U.S. patent number 3,666,750 [Application Number 04/885,313] was granted by the patent office on 1972-05-30 for hemostatic material.
This patent grant is currently assigned to Johnson & Johnson. Invention is credited to Theodore S. Briskin, Allen H. Remanick.
United States Patent |
3,666,750 |
Briskin , et al. |
May 30, 1972 |
HEMOSTATIC MATERIAL
Abstract
A new and improved hemostatic material formed of an oxidized
cellulosic material and method for its preparation wherein an
oxidized cellulosic material is treated with a borohydride under
alkaline conditions.
Inventors: |
Briskin; Theodore S. (Beverly
Hills, CA), Remanick; Allen H. (Pasadena, CA) |
Assignee: |
Johnson & Johnson (New
Brunswick, NJ)
|
Family
ID: |
25386623 |
Appl.
No.: |
04/885,313 |
Filed: |
December 15, 1969 |
Current U.S.
Class: |
536/56; 606/154;
602/49 |
Current CPC
Class: |
A61L
15/28 (20130101); C08B 15/00 (20130101); A61L
15/28 (20130101); C08L 1/04 (20130101); A61L
2400/04 (20130101) |
Current International
Class: |
A61L
15/28 (20060101); A61L 15/16 (20060101); C08B
15/00 (20060101); A61l 015/00 (); C08b 015/02 ();
C08b 023/02 () |
Field of
Search: |
;260/212 ;131/2
;128/325 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Czaja; Donald E.
Assistant Examiner: Griffin; Ronald W.
Claims
We claim:
1. In the method of stabilizing a hemostatic material consisting of
an oxycellulose pad, the improvement comprising immersing said
oxycellulose pad in an aqueous alcoholic solution containing a
borohydride for a period of from 0.1 to 5 hours at a temperature of
from 0.degree. to 70.degree. C. and a pH of 9-12.
2. A process as defined in claim 1 wherein said borohydride is
sodium borohydride.
3. A process as defined in claim 1 wherein said solution contains
at least 20 percent by weight of alcohol.
4. In the method of stabilizing a hemostatic material consisting of
a cellulosic pad, the improvement comprising first oxidizing said
cellulosic gauze pad with nitrogen dioxide and thereafter immersing
said cellulosic pad in an aqueous alcoholic solution at a pH of
from 9-12 wherein said solution contains an alkali borohydride.
5. A process as defined in claim 4 wherein said nitrogen dioxide is
in the liquid phase.
6. A process as defined in claim 4 wherein said nitrogen dioxide is
in the gaseous phase.
Description
This invention relates to materials for the control of bleeding,
and more particularly to hemostatic material formed of oxidized
cellulose.
It is known that cellulosic material may be selectively oxidized
with nitrogen dioxide to convert more than 90 percent of the
methylol groups in the cellulosic molecule to yield a product which
may be referred to as an oxycellulose or polyuronic acid. It is
similarly known, as illustrated by U.S. Pat. Nos. 1,197,400 and
2,232,990, that oxidized cellulose may be used as a hemostatic
material for the control of bleeding. The use of oxycellulose as
compared to other hemostatic materials heretofore known, such as
conventional gauze pads and the like treated with ferric chloride,
thrombin, etc., represents a significant improvement since
oxycellulose may be left in a closed wound without the result of a
severe local tissue reaction in response to the presence of foreign
material.
However, the primary disadvantage of hemostatic materials formed of
oxidized cellulose heretofore known is that they lack stability
whereby they must be used within a short time after manufacture, or
they must be stored under refrigeration. Various attempts to
overcome this disadvantage, such as by the washing of oxidized
cellulose after oxidation with an anhydrous alcohol as suggested by
U.S. Pat. No. 3,364,200, have been made. However, such attempts
have generally been unsuccessful in that the use of an anhydrous
alcohol is expensive, and does not significantly increase the
stability of the resulting oxidized cellulose.
It is accordingly an object of the present invention to provide a
new and improved hemostatic material formed of oxidized cellulose
which is stable at room temperatures, and need not be stored under
refrigeration.
