Water-insoluble polysaccharide hydrogel foam for medical applications

A water-insoluble polysaccharide hydrogel foam and a method and article of preparing a homogeneously foamed hydrogel from a two component aqueous system of water-soluble polysaccharides bearing pendant carboxylate groups. The hydrogel foam, when it incorporates an antimicrobial, has particular utility as a surgical preparation for vaginal or rectal surgery.

TECHNICAL FIELD 
This invention relates to the preparation of a waterinsoluble 
polysaccharide hydrogel foam, and in particular to a process and article 
useful for preparing the foamed hydrogel from a two component aqueous 
system. The hydrogel foam, when it incorporates an antimicrobial, has 
particular utility as a surgical preparation for vaginal or rectal 
surgery. 
BACKGROUND ART 
Gels formed by crosslinking polysaccharides bearing pendant carboxylate 
groups have been known and used for many years in the areas of dental 
health care and food preparation technologies. Of these gels, the most 
commonly encountered are composed of water-insoluble alginates which 
include, with the exception of magnesium and the alkali metal salts, the 
group II metal salts of alginic acid. These water-insoluble alginate gels 
are typically formed by the chemical conversion of water-soluble 
alginates, in an aqueous solution, into water-insoluble alginates. This 
conversion usually is accomplished by the reaction of a water-soluble 
alginate with polyvalent cations released from a soluble di- or trivalent 
metal salt. The water-soluble alginates include the ammonium, magnesium, 
potassium, sodium, and other alkali metal salts of alginic acid. 
The most common of the alginate gels is composed of calcium aliginate. 
Sources for the crosslinking calcium ions used in the formation of these 
gels generally include calcium carbonate, calcium sulfate, calcium 
chloride, calcium phosphate, and calcium tartrate. 
Controlling the time of gelatin has traditionally been an integral part of 
conventional methods of preparing these calcium alginate gels and is 
usually accomplished by regulating the concentration of free calcium ions 
in the solution. Typically the concentration of free calcium ions is 
controlled by manipulation of the ionization rate of the calcium salt 
and/or by the inclusion of other compounds in the solution which react 
with the free calcium ions. 
Conventional processes regulate the rate of ionization by selecting a 
calcium salt having the desired solubility and/or by adjusting the pH of 
the solution to increase the solubility of the calcium salt. The 
solubility of slightly soluble or water-insoluble calcium salts can be 
increased by lowering the pH of the solution. Generally the pH is lowered 
by the addition of an acid or by the addition of a substance such as an 
acid lactone that hydrolyzes to an acid. Commonly used pH adjusters 
include glucono-delta-lactone and acids such as acetic, adipic, citric, 
fumaric, lactic and tartaric acid. 
The availability of calcium ions can also be controlled by the addition of 
gel retarders. Known gel retarders are salts having an ion that forms a 
water-insoluble or slightly water-soluble bond to the calcium ions. The 
retarder competes with the water-soluble alginate for the free calcium 
ions thereby depriving the alginate of some of the crosslinking ions and 
delaying gelatin. Common retarders are the alkali metal phosphates, 
oxalates and citrates. 
Conventional methods for preparing these water-insoluble calcium alginate 
gels typically involve adding solid water-soluble alginate and solid 
calcium salt to an aqueous medium as disclosed in U.S. Pat. No. 3,455,701, 
and U.K. Patent Specification No. 1,579,324, published Nov. 19, 1980, or 
adding a solution or dispersion of calcium salt to an aqueous solution of 
water-soluble alginate as disclosed in U.S. Pat. Nos. 2,756,874, 4,381,947 
and 4,401,456. Typically these methods include the addition of gel 
retarders and/or pH adjusters to provide control over the rate of gelatin. 
Traditionally, water-insoluble alginate gels have been used extensively in 
dental impression materials and as thickening or setting agents in food 
preparations. Recently, however, water-insoluble alginate gels have found 
utility as a form-in-place wound dressing material as disclosed in Swedish 
Patent Application Publication No. 424,956, published Aug. 23, 1982. This 
dressing is prepared by mixing water-soluble alginate, a soluble metal 
salt having metal ions that react with the water-soluble alginate to form 
a crosslinked water-insoluble alginate, and water to form a reactive 
cream-like paste that is spread over the wound surface. After application 
to the wound surface the constant progression of the crosslinking reaction 
transforms the cream-like paste into an elastic rubber-like composition. 
Likewise, German Patent Application No. 3601132 (published July 23, 1987), 
discloses an alginate which gels in situ and is useful for protecting the 
mucosa and delivering disinfectants or pharmaceutically active agents. The 
composition consists of at least two components capable of forming a gel 
on mixing, such as a calcium salt and alginic acid, polyglucuronic acid, 
polymanuronic acid, propylene glycol alginic acid, polygalacturonic acid, 
polyarabinic acid, their salts or esters, pectin, gum arabic and their 
mixtures, to be simultaneously or sequentially placed onto the mucous 
membrane. 
Alginate gels have also been used to provide sustained release of drugs. 
Stockwell, et al., in "In Vitro Evaluation of Alginate Gel Systems as 
Sustained Release Drug Delivery Systems", Journal of Controlled Release, 
Volume 3, pp. 167-175 (1986), disclose gelatin capsules containing a 
powdered mixture of sodium alginate, calcium phosphate, sodium 
bicarbonate, lactose and a drug (chlorpheniramine, sodium salicylate or 
caffeine). In situ in the stomach the gelatin capsule dissolves, hydration 
and gelatin of the alginate and crosslinking by calcium occur to provide a 
gel barrier at the surface, and the sodium bicarbonate effervesces, 
releasing carbon dioxide which becomes entrapped in the gel network. 
Another sustained release device is disclosed in U.S. Pat. No. 4,613,497. 
Anhydrous tablets, capsules, powders or suppositories are made from a 
mixture of water soluble polysaccharide gum, a biocompatible gelling salt, 
an effervescent base, a water soluble biocompatible acid or acid salt and 
a pharmaceuticaly active material. These compositions find use in 
gastrically active compositions and vaginal contraceptives. 
Furthermore, German Patent No. 368,694 discloses a foaming dental adhesive 
made from an adhesive material, such as alginic acid or sodium alginate, 
at least one carbonate and/or hydrogen carbonate and at least one organic, 
water-soluble salt or a water-soluble acid salt of a polyboric acid. The 
later two components form CO.sub.2 in an aqueous environment and stimulate 
foaming of the adhesive. 
