyophilized at
less than about 0.degree. C. Next, the blend is crosslinked. The
product is then sterilized and chain scission is performed by
bombardment with gamma rays or a beam of electrons.
Inventors: |
Oliver; Dana A.;
(Jacksonville, FL) ; Halvorsen; Matthew J.;
(Hopkinton, NH) ; Kavanagh; Leah; (Jacksonville,
FL) |
Assignee: |
MEDTRONIC XOMED, INC.
Jacksonville
FL
|
Family ID: |
36034279 |
Appl. No.: |
12/956709 |
Filed: |
November 30, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10938999 |
Sep 10, 2004 |
7858107 |
|
|
12956709 |
|
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|
Current U.S.
Class: |
424/426 ;
514/54 |
Current CPC
Class: |
A61L 24/0042 20130101;
A61L 2202/21 20130101; A61P 17/02 20180101; A61L 2400/04 20130101;
A61K 31/728 20130101; A61L 24/0036 20130101; A61P 7/04 20180101;
A61L 2/0035 20130101; A61L 24/043 20130101 |
Class at
Publication: |
424/426 ;
514/54 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/728 20060101 A61K031/728; A61P 17/02 20060101
A61P017/02; A61P 7/04 20060101 A61P007/04 |
Claims
1. A method of making a flexible bioresorbable foam having a
preselectable in-vivo residence time comprising the steps of:
preparing a blend consisting of crosslinked collagen blended with a
hyaluronic acid component, mixing the blend with water to form a
suspension; freezing and lyophilizing the suspension at less than
about 0.degree. C.; crosslinking the suspension to form a
crosslinked product, and sterilizing and performing chain scission
on the product by means of bombardment with gamma rays or a beam of
electrons.
2. The method of making flexible bioresorbable foam of claim 1,
wherein the lyophilization is performed at a temperature of less
than about -40.degree. C.
3. The method of making flexible bioresorbable foam of claim 1,
wherein the crosslinking is achieved by means of a method selected
from dehydrothermal crosslinking and chemical crosslinking.
4. The method of making flexible bioresorbable foam of claim 1,
wherein crosslinking is achieved by use of formaldehyde vapor.
5. The method of making flexible bioresorbable foam of claim 4,
wherein the formaldehyde vapor is evacuated after a period of
between about 2 hours and about 7 hours.
6. The method of making flexible bioresorbable foam of claim 1,
wherein the blend comprises between about 70 percent and about 90
percent by weight of the esterified hyaluronic acid.
7. The method of making flexible bioresorbable foam composition of
claim 1, wherein the sterilizing is performed by bombardment with
gamma rays.
8. The method of making flexible bioresorbable foam of claim 1,
wherein the hyaluronic acid component is selected from hyaluronic
acid, esterified hyaluronic acid and mixtures thereof.
9. The method of making flexible bioresorbable foam of claim 8,
wherein the esterified hyaluronic acid has an esterification level
of between about 60 percent and about 70 percent.
10. The method of making flexible bioresorbable foam of claim 9,
wherein the esterified hyaluronic acid is selected from the group
consisting of a benzyl ester of hyaluronic acid, an ethyl ester of
hyaluronic acid and mixtures thereof.
11. The method of making flexible bioresorbable foam of claim 1,
wherein the crosslinked collagen is a microfibrillar collagen.
12. The method of making flexible bioresorbable foam of claim 1,
wherein the preselectable residence time ranges between about 5
days and about 14 days.
13. A method of making a flexible bioresorbable foam having a
preselectable in-vivo residence time, wherein the method comprises
the steps of: preparing a blend consisting of crosslinked collagen
blended with a hyaluronic acid component, mixing the blend with
water to form a mixture; freezing the mixture; lyophilizing the
mixture; crosslinking the mixture to form a crosslinked product,
and sterilizing and performing chain scission the product.
14. The method of making flexible bioresorbable foam of claim 13,
wherein crosslinking is achieved using formaldehyde vapor.
15. The method of making flexible bioresorbable foam of claim 14,
wherein the formaldehyde vapor is evacuated after a period of
between about 2 hours and about 7 hours.
