U.S. patent application number 10/744361 was filed with the patent office on 2005-01-06 for absorbent article.
This patent application is currently assigned to The Procter & Gamble Company. Invention is credited to Davis, Catherine Cornick, Hill, Donna Rene, Osborn, Thomas Ward III.
Application Number | 20050003725 10/744361 |
Document ID | / |
Family ID | 23168022 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050003725 |
Kind Code |
A1 |
Hill, Donna Rene ; et
al. |
January 6, 2005 |
Absorbent article
Abstract
An absorbent article has an absorbent material and an outer
surface including an inhibitor which is partially bound to the
absorbent material and substantially inhibits the colonization of
bacteria within the absorbent article. An absorbent article has an
absorbent material. The absorbent material has an outer surface.
The absorbent article includes a pre-toxin limiting agent which is
partially bound to the absorbent material and substantially retards
the production of bacteria-produced toxins by the bacteria residing
within the absorbent article. An absorbent article has an absorbent
material. The absorbent material has an outer surface. The
absorbent article includes a toxin enclosing agent. Tthe toxin
enclosing agent substantially inhibits the migration of toxin
outwardly from within the absorbent article towards the outer
surface of the absorbent article.
Inventors: |
Hill, Donna Rene; (Verona,
KY) ; Osborn, Thomas Ward III; (Clifton, OH) ;
Davis, Catherine Cornick; (Sharonville, OH) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY
INTELLECTUAL PROPERTY DIVISION
WINTON HILL TECHNICAL CENTER - BOX 161
6110 CENTER HILL AVENUE
CINCINNATI
OH
45224
US
|
Assignee: |
The Procter & Gamble
Company
|
Family ID: |
23168022 |
Appl. No.: |
10/744361 |
Filed: |
December 22, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10744361 |
Dec 22, 2003 |
|
|
|
PCT/US02/20617 |
Jun 28, 2002 |
|
|
|
60302507 |
Jun 29, 2001 |
|
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|
Current U.S.
Class: |
442/123 |
Current CPC
Class: |
A61L 2300/254 20130101;
A61L 15/46 20130101; Y10T 442/2525 20150401; A61L 2300/404
20130101; A61L 15/20 20130101; A61L 15/18 20130101; A61P 31/04
20180101 |
Class at
Publication: |
442/123 |
International
Class: |
B32B 027/04 |
Claims
What is claimed is:
1. An absorbent article having an absorbent material and an outer
surface, comprising:an inhibitor which is at least partially bound
to the absorbent material and substantially inhibits the
colonization of bacteria within the absorbent article.
2. The absorbent article of claim 1 wherein the inhibitor is an
antimicrobial agent.
3. The absorbent article of claim 1 wherein the inhibitor is an
antifouling agent.
4. The absorbent article of claim 1 wherein the inhibitor is
confined in an unbound state within the absorbent article by a
permeable structure which encases the absorbent material, the
permeable structure being configured to allow body fluids to flow
through the permeable structure in a first direction and
substantially prevents flow of the inhibitor from passing back
through the permeable structure and thereby exiting the absorbent
article.
5. An absorbent article having an absorbent material said absorbent
material having an outer surface, said absorbent article,
comprising: a pre-toxin limiting agent which is at least partially
bound to the absorbent material and that substantially retards the
production of bacteria-produced toxins by the bacteria residing
within the absorbent article.
6. An absorbent article having an absorbent material said absorbent
material having an outer surface, said absorbent article,
comprising: a pre-toxin limiting agent which is at least partially
bound to the absorbent material and a pre-toxin limiting agent that
substantially de-activates bacteria produced toxins arising from
bacteria residing within the absorbent article.
7. An absorbent article having absorbent material, said absorbent
material having an outer surface, said absorbent article,
comprising: a toxin enclosing agent, the toxin enclosing agent
substantially inhibiting the migration of toxin outwardly from
within the absorbent article towards the outer surface of the
absorbent article.
8. An absorbent article having absorbent material, said absorbent
material having an outer surface, said absorbent article,
comprising: a temperature limiting agent, the temperature limiting
agent substantially inhibiting the elevation of temperatures within
the absorbent article.
9. An absorbent article having absorbent material, said absorbent
material having an outer surface, said absorbent article,
comprising: a temperature equilibrium agent, the temperature
equilibrium agent substantially reducing the rate at which the
absorbent article raises above equilibrium in an ambient
environment.
10. An absorbent product having an absorbent material and an outer
surface, comprising: a material which inhibits a growth of bacteria
within the absorbent article, and said outer surface physically
separates the inhibitor from a vaginal mucosa tissue such that said
growth of bacteria on said vaginal mucosa is not disrupted.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation application of Prior
copending International Application No. PCT/US02/20617, filed Jun.
28, 2002, designating the U.S., which claims the benefit of U.S.
Provisional Application No. 60/302,507, filed Jun. 29, 2001.
FIELD OF INVENTION
[0002] The present invention relates to a tampon which employs
mechanisms to reduce the potential risk of Toxic Shock Syndrome
("TSS") associated with tampon wear or any other absorptive product
such as surgical gauze or any product whose use has been directly
associated with toxic shock syndrome, such as but not excluded to
diaphragms and cervical cups.