Medical uses for these gels brings with it new concerns with regard to the 
purity and sterility of the polysaccharide gel being formed. For example, 
it is generally desirable that retarders and suspending agents which leave 
residual deposits in the gel network not be present in the gel forming 
components used to form foamed polysaccharide hydrogels for medical uses 
Furthermore, to be effective in preventing contamination and infection, it 
is generally desirable that the hydrogel forming materials be sterile 
prior to their application. 
Theoretically, a sterile form-in-place polysaccharide hydrogel may be 
prepared by either (1) sterilizing the gel-forming components separately 
prior to mixing and maintaining the components in a sterile environment 
before, during and after mixing until the composite material is used, or 
(2) mixing the gel-forming components together first and then sterilizing 
the composite material immediately prior to use. The latter alternative, 
however, has little practical utility as it requires each batch to be 
individually sterilized prior to use, and thereby places unacceptable 
demands upon the time and facilities of the health care professional. 
Likewise, in order for the former alternative to be useful, sterile 
gel-forming components, and a method of mixing these components while 
maintaining them in a sterile environment, must be available to the health 
care professional. 
Thus, there is a need in the medical arts for a foam-in-place 
polysaccharide hydrogel which can be easily provided in a sterile form. 
Additionally, it is desirable for the gel-forming components to mix easily 
and quickly so as to minimize the demands on the health care 
professional's time and energy. It is further desirable to provide a foam 
forming mechanism which coordinates the rate of gel formation with the 
rate of foam formation, so as to assure uniform dispersal of foam within 
the gelled polysaccharide structure. Only in this way can a dimensionally 
stable foamed polysaccharide hydrogel be produced. 
Heretofore it has been unknown to employ polysaccharide hydrogels as 
preoperative preparations. There exists a need for an effective 
form-in-place surgical preparation, particularly one well suited for 
vaginal or rectal surgery. Nosocomial infections are more common after 
vaginal or rectal surgery largely because the surgical techniques are done 
through an already contaminated field. Attempts to reduce infections have 
been made using prophylactic antibiotics, (Ledger WJ, Sweet RI, Headington 
JT: "Prophylactic Cephaloridine in the Prevention of Post-Operative 
Infection in Premenopausal Women Undergoing Vaginal Hysterectomy." Am. J. 
Obstet Gynecol. 1973:115-766), various preoperative preparations (Telinde 
R: Operative Gynecology. Philadelphia, JB Lippincott Co., 1962, p.8.), 
different surgical techniques (Richardson AC, Lyon JB, Graham EE: 
"Abdominal Hysterectomy: Relationship Between Mortality and Surgical 
Technique." Am. J. Obstet. Gynecol. 115:953-961 (1973)), and specific 
drainage systems (Swartz WH, Tanaree P: "T-tube Suction Drainage and/or 
Prophylactic Antibiotics: Randomized Study of 451 Hysterectomies". Obstet 
Gynecol. 47:665-670 (1976)) with no significant decrease. 
Because none of these methods has been successful in decreasing infection 
following vaginal and/or rectal surgical procedures, there remains a need 
for a surgical preparation that 1) is capable of releasing antimicrobial 
in a prolonged manner for up to 24 hours or more; 2) swells to the shape 
of the cavity into which it is injected, thus delivering antimicrobial to 
a large surface area; 3) forms a stable, biocompatible, water-insoluble 
gel that will absorb exudates with very little swelling; and 4) can be 
easily removed from the body cavity as a complete unit. 
SUMMARY OF THE INVENTION 
The present invention provides a water-insoluble polysaccharide hydrogel 
foam which is prepared from an aqueous two component mixture. One 
component, Component A, comprises an aqueous suspension of certain 
water-insoluble di- or trivalent metal salts and an effervescent compound. 
The other component, Component B, comprises an aqueous solution of a 
water-soluble acid. At least one component, and preferably both, contain a 
water-soluble polysaccharide bearing pendant carboxylate groups. 
Optionally, for medical applications, at least one component, and 
preferably both, include a medicament. 
The water-insoluble polysaccharide hydrogel foam formed from the 
two-component aqueous system of the present invention comprises a) about 
0.02 to 60 percent by weight of one or more polysaccharides complexed with 
a di-or trivalent metal salt; b) the gaseous reaction product of an 
effervescent compound and a water-soluble acid in a concentration 
sufficient to provide the cured hydrogel foam with a density of from about 
0.1 to 1 g/cm.sup.3 ; c) from about 50 to 98 percent by weight of an 
aqueous medium; and d) optionally, for medical applications, about 0.001 
to 10 percent by weight of a medicament. 
The present invention further provides a preoperative preparation which is 
particularly useful for vaginal or rectal surgery. The preoperative 
preparation is formed in situ by applying a reactive gel-forming 
composition directly to the operative site. The reactive gel-forming 
composition comprises: (a) an aqueous solution of a water-soluble 
polysaccharide which bears pendant carboxylate groups, (b) a water-soluble 
acid dissolved therein, (c) particles of a water-insoluble di-or trivalent 
metal salt that will react with an acid to form a water-soluble metal 
salt, and which has a di- or trivalent metal ion capable of complexing 
with the pendant carboxylate groups of said water-soluble polysaccharide 
to form a water-insoluble polysaccharide hydrogel, suspended therein, (d) 
an effervescent compound which effervesces upon reaction with an acid, and 
e) a medicament. The reactive composition can be dispensed into a body 
cavity and will form a stable medicated water-insoluble polysaccharide 
hydrogel foam which exactly fits the shape and contour of the cavity 
within about 1 to 8 minutes. The medicated foam can provide prolonged 
release of the medicament in the body cavity for up to 24 hours or more. 
The medicated polysaccharide hydrogel foam prepared according to the 
invention is bio-compatible and dimensionally stable. It is capable of 
absorbing exudates from the body cavity without any appreciable swelling. 
The hydrogel foam remains moist, thereby reducing trauma and irritation to 
the surrounding tissue, but has sufficient structural integrity to be 
removed from the body cavity in one piece, even though it may be saturated 
with body fluids or other aqueous fluids. 
While the medicated water-insoluble polysaccharide hydrogel foams of the 
invention have particular utility as a preoperative preparation for the 
vaginal and/or rectal cavity to provide an improved aseptic environment, 
they also have utility as medicament(s) dispensing devices for any body 
cavity or surface. For example, they may be used as wound dressings, 
sustained release drugs or vaginal contraceptives. 
Additionally, the present invention provides a self-contained device 
ideally suited for the preparation and delivery of a sterile medicated 
water-insoluble polysaccharide hydrogel foam. The device comprises a first 
chamber containing a first liquid component comprising an aqueous 
suspension of a water-insoluble di-or trivalent metal salt and a substance 
which effervesces upon reaction with an acid; a second chamber containing 
a second liquid component comprising an aqueous solution of a 
biocompatible water-soluble acid, wherein either or both the first or 
second liquid components further comprise a water-soluble polysaccharide 
having pendant carboxylate groups and a medicament dissolved or suspended 
therein; and a means connected to the first and second chambers for 
allowing intermixing of the first and second liquid components.