It is another object of the present invention to provide a simple
and inexpensive method for treating oxidized cellulose to improve
the thermal stability of oxidized cellulose for use in hemostatic
materials.
These and other objects and advantages of the present invention
will appear hereinafter, and, it will be understood that the
following specific examples are provided by way of illustration,
and not by way of limitation, of the concepts of the present
invention.
The present invention is addressed to a method for the treatment of
an oxidized cellulosic material in order to improve the thermal
stability of the oxidized cellulosic material when used as a
hemostatic material. The oxidized cellulose to be treated in
accordance with the practice of the present invention may be
derived from any of a wide variety of cellulosic material,
including but not limited to wood pulp, cotton, cotton linters,
ramie, jute, paper, hemp, regenerated cellulose or rayon as well as
a wide variety of others known to those skilled in the art.
However, it is generally preferred to make use of cellulose in the
form of cotton or regenerated cellulose, such as that prepared by
the viscose process, because of their greater purity. The oxidized
cellulosic material may be in the form of a knit or a woven fabric,
such as gauze or in a fibrous thread or film form.
The oxidized cellulosic material may be prepared by the selective
oxidation using nitrogen dioxide, using a wide variety of
techniques. For example, it is possible to form the oxidized
cellulosic material by treatment of the raw cellulosic material
with liquid nitrogen dioxide in the ratio of 1 part by weight
cellulose per 5-1,000 parts by weight liquid nitrogen dioxide, and
preferably 1 part by weight cellulosic material to 25-50 parts by
weight of the liquid nitrogen dioxide, as disclosed in copending
application, Ser. No. 745,221, filed July 16, 1968, now U.S. Pat.
No. 3,516,416, issued June 23, 1970. The reaction described therein
is carried out at a temperature of 15.degree.-65.degree. C., and at
autogenous pressure when the reaction temperature exceeds
21.degree. C., the boiling point of nitrogen dioxide. Another
method for effecting this oxidation is disclosed in copending
application, Ser. No. 745,135, filed July 16, 1968, now U.S. Pat.
No. 3,491,766, issued Jan. 27, 1970, wherein the oxidation
reaction, including reaction rate and amount of conversion, is
materially improved by formulation of the oxidation reaction
mixture to contain up to 8 percent by weight water in the liquid
nitrogen dioxide system and by carrying out the reaction at
elevated temperatures, generally about 15.degree. C., and
preferably within the range of 20.degree.-45.degree. C., depending
somewhat upon the amount of moisture present in the reaction
medium, whereby the reaction medium is rendered relatively
non-electrically conductive so that the presence of water in the
reaction medium will not result in attack or degradation of the
cellulosic material to be oxidized, and wherein the formulation to
include aqueous medium in the reaction mixture of liquid nitrogen
dioxide also operates to adjust the specific gravity of the
reaction mixture in the direction toward the specific gravity of
the cellulosic material whereby suspension of the cellulosic
material in the reaction medium is easier to achieve and maintain.
The result is a more rapid and uniform oxidation reaction of the
cellulosic material to produce a higher quality product at a more
rapid rate.
It is also possible, and frequently preferred in accordance with
the practice of the present invention, to employ an oxidized
cellulose which has been prepared by the selective oxidation of
cellulose with gaseous nitrogen dioxide or a mixture of gaseous
nitrogen dioxide and nitric oxide. The reaction may be conveniently
carried out by contacting the cellulose to be oxidized with the
gaseous nitrogen oxide or oxides at a temperature within the range
of 30.degree.-220.degree. C. for a period of up to 40 hours to
oxidize at least 80 percent of the methylol groups present in the
cellulose molecule.
A further method for effecting the gaseous phase oxidation of
cellulose is disclosed in copending application, Ser. No. 774,064,
filed Nov. 7, 1968, now U.S. Pat. No. 3,577,994, issued May 11,
1971, wherein the cellulosic material is first wetted with a liquid
nitrogen dioxide, which may optionally contain up to 8 percent by
weight water, and then is exposed to hot gaseous nitrogen dioxide.