BACKGROUND OF THE INVENTION
[0003] Disposable absorbent devices for the absorption of human
exudates are widely used. These disposable devices typically have a
compressed mass of absorbent formed in the desired shape, which is
typically dictated by the intended consumer use. For example, in
the case of menstrual tampons, the device is intended to be
inserted at least partially into a body cavity for absorption of
the body fluids generally discharged during a woman's menstrual
period.
[0004] There exists in the human female body a complex process
which maintains the vagina and physiologically related areas in a
healthy state. In females between the age of menarche and
menopause, the normal vagina provides an ecosystem for a variety of
microorganisms, which must be maintained in a relatively delicate
balance. Bacteria are the predominate type of microorganisms
present in the vagina, and most women harbor about 10.sup.9
bacteria per gram of vaginal secretions. The bacterial flora of the
vagina is comprised of both aerobic and anaerobic bacteria. The
more commonly isolated bacteria include Lactobacillus species,
Corynebacteria species, Gardnerella vaginalis, Staphylococcus
species, Peptococcus species, aerobic and anaerobic Streptococcal
species, and Bacteroides/Preuotella species. Other microorganisms
that have been isolated from the vagina on occasion include yeast
(Candida albicans), protozoa (Trichomonas vaginalis), mycoplasma
(Mycoplasma hominis), chlamydia (Chlamydia trachomatis), and
viruses (Herpes simplex). These latter organisms are generally
associated with vaginitis or sexually transmitted diseases,
although they may be present in low numbers without causing
symptoms.
[0005] Physiological, social and idiosyncratic factors affect the
quantity and species of bacteria present in the vagina.
Physiological factors include age, days of the menstrual cycle, and
pregnancy. For example, vaginal flora present in the vagina
throughout the menstrual cycle can include Lactobacilli,
corynebacterium, ureaplasma, and mycoplasma. Social and
idiosyncratic factors include presence and method of birth control,
sexual practices, systemic disease (e.g., diabetes), and
medication.
[0006] Bacterial proteins and metabolic products produced in the
vagina can affect other microorganisms and the human host. For
example, generally the pH of the vagina between menstrual periods
is mildly acidic, having a pH ranging from about 3.8 to about 4.5.
This pH range is generally considered the most favorable condition
for the maintenance of normal flora. At that pH, the vagina
normally harbors the numerous species of microorganisms in a
balanced ecology, playing a beneficial role in providing protection
and resistance to infection and making the vagina inhospitable to
some species of bacteria such as S. aureus. The low pH is a
consequence of the growth of Lactobacilli and their production of
acidic products. Microorganisms in the vagina can also produce
antimicrobial compounds such as hydrogen peroxide and bacteriocins
which attack and eliminate other bacterial species. One example is
the lactocins, bacteriocin-like products of Lactobacilli directed
against other species of Lactobacilli. Some microbial products may
affect the human host. For example, S. aureus can produce and
excrete into its environment a variety of exoproteins including
enterotoxins, toxic shock syndrome toxin-1 ("TSST-1"), and enzymes
such as protease and lipase.
[0007] Vaginal menstrual toxic shock syndrome is a rare syndrome
characterized by rapid onset of high fever, vomiting, diarrhea, and
rash followed by a rapid drop in blood pressure and vital organ
failure. TSS is associated with the presence of S. aureus bacteria
and one or more exotoxins which are produced by the bacteria. The
exotoxins associated with TSS include but may not be limited to
Streptococcus: Exotoxin A, Exotoxin B, Exotoxin C and
Staphylococca: Pyrogenic Exotoxin C, Enterotoxin A, Enterotoxin B,
Enterotoxin C, Enterotoxin F, and TSST-1. Using traditional culture
based techniques, S. aureus has been identified in the vagina of
approximately 16% of healthy women of menstrual age (Recent
clinical studies using DNA based techniques have shown this number
to be much higher). It has been found that approximately 10% of the
S. aureus isolated from the vagina are capable of producing TSST-1.
TSS is not caused by the bacteria per se but rather by the toxic
effects of the associated exotoxin which can pass from the vagina
and other internal body cavities into the blood stream.
[0008] TSS has been associated with the use of absorbent pads
within the vagina which may promote the growth of bacteria and the
production of exotoxin in their vicinity. The syndrome has been
observed with surgical dressings, and is also associated with the
use of catamenial tampons. The syndrome appears to occur with
elevated frequency in association with those absorbent pads which
are characterized by high levels of absorbency and which
accordingly are left inside the body for extended periods.
[0009] While a preferred approach for reducing the risk of TSS when
using absorbent pads is proper use and frequent changes of new pads
for used ones, various other approaches have been proposed by the
art for reducing the risk of TSS associated with an internal
absorbent pad. One approach is the incorporation of antimicrobial
or bacteriocidal agents into the absorbent pad such as the use of
iodine bactericides in tampons and catarnenial sponges. Such an
approach is not always suitable for use in the catamenial product,
however, because a bactericide which is active against S. aureus
can adversely affect other beneficial bacteria which make up the
vaginal flora, thereby upsetting the healthy balance discussed
above. Another related method describes the use of catamenial
tampons comprising substances such as organic acids which will
maintain a pH of about 4.5 to about 2.5 in the fluids absorbed
during the use of the tampon such that the growth of pathogenic
bacteria is inhibited.