DETAILED DESCRIPTION OF THE INVENTION 
The invention provides a homogeneous water-insoluble polysaccharide 
hydrogel foam composed of one or more water-insoluble polysaccharides 
complexed with salts which include (with the exception of magnesium) the 
alkaline earth metal salts and the group III metal salts. The homogeneous 
polysaccharide hydrogel foam is formed by mixing together a first liquid 
component (Component A) comprising an aqueous suspension of particles of a 
water-insoluble di- or trivalent metal salt, and an effervescent compound 
which effervesces upon reaction with an acid; and a second liquid 
component (Component B) comprising an aqueous solution of a water-soluble 
acid; wherein at least one of Components A and B further comprises a 
water-soluble polysaccharide having pendant carboxylate groups. It is 
preferred that the water-soluble polysaccharide be dissolved in Component 
A, and more preferred that the water-soluble polysaccharide be dissolved 
in both Component A and Component B. It is further preferred for medical 
applications, that a medicament be dissolved or suspended in both 
Component A and Component B, and more preferred that it be dissolved or 
suspended in Component A. 
Upon mixing Components A and B, the water-insoluble metal salt reacts with 
the water-soluble acid to form a water-soluble metal salt that is 
subsequently ionized. The polyvalent cations released from the 
water-soluble metal salt complex with the pendant carboxylate groups of 
the water-soluble polysaccharide causing the formation and precipitation 
of a water-insoluble polysaccharide hydrogel. At the same time, the 
effervescent compound is reacting with the water-soluble acid with the 
resultant evolution of gases which become entrapped in the forming gel 
network, causing the formation of a stable hydrogel foam. 
The polysaccharides useful in the present invention are biocompatible, 
water-soluble, have pendant carboxylate groups, and complex with 
polyvalent cations to form hydrogels. Suitable polysaccharides include the 
water-soluble salts of alginic, pectic and hyaluronic acids; the 
water-soluble salts or esters of polyglucuronic acid, polymanuronic acid, 
polylygalacturonic acid and polyarabinic acid; and gum kappa-carrageenan. 
The preferred polysaccharides are the ammonium, magnesium, potassium, 
sodium and other alkali metal salts of alginic acid, and the most 
preferred polysaccharide is sodium alginate. 
Alginate is the general name given to alginic acid and its salts. Alginates 
are composed of D-mannosyluronic (mannuronic) and L-gulopyranosyluronic 
(guluronic) acid residues. The ratio between mannuronic/guluronic acid 
affects the properties of the alginates. Alginates high in mannuronic acid 
are best suited for thickening applications, whereas alginates with a high 
level of guluronic acid are best for forming gels. For this invention it 
is preferred that the alginate have a high level of guluronic acid, i.e., 
greater than about 50 percent by weight. For example alginates from the 
algae Laminaria lyperburea, stem, whole plant or frond, have a high level 
of guluronic acid and are particularly preferred. 
The water-insoluble di- or trivalent metal salts useful in the present 
invention must satisfy two requirements. First, the water-insoluble metal 
salt must contain a di-or trivalent metal ion capable of complexing with 
the pendant carboxylate groups of the water-soluble polysaccharide to 
cause the formation of a water-insoluble polysaccharide gel. Second, the 
water-insoluble metal salt must react with a water-soluble acid to form a 
water-soluble metal salt. Preferred water-insoluble metal salts useful in 
the present invention include calcium carbonate, calcium phosphate dibasic 
(CaHPO.sub.4), barium carbonate and zinc carbonate, with calcium carbonate 
being the most preferred. 
The water-soluble acids useful in the present invention may be chosen from 
monocarboxylic and polycarboxylic acids. For medical applications, the 
water-soluble acid must also be biocompatible. Examples of suitable acids 
include acetic acid, citric acid, tartaric acid, succinic acid, formic 
acid, glycolic acid, malonic acid, dichloroacetic acid, oxalic acid, 
lactic acid, malic acid, gluconic acid, adipic acid, fumaric acid, alginic 
acid and maleic acid. The most preferred water-soluble acid is acetic 
acid. 
The effervescent compound used in the present invention must effervesce 
upon reaction with the water-soluble acid. Useful effervescent compounds 
may be chosen from the alkali metal carbonates or bicarbonates, such as 
sodium bicarbonate, sodium carbonate, calcium carbonate and potassium 
carbonate. The most preferred effervescent compound is sodium carbonate. 
Although recited as separate elements of Component A, it should be 
understood that in some cases the water-insoluble di- or trivalent metal 
salt and the effervescent compound may both be provided by a single 
compound. For example, the preferred water-insoluble metal salt, calcium 
carbonate, releases carbon dioxide gas upon reaction with the acid in 
Component B and, thus, produces a hydrogel foam without the inclusion of 
any other effervescent compounds. The resultant foam, however, generally 
has a relatively high density and low void volume due to the small amount 
of carbon dioxide typically produced by this reaction. Thus, even if the 
water-insoluble di- or trivalent metal salt effervesces, it may still be 
desirable to include an additional effervescent compound in order to 
obtain a hydrogel foam having a greater void volume and lower density. 
The medicament useful in the present invention is chosen from any 
physiologically or pharmacologically active substance that produces a 
local or systemic effect when released in a biological environment. The 
active medicament can be inorganic or organic compounds including drugs 
that act on the nervous system; drugs that act on tissues, muscles, and 
organs; analgesics; anti-inflammatory agents; prostaglandins; 
antimicrobials; anti-virals; antifungal agents; and hormones Resources for 
beneficial drugs and doses are REMINGTON'S PHARMACEUTICAL SCIENCES, 14th 
Edition, 1970; Mack Publishing Co., Easton, PA.; and Goodman and Gilman, 
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th Edition, 1985; MacMillian 
Company, New York, New York; both of which are incorporated herein by 
reference. 
Antimicrobials are the preferred medicament. Three particularly preferred 
antimicrobials are iodophors, iodine and bacitracin. Preferred iodophors 
include combinations of elemental iodine with detergent polymers such as 
nonylphenoxy poly(ethylenoxy) ethanol and undecoylium chloride; or 
complexes of iodine with a nonionic, non detergent, non-surface active, 
water-soluble organic polymer, such as polyvinylpyrrolidone (povidone), 
polydextrose or a copolymer of sucrose and epichlorohydrin. Povidone and 
polydextrose are particularly preferred nonionic, non-detergent 
water-soluble polymers U.S. Pat. No. 4,576,818, incorporated herein by 
reference, describes the preparation of polydextrose iodine from 
polydextrose and iodine. U.S. Pat. No 2,739,922, incorporated herein by 
reference, describes the preparation of polyvinylpyrrolidone-iodine from 
polyvinylpyrrolidone and iodine. 