This particular method can be advantageously used in the form of a
continuous process for the production of large quantities of
oxidized cellulosic material.
The concepts of the present invention reside in a process for the
treatment of oxidized cellulosic material, independent of the
method by which the cellulosic material is oxidized, with a
borohydride under alkaline conditions to improve the thermal
stability of the treated oxidized cellulose during storage. In
accordance with the practice of the present invention, an oxidized
cellulosic material is treated with a borohydride, such as ammonium
borohydride, an alkali metal borohydride (e.g., lithium
borohydride, sodium borohydride, potassium borohydride, etc.) or an
alkaline earth metal borohydride (e.g., magnesium borohydride,
calcium borohydride, etc.) at an alkaline pH. Thereafter the
treated oxidized cellulose is washed with dilute acid to destroy
the borohydride, and then washed again with alcohol to remove any
remaining acid and dried. It has been found that oxidized
cellulosic materials treated in this manner may be used as
hemostatic materials which are completely stable at room
temperatures, and can be stored for long periods of time without
the need to store under refrigeration conditions.
The treatment of the oxidized cellulosic material with the
borohydride may be conveniently carried out by placing the oxidized
cellulosic material in contact with a water-alcohol mixture, and
then raising the pH of the resulting mixture to at least 8.5, and
preferably to a pH within the range of 9-12 by adding thereto a
base, such as an alkali metal hydroxide or an ammonium hydroxide.
Thereafter, the borohydride may be added to the basic
oxycellulose-water-alcohol mixture to provide a ratio of 1 part by
weight borohydride for every 1-100 parts by weight of oxidized
cellulose. The resulting solution containing the borohydride may
then be allowed to stand at a temperature within the range of
0.degree.-70.degree. C. for a period of 0.1 to 5 hours.
The water-alcohol mixture preferably comprises a mixture of water
and an alkanol having one to five carbon atoms, such as methanol,
ethanol, isopropanol, etc., wherein the alcohol is present in an
amount constituting at least 20 percent by weight, and preferably
50-85 percent by weight, of the water-alcohol mixture. After the
treatment with the borohydride has been completed, the treated
oxidized cellulose may then be removed and washed with a dilute
mineral acid, such as dilute hydrochloric acid or a mixture of
dilute hydrochloric acid and an aliphatic alcohol, to destroy the
borohydride and to remove any metal salts which may be present in
the treated oxidized cellulosic material. Thereafter, the treated
oxidized cellulosic material is preferably washed again with an
alcohol to remove any acid remaining. The treated cellulose may
then be dried and sterilized in a conventional manner, such as by
the treatment of the oxidized cellulosic material with
formaldehyde.
The following examples will serve to illustrate the principal
concepts of the present invention.
EXAMPLE 1
A piece of cotton gauze is oxidized by contacting it with gaseous
nitrogen dioxide for a period of 25 hours at 20.degree. C. After
the oxidation reaction is completed, the gauze of oxidized
cellulose is washed with a mixture of equal parts by weight of
water and ethanol to remove remaining nitrogen oxides and to
prevent shrinkage.
Thereafter, the gauze of oxidized cellulose is immersed in a
mixture of 70 percent by weight methanol and 30 percent by weight
water, and a sufficient quantity of a solution of 0.5 N sodium
hydroxide is added to raise the pH of the solution to about 10.5.
Next, sodium borohydride is added to the solution to provide a
ratio of 0.1 parts by weight sodium borohydride per 1 part oxidized
cellulose. The oxidized cellulose is allowed to remain in contact
with the borohydride solution for 1 hour at room temperature, and
then the treated oxidized cellulose is removed from the solution,
washed with dilute hydrochloric acid, and washed with ethanol.
The resulting product is dried and sterilized, and is found to have
excellent stability at room temperatures.