16. The method of making flexible bioresorbable foam of claim 13,
wherein the blend comprises between about 70 percent and about 90
percent by weight of the esterified hyaluronic acid.
17. The method of making flexible bioresorbable foam composition of
claim 13, wherein the sterilizing is performed by bombardment with
gamma rays.
18. The method of making flexible bioresorbable foam of claim 13,
wherein the hyaluronic acid component is selected from hyaluronic
acid, esterified hyaluronic acid and mixtures thereof.
19. The method of making flexible bioresorbable foam of claim 18,
wherein the esterified hyaluronic acid has an esterification level
of between about 60 percent and about 70 percent.
20. The method of making flexible bioresorbable foam of claim 19,
wherein the esterified hyaluronic acid is selected from the group
consisting of a benzyl ester of hyaluronic acid, an ethyl ester of
hyaluronic acid and mixtures thereof.
21. The method of making flexible bioresorbable foam of claim 13,
wherein the crosslinked collagen is a microfibrillar collagen.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application No. 10/938,999, which was filed on Sep. 10, 2004, the
contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
bioresorbable packing and stents, and more specifically to a method
of making flexible bioresorbable foam, useful for post-operative or
drug delivery use, having both hemostatic properties and a
preselectable in-vivo residence time.
BACKGROUND OF THE INVENTION
[0003] Various types of sterile packing and stents are used in the
medical and surgical fields for keeping tissues apart or preventing
adhesion. Such uses include, but are not limited to, nasal packing
and sinus stents, packing for inner ear surgery, tympanoplasty,
exostosis, orbital decompression, as well as various orifice
restenosis prevention uses. Personal uses such as tampons,
bandaging and the like also involve sterile packing materials.
[0004] Such packing and stents have been made from gauzes,
microfibers, non-fibrous expandable packing, such as tampons, and
the like. These types of packing are not bioresorbable and can
cause injury or discomfort upon removal, as well as causing toxic
shock syndrome if left internally for more than a day or two.
[0005] In an attempt to prevent such reactions, while continuing to
prevent adhesion and tissue necrosis, resorbable packing and stent
devices have been developed. Such packing materials have typically
included hyaluronic acid (HA), or salts of hyaluronic acids, which
are naturally occurring mucopolysaccharides found in various body
fluids and connective tissues. Thus, HA is biocompatible. It has
been adapted for use as a surgical aid to prevent tissue contact
and adhesion formation.
[0006] However, HA has a very high solubility, and thus poor liquid
absorption, and tends to quickly disperse when exposed to such
liquids. This reduces HA materials' effectiveness in areas such as
surgical wounds that exude blood and other fluids. Crosslinking has
created somewhat insoluble HA materials.
[0007] Further, other biocompatible materials such as
polysaccharides, especially methylcellulosic materials have been
combined with the hyaluronic acid to produce packing materials that
are resorbable but are also insoluble and have a longer in-vivo
residence time before they dissolve into gels and are absorbed by
the body tissues. These materials also have increased fluid
absorption capabilities. Such materials stop bleeding only by
effect of compression and packing and do not have any inherent
hemostatic properties.
[0008] Collagen is also known for use in the medical field. It is a
major protein constituent of connective tissue and is widely used
in medical and surgical applications such as sutures, grafts and
surgical prostheses. Typical sources include calfskin, bovine
Achilles tendons, cattle bones, porcine tissue, human cadaver
tissue, and rat tails. Collagen, as an animal protein, is
bioresorbable, even when crosslinked to reasonable levels. Collagen
is available in a variety of forms including powders and fibrils,
and in aqueous solution. Collagen may be provided in insoluble or
soluble forms.
[0009] It has now been discovered that a flexible bioresorbable
foam for packing, post-operative use, and other medical uses may be
created having both hemostatic properties and a variable
preselectable resorption time (also known as an in-vivo residence
time). The foam is formed from a blend of collagen and hyaluronic
acid or derivative thereof.