Preferred iodine preparations are in the form of aqueous or alcoholic 
solutions such as iodine and postassium or sodium iodide in water, ethyl 
alcohol, and glycerol, or in a mixture of these solvents. The following 
preparations are preferred: iodine topical solution, an aqueous solution 
containing 2.0% by wt. iodine and 2.4% by wt. sodium iodide; strong iodine 
solution, an aqueous solution containing 5% by wt. iodine and 10% by wt. 
potassium iodide; and iodine tincture in aqueous ethanol (1:1) solution 
containing 2% by wt. iodine and 2.4% by wt. sodium iodide. The 
concentration of iodine depends on the germicidal strength required, the 
propensity of the iodine to cause irritation, and the length of use. The 
preferred concentration is 0.1 to 5% by weight available iodine and the 
most preferred concentration is 0.5 to 1.5% by weight available iodine 
Bacitracin is one or more of the antimicrobial polypeptides produced by 
certain strains of Bacillus licheniformis and by Bacillus subtilis variety 
Tracy. It usually contains not less than 55 units per mg calculated with 
reference to dried substance. The preferred concentration of bacitracin is 
250 units/ml to 150,000 units/ml and the most preferred concentration is 
5000 units/ml to 50,000 units/ml. 
The aqueous medium in which the constituents of Components A and B are 
carried can comprise any compatible solvent in which the particular 
components are soluble or dispersible. Preferably, distilled water is 
employed. 
The water-insoluble polysaccharide hydrogel foam of this invention is 
formed simply by mixing together the first liquid component, Component A, 
and the second liquid component, Component B, and allowing the reaction 
mixture to cure to a dimensionally stable homogeneous hydrogel foam. The 
rate of cure is governed by the rate of the reaction between the 
water-soluble acid and the water-insoluble metal salt and is thus 
controlled by the amounts of the metal salt and acid in the solution. The 
water-insoluble metal salt is present in Component A in a concentration of 
from about 0.01 to 10.0 percent by weight of Component A, preferably from 
about 0.5 to 2.0 percent by weight, and most preferably from about 1.0 to 
1.5 percent by weight. The water-soluble acid is present in Component B in 
a concentration of from about 0.01 to 10.0 percent by weight of Component 
B, preferably from about 1 to 4 percent by weight and most preferably from 
about 2 to 3 percent by weight. Using the preferred concentration of 
ingredients, a hydrogel having a cure time of from one to eight minutes 
can be provided. 
The concentrations of the other constituents of Components A and B are as 
follows. If an effervescent compound, other than the metal salt, is 
present in Component A, it is present in a concentration of from about 
0.01 to 10.0 percent by weight of Component A preferably from about 0.5 to 
3 percent by weight, and most preferably from about 1 to 2 percent by 
weight. 
The water-soluble polysaccharide is present in either Component A or 
Component B in a concentration of from about 0.01 to 50.0 percent by 
weight of that component. Preferably the polysaccharide is present in both 
Components A and B in a concentration of about 0.5 to 10.0 percent by 
weight of each component, most preferably between about 2 and 7 percent by 
weight of each component. 
The medicament concentration is dependent upon the medicament identity and 
the use intended for the polysaccharide hydrogel foam. For most uses, when 
the medicament is an antimicrobial, the concentration of medicament 
present in either Component A or Component B is sufficient to provide the 
reacted polysaccharide hydrogel foam with from about 0.001 to 10 by 
weight, preferably from 0.5 to 4.0 by weight medicament. 
The aqueous medium which constitutes the remainder of Components A and B, 
forms from about 50 to 98 percent by weight of each component. Preferably 
water constitutes about 75 to 97 percent by weight of Component A and 
Component B. Most preferably water forms about 85 to 95 percent by weight 
of Component A and about 85 to 95 percent by weight of Component B. 
The cured water-insoluble polysaccharide hydrogel foam comprises: 
polysaccharide complexed with an di- or trivalent metal salt in a 
concentration of from about 0.02 to 60 percent by weight, preferably from 
about 1 to 12 percent by weight, and most preferably from about 3 to 8.5 
percent by weight of the cured hydrogel foam; the gaseous reaction product 
of an effervescent compound and a biocompatible, water-soluble acid in a 
concentration sufficient to provide the cured hydrogel foam with a density 
of from about 0.1 to 1 g/cm.sup.3, preferably about 0.25 to 0.7 
g/cm.sup.3, and most preferably about 0.35 to 0.5 g/cm.sup.3 ; with the 
remainder of the cured hydrogel foam comprising the aqueous medium. 
Preferably the aqueous medium comprises about 50 to 98 percent by weight 
of the cured foam, most preferably about 85 to 95 percent by weight of the 
cured foam. Optionally, for medical applications, a medicament is present 
in a concentration of about 0.001 to 10 percent by weight, preferably 
about 0.01 to 8 percent by weight, and most preferably about 0.05 to 4 
percent by weight of the cured foam. 
The medicated water-insoluble polysaccharide hydrogel foam of this 
invention is formed in place in, for example, the vaginal or rectal 
cavity, simply by mixing Component A with Component B and applying the 
reactive composite mixture directly into the body cavity. The reaction 
mixture swells and cures to a homogeneous, dimensionally stable 
polysaccharide hydrogel in normally 2 to 3 minutes. The cured hydrogel 
exactly fits the cavity or surface to which it is applied, enabling 
medication to be delivered evenly through a prolonged release mode. 
While the medicated polysaccharide hydrogel foams of this invention are 
particularly useful as preoperative preparations for vaginal or rectal 
surgery, to minimize contaminations preoperatively and thus infections 
postoperatively, they also find use as medicament(s) dispensing devices 
for body cavities or surfaces. A preferred use of the medicated hydrogel 
foam is as a suppository for the delivery of medicament. 
In practice, the water-insoluble polysaccharide hydrogel foam can be 
prepared and applied using a self-contained article comprising a first 
chamber containing Component A, a second chamber containing Component B, 
and a means connected to said first and second chambers for intermixing 
Components A and B without exposing them to the atmosphere or to any 
external mixing devices. One example of such an article is a closed bag 
divided into two compartments by a removable closure, with Component A 
contained within the compartment on one side of the closure and Component 
B contained within the compartment on the opposite side of the closure. In 
this embodiment of the article, mixing of the two components can be 
accomplished simply by removing the closure and manually forcing the two 
components together. 