It will be understood that the step of washing the oxidized
cellulosic material with an aliphatic alcohol, such as methanol,
ethanol, isopropanol, or water, or mixtures thereof prior to the
borohydride treatment(the use of an ethanol-water mixture as
exemplified in Example 1 is an optional step. It is frequently
preferred to wash the oxidized cellulosic material in this manner
subsequent to oxidation in order to insure the dimensional
stability and thereby avoid shrinkage.
EXAMPLE 2
A gauze pad formed of rayon is wetted with liquid nitrogen dioxide
at ambient temperature and atmospheric pressure, and allowed to dry
until it has a dry appearance. Thereafter, the pad is exposed to
gaseous nitrogen dioxide at atmospheric pressure at a temperature
of 70.degree. C. An oxidation level corresponding to oxidation of
about 25 percent of methylol groups present is obtained.
Repetition of the foregoing cycle of wetting with nitrogen dioxide,
drying and contacting with gaseous nitrogen dioxide is repeated
until the oxidation level reaches at least 90 percent.
Thereafter, the pad is immersed in a methanol-water mixture
containing 65 percent by weight methanol, and the pH of the
solution is raised by adding sufficient 0.5 N KOH until the pH is
about 10. Then, sodium borohydride is added to the solution in an
amount to provide a ratio of about 0.2 parts by weight borohydride
per 1 part of oxidized cellulose, and the oxidized cellulose is
allowed to remain in contact with the solution for a period of 50
minutes.
The treated oxidized cellulose is then removed from the solution,
washed with a dilute HCl-methanol mixture and washed again with
ethanol. After drying and sterilization, the pad is found to have
excellent stability at room temperatures.
EXAMPLE 3
A pad of cotton fibers is wetted with liquid nitrogen dioxide
containing 2 percent water, and is then exposed, while still wet
with liquid nitrogen dioxide, to hot gaseous nitrogen dioxide at
70.degree. C. and atmospheric pressure. The cellulose is found to
be 45 percent oxidized based upon the methylol groups in the
cellulose.
The foregoing procedure is repeated until the cellulose is at least
90 percent oxidized, and then the pad is washed with aqueous
methanol. Thereafter, the pad is immersed in an ethanol-water
mixture containing 75 percent by weight methanol, and the pH of the
solution is raised to about 10 by adding 0.6 N NaOH.
Potassium borohydride is added, and the mixture is allowed to stand
for 1.5 hours at ambient temperatures. The treated oxidized
cellulose is removed from the solution, washed in the manner shown
in Example 1, dried and sterilized.
The hemostatic materials of oxidized cellulose treated in
accordance with the practice of the invention are susceptible to a
wide variety of uses. Oxidized cellulose treated in accordance with
the present invention is a natural hemostat, and forms, when
contacted with human blood, a dark gellatinous mass which in effect
serves as an artificial clot within the area of the bleeding within
a few minutes from the time the oxidized cellulose is applied.
One of the principal advantages of the use of an oxidized cellulose
treated in accordance with the concepts of the present invention is
that it gradually dissolves and/or absorbed by body fluid which
makes it possible to utilize hemostatic materials formed of the
material in closed wounds without the concommitant occurrence of an
adverse tissue reaction.
The hemostatic materials of the present invention in the form of
knitted fabrics, carded fiber pads, sutures and like articles have
broad application in any type of surgery,and in other situations
where the control of bleeding is required. The material is placed
in contact with the bleeding vessel whereby a clot forms within a
few minutes. The wound may be, if conditions dictate, closed with
the hemostatic material in place, and the hemostat will be
dissolved by body fluids. Alternatively, the material may be
removed after a clot has formed without sticking of the material to
the wound or renewed bleeding since the portion of the material
directly in contact with the wound has dissolved.
It will be apparent from the foregoing that the present invention
provides a new and improved oxidized cellulosic material which may
be used as a hemostatic material having heretofore unattainable
stability, and which may be prepared by a simple and economic
process without the need to employ expensive reagents.
It will be understood that various changes and modifications may be
made in the details of formulation and procedure and use which
provide the characteristics of the invention without departing from
the spirit thereof, particularly as defined in the following
claims.
* * * * *