SUMMARY OF THE INVENTION
[0010] An embodiment of the invention provides a method of making
flexible bioresorbable foam having hemostatic properties and a
variable preselectable resorption time comprising the steps of:
[0011] providing a blend of collagen and an hyaluronic acid
component comprising from about 70 to about 90 weight percent of
the esterified hyaluronic acid; [0012] mixing with water to form a
suspension; [0013] freezing and lyophilizing the blend at 0.degree.
C. or below; [0014] crosslinking to form a flexible crosslinked
product; and [0015] sterilizing and performing chain scission on
the crosslinked product by means of bombardment with gamma rays or
electrons.
[0016] In one method of making the bioresorbable flexible foam of
an embodiment of the invention, the foam is crosslinked using a
chemical crosslinking agent.
[0017] These terms when used herein have the following
meanings.
[0018] The term "bioresorbable" as used herein, means capable of
being absorbed by the body.
[0019] The term " hemostat" means a device or material which stops
blood flow.
[0020] The term "stent" means a material or device used for
separating tissue and holding it in such separated position.
[0021] The term "lyophilizing" means freeze-drying.
[0022] The term "resorption time" and "in-vivo residence time" are
used interchangeably, and refer to the time between insertion into
the body and the time at which the material has been substantially
absorbed into the tissues.
[0023] The term "adhesion" as used herein, refers to the sticking
together of tissues which are in intimate contact for extended
periods.
[0024] The term "preselectable in-vivo residence time" means that
foams of the invention may be formed that will have different
in-vivo residence times to be useful for different
applications.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] The following detailed description describes certain
embodiments and is not to be taken in a limiting sense. The scope
of the present invention is defined by the appended claims.
[0026] The bioresorbable hemostatic packing provided herein may be
used in any manner in which sterile packing and/or stents are
normally used in the surgical or medical fields, including uses for
which control of low weight bleeding and adhesion prevention are
important. Such uses include, but are not limited to, nasal packing
and sinus stents, packing for inner ear surgery, tympanoplasty,
exostosis, orbital decompression, as well as various orifice
restenosis prevention uses. The packing materials may also be used
as single or combination drug delivery systems for humans or
mammals.
[0027] Bioresorbable foams of an embodiment of the invention are
formed from a blend of a hyaluronic acid component and collagen.
Varying ratios of the components may be used in the blends
according to the application desired, e.g., 50/50, 60/40 etc. A
typical blend may comprise from about 70 to about 90 weight percent
of the hyaluronic acid component, and correspondingly from about 10
to about 30 weight percent of collagen. In one embodiment, the
blend contains from about 70 to about 80 weight percent of the
hyaluronic acid or derivative thereof. The ratios of such blends
can be selected by the particular application anticipated. For
example, higher amounts of collagen will increase the hemostatic
effect somewhat.
[0028] Collagen materials useful in blends of an embodiment of the
invention are absorbable collagen materials from any source, e.g.,
corium collagen, tendon collagen, and the like, available
commercially from such companies as Datascope.RTM. and Fibrogen,
Inc. In one embodiment, the blends are formed of a microfibrillar
collagen foam that includes a collagen flour. Such collagen
materials are available from Davol Inc., a subsidiary of C. R.
Bard, Inc., as Avitene.RTM..
[0029] Useful hyaluronic acid components include hyaluronic acid,
derivatives thereof, and mixtures thereof. One particularly useful
derivative is esterified hyaluronic acid. Useful ester derivatives
may be partial or total esters of hyaluronic acid; e.g., hyaluronic
acid esterified with aliphatic or araliphatic esters such as ethyl
esters, octadecyl esters, benzyl esters and mixtures thereof. In
one embodiment the blend comprises a partial esterified hyaluronic
acid; especially, an esterified HA having an esterification of at
least about 60%. One useful esterified hyaluronic acid has an
esterification level of from about 60% to about 70%. Such materials
are available commercially from Fidia Advanced Biopolymers, S.r.l.
under the trade name Hyaff.RTM..
[0030] The in-vivo residence times of flexible foams of an
embodiment of the invention may be selected to be from about 5 days
to about 28 days; in some embodiments, the foam will have an
in-vivo residence time of from about 5 days to about 14 days. The
in-vivo residence time for the flexible bioresorbable foams of an
embodiment of the invention is controlled by adjusting the
re-suspension shear parameters, the level of crosslinking of the
foam ingredients to produce the desired level; the sterilization
bombardment must also be controlled in order to control the chain
scission caused by such bombardment.