Another example of such an article comprises two permanently separated 
component-containing chambers wherein each component-containing chamber is 
equipped with a discharge opening leading to a common mixing chamber. In 
this embodiment of the article, mixing of the two components can be 
accomplished by forcing each of the components from their respective 
chambers into the mixing chamber. Preferably the mixing chamber is in the 
form of a baffled discharge tube so that the components are mixed as they 
are discharged from the article through the discharge tube. A useful 
example of such an article is a double-barreled syringe assembly equipped 
with a standard mixing tip. Such an article is illustrated in FIG. 1. 
Referring now to FIG. 1, there is shown an exploded view in perspective of 
a preferred embodiment of the device of this invention. Syringe 1 has two 
parallel internal chambers, 2 and 3, each of which is intended to be 
filled with Component A or Component B. The chambers 2 and 3 in syringe 1 
are separated by barrier 4. When plungers 5 and 6 are forced into chambers 
2 and 3, respectively, the contents of the syringe exit via outlet 7. The 
contents of chamber 2 exit outlet 7 by flowing through outlet passage 8. 
The contents of chamber 3 exit outlet 7 by flowing through outlet passage 
9. The contents of both chambers 2 and 3 are intimately mixed by static 
mixing element 10 to form a homogeneous mass in mixing tip 11. The 
homogeneous mass rapidly reacts to form a stable foam following expulsion 
from outlet 12 of mixing tip 11. Static mixing element 10 is prevented 
from being expelled during use from the outlet end 12 of mixing tip 11 by 
a suitable constriction in the inside diameter of tip 11 proximate outlet 
end 12. Mixing element 10 comprises multiple counter-rotated auger-like 
mixing blades 13. Preferably, the inlet end 18 of static mixing element 10 
is aligned generally perpendicular to the plane of contiguity between the 
two streams exiting syringe 1 through exit passages 8 and 9. Means of 
accomplishing this orientation are described in U.S. Pat. No. 4,538,920, 
incorporated herein by reference. 
Attachment of mixing tip 11 to syringe 1 is achieved by a suitable mounting 
means (e.g., a bayonet mount). Bayonet locking tabs 14 have locking prongs 
15 and step surfaces 17. Mixing tip 11 has locking ramps 19 and step 
surfaces 21. Mixing tip 11 is mounted on syringe 1 by centering the inlet 
16 of mixing tip 11 over outlet 7 of syringe 1, while aligning mixing tip 
11 so that it can be pushed between bayonet locking tabs 14. Mixing tip 11 
is then inserted firmly over outlet 7, and rotated approximately 
90.degree. clockwise (as viewed from the outlet 12 of the mixing tip) so 
that the locking ramps 19 are wedged between locking prongs 15 and the 
main body of syringe 1, and stop surfaces 17 engage stop surfaces 21. 
Static mixing element 10 and mixing tip 11 are firmly attached to syringe 
1, but can be readily removed and discarded after use by rotating mixing 
tip 11 approximately 90.degree. counterclockwise (as viewed from the 
outlet 12 of the mixing tip) and pulling mixing tip 11 away from syringe 
1. 
A preferred self-contained article for preparing and applying the 
polysaccharide hydrogel foam of this invention is disclosed in U.S. Pat. 
No. 4,538,920, incorporated herein by reference. A preferred dispenser 
device for causing the plungers 5 and 6 to move within the chambers 2 and 
3 is the 3M "Express Dispenser " commercially available from 3M St. Paul, 
Minn. 
The invention is further illustrated by the following non-limiting examples 
wherein all percentages are by weight unless otherwise specified. 
EXAMPLE 1 
PREATION OF A SLIGHTLY FOAMED ALGINATE GEL 
A suspension of calcium carbonate (CaCO.sub.3) in an aqueous solution of 
sodium alginate was prepared by adding 0.21 g solid CaCO.sub.3 to 38.6 g 
of a 4.5% aqueous sodium alginate solution. 
An aqueous sodium alginate solution containing enough acetic acid to react 
with all of the CaCO: was prepared by adding 0.35 g of a 50% aqueous 
acetic acid solution to 37.66 g of a 4.5% aqueous sodium alginate 
solution. 
The two alginate solutions were loaded into a double-barreled syringe 
assembly fitted with a 12-element mixing tip. The two solutions mixed as 
they were discharged through the tip and formed a slightly foamed 
homogeneous gel in approximately one minute. 
EXAMPLE 2 
PREATION OF A HIGHLY FOAMED ALGINATE GEL 
A suspension of calcium carbonate (CaCO.sub.3) and sodium carbonate 
(Na.sub.2 CO.sub.3) in an aqueous sodium alginate solution was prepared by 
adding 0.41 g CaCO.sub.3 and 0.83 g Na.sub.2 CO.sub.3 to 36.64 g of a 4.5% 
aqueous sodium alginate solution. 
An aqueous sodium alginate solution containing acetic acid was prepared by 
adding 1.4 g of a 50% aqueous acetic acid solution to 37.0 g of a 4.5% 
aqueous sodium alginate solution. 
The two alginate solutions were mixed via the double-barreled syringe 
assembly of Example 1. Foaming began immediately upon mixing and a stable 
highly foamed homogeneous gel formed in approximately two minutes. 
EXAMPLE 3 
An alginate hydrogel foam containing iodine was prepared as follows: 
1. Component A was prepared by mixing 2.2 g of sodium alginate commercially 
available as "Protanal LF 20/60 Sodium Alginate" from Protan Inc. of North 
Hampton, N.H. with 0.90 g of sodium carbonate and 38.4 g of deionized 
water, at room temperature. The mixture was stirred until completely 
homogenous. Then 0.90 g of calcium carbonate was added. 
2. Component B was prepared by mixing 0.42 g of sodium iodide and 0.42 g of 
iodine with 37.68 g of deionized water at room temperature. The mixture 
was stirred until the iodide and iodine were completely dissolved. Then 
2.2 g of glacial acetic acid was added. Next 2.2 g of the same sodium 
alginate used in the preparation of Component A was added and the mixture 
stirred until the alginate was completely dissolved. 
3. Components A and B were loaded, in equal volumes, into separate barrels 
of a double-barreled mixing syringe assembly fitted with a 3-inch, 6-turn 
mixing tip and 
4. Components A and B were discharged through the mixing tip of the mixing 
syringe into a 50 ml conical tube and allowed to foam and cure for 3 
minutes. 
EXAMPLES 4-11 
Medicated alginate hydrogel foams were prepared by the same method and from 
the same reactants used in the preparation of the alginate hydrogel foam 
of Example 3. The preparation of the alginate hydrogel foams of Examples 
differs from the preparation of the foam of Example 3 only in the ratios 
of the iodine/sodium iodide (% wt/v) used. The ratios of iodine/sodium 
iodide (% wt/v) used to prepare the foams of Examples 4-11 are shown in 
Tables I and II. 
The bacteriostatic and bacteriocidal capabilities of the medicated hydrogel 
foams were measured by determining the Zone of Inhibition of microorganism 
growth in agar. The microorganism Log.sub.10 reduction method was used to 
determine the effectiveness of the medicated hydrogel foam for eliminating 
the microbial flora commonly found in an operative field. 
(A) Zone of Inhibition 
As in Example 3, Component A and Component B were mixed and allowed to cure 
in a 50 ml conical tube. A 1.5 g disk, 28 mm in diameter, was cut out of 
each cured hydrogel foam and aseptically placed in a petri dish on 
solidified nutrient agar, commercially available from Difco Laboratory, 
Inc., Detroit, Mich. Sterile nutrient agar at 43.degree. C. was inoculated 
with Staphyloccus epidermidis (ATCC #12228), Pseudomonas aeruginosa (ATCC 
#15422), or Escherichia coli (ATCC #15221) obtained from log phase 
overnight cultures grown in nutrient media commercially available as 
"rypticase Soy Broth" from Difco Laboratory, Inc. Detroit, Mich. at 
36.degree. C. Ten ml of the inoculated agar was poured onto the agar in 
the petri dish containing the hydrogel foam and the inoculated agar was 
allowed to solidify at room temperature. The petri dish with inoculated 
agar and hydrogel foam disk was incubated overnight at 36.degree. C. The 
Zone of Inhibition was determined by measurement of diameter of the disk 
without microorganism growth. The following code was used: 
______________________________________ 
Zone Diameter Zone Results 
______________________________________ 
20-greater mm +++++ 
15-20 mm ++++ 
10-15 mm +++ 
5-10 mm ++ 
0-05 mm + 
______________________________________ 
The results are shown in Table I and indicate that increasing the ratio of 
iodine/sodium iodide (% wt/v) in the medicated foam causes a steady 
increase in the Zone of Inhibition. 
TABLE I 
______________________________________ 
Ex. Iodine/Sodium 
Zone of Inhibition 
No. Iodide (% wt/v) 
S. epid E. coli P. aerug 
______________________________________ 
4 0.25 + + + 
5 0.50 ++ ++ ++ 
6 0.75 ++ ++ ++ 
7 1.00 +++ +++ +++ 
8 1.25 +++ +++ +++ 
9 1.50 ++++ ++++ ++++ 
10 1.75 +++++ +++++ +++++ 
11 2.00 +++++ +++++ +++++ 
______________________________________ 
(B) Microorganism Log.sub.10 Reduction 
Microorganism loaded membrane filters were prepared by: 
(1) growing cultures overnight of each of the 
following: Staphyloccus epidermidis (ATCC #1228), Pseudomonas aeruginosa 
(ATCC #15422), and Escherichia coli (ATCC #15221) in nutrient media 
commercially available as "Trypticase Soy Broth" from Difco Laboratories, 
Detroit, Mich. at 36.degree. C.; 
(2) centrifuging each culture at 2700 rpms for 30 minutes at 4.degree. C.; 
(3) resuspending the microorganisms in a sterile saline solution (0.85% 
wt/v) to an optical density of 0.4 at 660 nm with a 1.5 cm light path; 
(4) loading each suspension in a 3 cc disposable syringe equipped with a 
3.81 cm (1.5 inch), 22 gauge needle; and 
(5) evenly dispersing a 2.0 ml volume of each suspension onto an analytical 
membrane filter, commercially available as "Falcon 7103, Disposable 
Sterile Filter Unit" from Fisher Scientific, Pittsburgh, Pa. The filter 
matrix is cellulose nitrate, 5 cm in diameter with a pore size of 0.22 
microns. 
Upon each microorganism loaded membrane filter, 22.3 g of Component A and 
22.3 g of Component B (as described in Example 3) were dispensed and 
allowed to foam and gel for 3 minutes. 
The filter unit was briefly evacuated with a cold water aspirator to a 
vacuum of 29 inches of Hg, for 10-15 seconds, placed on a clean bench, and 
covered ajar for 3.5 minutes of incubation at room temperature. The filter 
was harvested by unlocking the unit and aseptically transferring the 
intact membrane to 100 ml of sterile saline solution containing 0.1% 
(wt/v) sodium thiosulfate and 0.1% (wt/v) sodium benzoate contained in a 
glass Waring Blender jar. Each filter was thoroughly disintegrated by a 5 
minute high-speed agitation to enhance recovery of viable microorganisms 
and to neutralize residual antimicrobial agents. A 2 ml aliquot was 
removed from the homogenized suspension for a viability count. Duplicate 
agar plates were prepared from 1 ml of undiluted aliquot and the following 
aliquot dilutions: 10.sup.-1, 10.sup.-2, 10.sup.-3, 10.sup.-4, and 
10.sup.-5. The plates were incubated overnight at 36.degree. C., or longer 
if necessary, to allow automated counting with the "Biotran II Automated 
Colony Counter" commercially available from New Brunswick Scientific Co., 
Inc., Edison, N.J. An average number of colonies was determined by 
counting each of the duplicate plates four times and taking the average. 
The same process was repeated on loaded membrane filters which were not 
treated with medicated foam. The Log.sub.10 Reduction achieved with the 
medicated foam was determined by subtracting the Log.sub.10 of the average 
number of colonies on the plates prepared using the medicated foam from 
the Log.sub.10 of the average number of colonies on the plates prepared 
without using the medicated foam. The results are shown in Table II. 
TABLE II 
______________________________________ 
Log.sub.10 Reduction 
Ex Iodine/Sodium after 3.5 Minutes 
No. Iodide (% wt/v) 
S. epid E. coli P. aerug 
______________________________________ 
4 0.25 1.0 0.0 0.0 
5 0.50 1.0 1.0 1.0 
6 0.75 2.0 2.0 1.0 
7 1.00 3.0 2.0 2.0 
8 1.25 4.0 3.0 2.5 
9 1.50 4.0 4.0 3.0 
10 1.75 5.0 5.0 4.0 
11 2.00 5.0 5.0 5.0 
______________________________________ 
Increasing the ratio of iodine/sodium iodide (%wt/v) in Component B results 
in a decrease in the average number of colonies. Table II illustrates that 
the medicated foam with a ratio of iodine/sodium iodide (%wt/v) of at 
least 1.00 would be effective for eliminating the microbial flora used in 
these examples. 