[0031] In one embodiment, the foams are formed by a method that
includes the formation of a suspension of the collagen and the
esterified hyaluronic acid in water. The suspension is formed by
mixing with conventional mixers until suspended. The suspension is
mixed at a shear rate of from about 0.25 minutes/liter to about 3.0
minutes/liter, and at a speed of from about 7,000 rpm to about
10,000 rpm. The suspension is then metered into lyophilization
trays with a series of cavities. Typical trays have cavities
nominally about 4 cm by 1.3 cm by 1 cm.
[0032] The suspended solution is then freeze-dried into solid foam
blocks using well known procedure involving vacuum conditions at
temperatures that are less than the freezing temperature of water,
i.e., less than 0.degree. C. After 0.degree. C. is reached, the
temperature is then reduced further over time, and cycled; e.g.,
the temperature is reduced by a few degrees then maintained at the
lower temperature for a period of time, and then reduced again.
[0033] Finally, the temperature reaches a low of about -45.degree.
C. where it is maintained for the period required to complete the
lyophilization. In certain embodiments, the lyophilization can be
more than 10 hours, and perhaps as much as 24-30 hours. The drying
portion of the lyophilization is performed at a vacuum set point of
about 75 mm of mercury (Hg) with the temperature being raised to
about 0.degree. C. and maintained there for at least about 2 hours,
and up to about 6 hours, then raised to at least about 25.degree.
C. to a period of from about 4 hours to about 40 hours.
[0034] Upon completion of lyophilization, the foam is then ready to
be crosslinked. Crosslinking may be accomplished by dehydrothermal
crosslinking, or by exposure to a chemical crosslinking agent. In
dehydrothermal crosslinking, the foam is dehydrated to reduce the
moisture content to the temperature at which crosslinking occurs,
typically to less than about 1%. The product is subjected to
elevated temperatures and/or vacuum conditions until crosslinking
occurs. Useful combinations of such conditions include vacuum of at
least about 10-5 mm of mercury, and temperatures of at least about
35.degree. C. Naturally, if vacuum is not used, much higher
temperatures are required, e.g., above 75.degree. C. The conditions
are maintained for at least about 10 hours, typically for about 24
hours until the desired molecular weight has been achieved.
[0035] If chemical crosslinking is desired, useful chemical
crosslinking agents include aldehydes, e.g., formaldehyde vapor,
which can be used by pumping it into a room containing the
lyophilized foam and allowed to contact the foam for at least about
2 hours, preferably at least about 5 hours. After the desired
exposure time is complete, the crosslinking agent is evacuated from
the room.
[0036] After crosslinking, the foam is then ready for compression,
packaging and sterilization, typically by bombardment with gamma
rays or electron beam bombardment. The bombardment both kills
bacteria and performs chain scission on the foam. It is important
that the sterilization/chain scission procedure and the
crosslinking procedure be balanced to produce the desired
crosslinking level to achieve the in-vivo residence time desired.
The bioresorbable foam of the invention is flexible and does not
require any rehydration.
[0037] The bioresorbable foam of the invention can be easily
handled either wet or dry and may be squeezed, and/or cut to
required size. The foam will contour to the body cavity or wound as
required, and provides chemical hemostasis as well as preventing
adhesion, and minimizing swelling and edema.
[0038] Although specific embodiments have been illustrated and
described herein for purposes of description of the preferred
embodiment, it will be appreciated by those of ordinary skill in
the art that a wide variety of alternate and/or equivalent
implementations calculated to achieve the same purposes may be
substituted for the specific embodiments shown and described
without departing from the scope of the present invention. Those
with skill in the chemical, mechanical, biomedical, and
biomaterials arts will readily appreciate that the present
invention may be implemented in a very wide variety of embodiments.
This application is intended to cover any adaptations or variations
of the preferred embodiments discussed herein. Therefore, it is
manifestly intended that this invention be limited only by the
claims and the equivalents thereof.
* * * * *