EXAMPLE 12 
An alginate hydrogel foam containing povidone/iodine was prepared as 
follows: 
1 Component A was prepared by mixing 2.2 g of sodium alginate commercially 
available as "Protanal LF 20/60 Sodium Alginate" from Protan Inc. of North 
Hampton, New Hampshire, with 0.90 g of sodium carbonate and 38.4 g of 
deionized water, at room temperature. The mixture was stirred until 
completely homogenous. Then 0.90 g of calcium carbonate was added with 
thorough mixing. 
2. Component B was prepared by mixing 4.28 g of povidone and 0.42 g of 
iodine powder, USP, commercially available from Napp Chemicals, Inc. of 
Lodi, NJ, with 34.12 g of deionized water at room temperature. The mixture 
was stirred until completely dissolved. Then 2.2 g of glacial acetic acid 
was added with thorough mixing. Next 2.2 g of the same sodium alginate 
used in the preparation of Component A was added and the mixture was 
stirred until the alginate was completely dissolved. 
3. Components A and B were loaded, in equal volumes, into separate barrels 
of a double-barreled mixing syringe assembly fitted with a 3-inch, 6-turn 
mixing tip; and 
4. Components A and B were discharged through the mixing tip of the mixing 
syringe into as 50 ml conical tube and allowed to foam and cure for 3 
minutes. 
EXAMPLES 13-18 
Medicated alginate hydrogel foams were prepared by the same method and from 
the same reactants used in the preparation of the alginate hydrogel foam 
of Example 12. The preparation of the alginate hydrogel foams of Examples 
13-17 differs from the preparation of the foam of Example 12 only in the 
ratios of povidone/iodine (%wt/v) used. The ratios of povidone/iodione 
(%wt/v) used to prepare the foams of Examples 13-17 are shown in Tables 
III and IV. 
The bacteriostatic and bacteriocidal capabilities of the medicated hydrogel 
foams were measured by determining the Zone of Inhibition of microorganism 
growth in agar as described in Examples 4-11. The results are recorded in 
Table III. 
TABLE III 
______________________________________ 
Ex. Povidone/Iodine 
Zone of Inhibition 
No. Iodide (% wt/v) 
S. epid E. coli P. aerug 
______________________________________ 
13 2.0 + + + 
14 4.0 ++ + + 
15 6.0 ++ ++ ++ 
16 8.0 +++ +++ +++ 
17 10.0 ++++ ++++ ++++ 
______________________________________ 
Increasing the ratio of povidone/iodine (%wt/v) in the medicated foam 
results in a steady increase in the Zone of Inhibition. 
The microorganism Log.sub.10 reduction method described in Examples 4-11 
was used to determine the effectiveness of the medicated hydrogel foams 
for eliminating microbial flora commonly found in an operative field. The 
results are recorded in Table IV. 
TABLE IV 
______________________________________ 
Log.sub.10 Reduction 
Ex. Povidone/Iodine 
after 3.5 Minutes 
No. Iodide (% wt/v) 
S. epid E. coli P. aerug 
______________________________________ 
13 2.0 0.5 0.5 0.5 
14 4.0 1.0 1.0 1.0 
15 6.0 1.0 1.0 1.0 
16 8.0 2.0 2.0 2.0 
17 10.0 3.0 3.0 3.0 
______________________________________ 
Increasing the ratio of povidone/iodine (%wt/v) results in a decrease in 
the average number of colonies. The medicated foam with a ratio of 
povidone/iodine (%wt/v) of at least 10.0 is effective for eliminating the 
microbial flora used in these examples. 
EXAMPLE 18 
An alginate hydrogel foam containing bacitracin was prepared as follows: 
1. Component A was prepared by mixing 2.2 g of sodium alginate commercially 
available as "Protanal LF 20/60 Sodium Alginate" from Protan Inc. of North 
Hampton, New Hampshire, with 0.90 g of sodium carbonate and 38.4 g of 
deionized water, at room temperature The mixture was stirred until 
completely homogenous. Then 0.90 g of calcium carbonate was added with 
thorough mixing 
2. Component B was prepared by mixing 5.0 g of bacitracin, USP, 50,000 
units, commercially available from Pfizer, Inc, New York, NY, with 33.4 g 
of deionized water at room temperature. The mixture was stirred until 
completely dissolved. Then 2.2 g of glacial acetic acid was added with 
thorough mixing. Next 2.2 g of the same sodium alginate used in the 
preparation of Component A was added and the mixture was stirred until the 
alginate was completely dissolved. 
3. Components A and B were loaded, in equal volumes, into separate barrels 
of a double-barreled mixing syringe assembly fitted with a 3-inch, 6-turn 
mixing tip; and 
4. Components A and B were discharged through the mixing tip of the mixing 
syringe into a 50 ml conical tube and allowed to foam and cure for 3 
minutes. 
EXAMPLES 19-26 
Medicated alginate hydrogel foams were prepared by the same method and from 
the same reactants used in the preparation of the alginate hydrogel foam 
of Example 18. The preparation of the alginate hydrogel foams of Examples 
19-26 differs from the preparation of the foam of Example only in the 
concentration of bacitracin used. The concentrations of bacitracin used to 
prepare the foams of Examples 19-26 are shown in Tables V and VI. The 
bacteriostatic and bacteriocidal capabilities of the medicated hydrogel 
foams were measured by determining the Zone of Inhibition of microorganism 
growth in agar as described in Examples 4-11. The results are recorded in 
Table V. 
TABLE V 
______________________________________ 
Ex. Bacitracin Zone of Inhibition 
No. (units/ml) S. epid E. coli P. aerug 
______________________________________ 
19 250 ++ + + 
20 500 ++ + + 
21 750 +++ ++ ++ 
22 1000 +++ ++ ++ 
23 5000 ++++ +++ +++ 
24 10000 ++++ ++++ ++++ 
25 25000 +++++ ++++ ++++ 
26 50000 +++++ ++++ ++++ 
______________________________________ 
Increasing the concentration of bacitracin in the foam results in a steady 
increase in the Zone of Inhibition. 
The microorganism Log.sub.10 reduction method as described in Examples 4-11 
was used to determine the effectiveness of the medicated hydrogel foam for 
eliminating microbial flora commonly found in an operative field. The 
results are recorded in Table VI. 
TABLE VI 
______________________________________ 
Log.sub.10 Reduction 
Ex. Bacitracin 
after 3.5 Minutes 
No. (units/ml) 
S. epid E. coli 
P. aerug 
______________________________________ 
19 250 1.0 1.0 1.0 
20 500 1.0 1.0 1.0 
21 750 1.0 1.0 1.0 
22 1000 1.0 1.0 1.0 
23 5000 1.0 1.0 1.0 
24 10000 1.0 1.0 1.0 
25 25000 1.0 2.0 1.0 
26 50000 1.0 2.0 1.0 
______________________________________ 
Increasing the concentration of bacitracin results in only a small decrease 
in the average number of colonies; therefore, foams with concentrations of 
bacitracin of at least 50,000 units would not be effective for eliminating 
the microbial flora within 3.5 minutes. However, a longer exposure time 
would be effective as indicated by the results of the Zone of Inhibition 
Method. 
EXAMPLES 27-38 
An alginate hydrogel foam was prepared as follows: 
(1) Component A was prepared by combining sodium alginate (commercially 
available from Protan Inc. of North Hampton, New Hampshire, under the 
trade designation Protanal LF 20/60), sodium carbonate and deionized 
water; stirring the combination until homogeneous; and then adding calcium 
carbonate. 
(2) Component B was prepared by combining the same sodium alginate used in 
the preparation of Component A with deionized water, at room temperature; 
stirring until the alginate was completely dissolved; and then adding 
acetic acid. 
The amounts of calcium carbonate, sodium carbonate and acetic acid used in 
Components A and B are shown in Table VII. The units used are grams. 
(3) Components A and B were loaded, in equal volumes, into separate barrels 
of a double-barreled mixing syringe assembly fitted with a 3-inch, 6-turn 
mixing tip; and 
(4) Components A and B were discharged through the mixing tip of the mixing 
syringe into three vials of known and equal volume and allowed to foam and 
cure. The vials were filled to overflowing, and as soon as the foaming 
action subsided, any material exceeding the volume of the vials was 
removed. 
TABLE VII 
__________________________________________________________________________ 
Component A Component B 
Ex. Sodium 
Sodium 
Calcium Sodium 
Acetic 
No. 
Water 
Alginate 
Carbonate 
Carbonate 
Water 
Alginate 
Acid 
__________________________________________________________________________ 
27 84.0 
3.8 1.9 0.5 80.0 
3.8 2.4 
28 84.0 
3.8 1.9 0.5 80.0 
3.8 3.0 
29 84.0 
3.8 1.9 0.5 80.0 
3.8 3.6 
30 84.0 
3.8 1.9 1.0 80.0 
3.8 2.7 
31 84.0 
3.8 1.9 1.0 80.0 
3.8 3.3 
32 84.0 
3.8 1.9 1.0 80.0 
3.8 4.2 
33 84.0 
3.8 1.9 2.0 80.0 
3.8 3.3 
34 84.0 
3.8 1.9 2.0 80.0 
3.8 4.2 
35 84.0 
3.8 1.9 2.0 80.0 
3.8 4.9 
36 84.0 
3.8 1.9 2.0 80.0 
3.8 2.5 
37 84.0 
3.8 1.9 2.0 80.0 
3.8 1.7 
38 84.0 
3.8 0 1.3 80.0 
3.8 1.7 
__________________________________________________________________________ 
The time required for the production of a cured hydrogel foam was measured 
for each sample of each of the examples. In this regard cure time 
represents the time elapsed between the mixing of Components A and B and 
the point at which no further changes in the tackiness of the foam were 
detectable by touch. The average cure times for the three samples of each 
of the hydrogel foams produced in Examples 27-38 are shown in Table VIII. 
TABLE VIII 
______________________________________ 
Example No. Cure Time (minutes) 
______________________________________ 
27 22.7 
28 10.7 
29 7.7 
30 6.7 
31 4.7 
32 3.3 
33 2.3 
34 2.0 
35 1.5 
36 3.0 
37 50.0.sup.1 
38 1.0 
______________________________________ 
.sup.1 cure time measurements terminated with hydrogel foam still in tack 
state. 
Particularly in medical applications minimizing the application time of the 
hydrogel is highly desired since this reduces nursing time and the 
inconvenience to the patient. However, the cure time of the hydrogel must 
be of sufficient duration to allow the hydrogel forming solution to be 
applied to the body prior to the gelling and foaming activity. Preferably 
the hydrogel foam forms and cures in a period of from about 2 to 5 
minutes. 
As shown in Tables VII and VIII, the cure time can be regulated via the 
concentration of the acid in Component A and the amount of polyvalent 
metal salt suspended in Component B. Cure times decrease as the 
concentration of the acid in Component A is increased and as the amount of 
the polyvalent metal salt suspended in Component B is increased. While 
varying the amount of either reactant can be used to control the cure 
time, it is preferable to use the minimum amount of acid necessary and 
regulate the cure time via the amount of metal salt present, since 
excessive acidity may have undesirable effects on the tissue compatibility 
of the mixture. Accordingly, the composition of Example 36, which produced 
a cured hydrogel foam in 3.0 minutes, and which had the lowest acid 
concentration of any of the compositions producing cured hydrogel foams 
within the desired range of cure times, is preferred over the other 
compositions tested. 
Additionally, the density of the hydrogel foams produced in Examples 27-37, 
and the absorbency of the hydrogel foams produced in Examples 27-36 and 38 
were measured. These are recorded in Table IX. The recorded density and 
absorbency reflects the average for the three samples made in each 
example. 
TABLE IX 
______________________________________ 
Example No. Density (g/cm.sub.3) 
Absorbency (%) 
______________________________________ 
27 0.38 62 
28 0.31 66 
29 0.29 68 
30 0.33 56 
31 0.30 49 
32 0.28 49 
33 0.30 71 
34 0.29 43 
35 0.29 27 
36 0.34 147 
37 0.57 -- 
38 8 
______________________________________ 
The density was calculated simply by removing the foam sample from the 
vial, weighing it and dividing the weight by the volume of the vial. 
The absorbency was measured by immersing the foam samples in a 0.9 weight 
percent solution of sodium chloride in water. After 24 hours, the test 
samples were removed from the solution, the excess solution on the surface 
of the samples was removed by blotting, and the samples were weighed. The 
absorbencies recorded in Table IX reflect the weight of the saline 
solution absorbed as a percentage of the initial weight of the sample, and 
were calculated by dividing the difference in the weight of the sample 
before and after immersion in the saline solution by the initial weight of 
the sample. 
The absorbency data recorded in Table IX demonstrates that the ability of 
the hydrogel foam to absorb saline fluids is related to the void volume of 
the foam. The low void volume foam of Example 38, prepared without sodium 
carbonate, had a much lower absorbency than the higher void volume foams 
prepared in Examples 27-36.