[0010] Other approaches are directed to inactivation of the TSS
toxin such as the administration of L-ascorbic acid for the
detoxification of the S. aureus toxins, Pyrogenic, Exotoxin C
(Schlievert) and Staphylococcal Enterotoxin F (Bergdoll) TSS-1.
While this method does not ascribe a mechanism for the
effectiveness of ascorbic acid at neutralizing TSS-1, it observes
that L-ascorbic acid is known to be a reducing agent and strong
antioxidant and that it may operate to inactivate bacterial toxins
by reducing disulfide bonds within the toxins.
[0011] Another approach is directed to the incorporation of
substances within an absorbent pad which inhibit the production of
TSS exotoxins by S. aureus. This method describes the incorporation
of non-toxic divalent magnesium cations in absorbent pads to reduce
the concentrations of available magnesium binding ions below those
critical for optimal production of TSST-1 and other staphylococcus
products.
[0012] Despite these developments, there remains a desire in the
art for absorbent pads suitable for internal use, including
catamenial tampons, which are characterized by improved
immobilization of TSST-1 toxin generated within the absorbent
product without adversely affecting the normal vaginal flora.
SUMMARY OF THE INVENTION
[0013] The present invention encompasses an absorbent article
having an absorbent material and an outer surface including an
inhibitor which is at least partially bound to the absorbent
material and substantially inhibits the colonization of bacteria
within the absorbent article.
[0014] The present invention can also encompass an absorbent
article having an absorbent material. The absorbent material has an
outer surface. The absorbent article includes a pre-toxin limiting
agent which is at least partially bound to the absorbent material
and that substantially retards the production of bacteria-produced
toxins by the bacteria residing within the absorbent article.
[0015] In another embodiment, an absorbent article has an absorbent
material. The absorbent material has an outer surface. The
absorbent article includes a pre-toxin limiting agent which is at
least partially bound to the absorbent material and a pre-toxin
limiting agent that substantially de-activates bacteria produced
toxins arising from bacteria residing within the absorbent
article.
[0016] In yet another embodiment, an absorbent article has an
absorbent material. The absorbent material has an outer surface.
The absorbent article includes a toxin enclosing agent. The toxin
enclosing agent substantially inhibits the migration of toxin
outwardly from within the absorbent article towards the outer
surface of the absorbent article.
[0017] In another aspect, an absorbent article has an absorbent
material. The absorbent material has an outer surface. The
absorbent article includes a temperature limiting agent. The
temperature limiting agent substantially inhibits the elevation of
temperatures within the absorbent article.
[0018] In yet another aspect, an absorbent article has an absorbent
material. The absorbent material has an outer surface. The
absorbent article includes a temperature equilibrium agent. The
temperature equilibrium agent substantially reduces the rate at
which the absorbent article raises above equilibrium in an ambient
environment.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The physiological/microbial activity occurring in the tampon
during menstrual wear indicates a possibility that if the toxin
producing strain of S. aureus is present it may produce toxin
within or near the surface of the tampon. Moreover, the toxin
initiates disease by coming into contact with and penetrating the
vaginal mucosa. The risk of TSS can be reduced by 1) preventing S.
aureus from colonizing the tampon; 2) altering the conditions
within the tampon to insure that the perceived required conditions
for toxin production are not present; 3) disrupting the epithelial
or antigen presenting cell and T-cell binding sites for the toxin;
4) and/or retaining the toxin within the tampon.
[0020] Section A will provide terms which will assist the reader in
best understanding the features of the invention and not to
introduce limitations in the terms not consistent with the context
in which they are used in this specification. Theses definitions
are not intended to be limiting.
[0021] There are three phases to prevent a diseased state. Section
B will discuss Phase I which involves the decrease in and/or
prevention of surface or internal bacterial colonization of the
tampon. Section C will discuss Phase II which addresses potential
toxin production by the TSST-1 producing strain of S. aureus and
therefore attempt to inhibit production of toxin within and/or on
the surface of the tampon. Section D will discuss Phase III in
which the goal is to deactivate the binding site of the toxin
and/or prevent the toxin from coming into contact with the vaginal
mucosa when the tampon is colonized by the TSST-1 producing strain
of S. aureus and it is exposed to the required conditions for toxin
production.
[0022] A. Terms
[0023] In general in this specification, the term "tampon" is used
to refer to a finished tampon typically after a compression process
and to any type of absorbent structure that is inserted into the
vaginal canal or other body cavities for the absorption of fluid
therefrom.
[0024] As used herein the terms "vaginal cavity," "within the
vagina," and "vaginal interior," are intended to be synonymous and
refer to the internal genitalia of the human female in the pudendal
region of the body. The term "vaginal cavity" as used herein is
intended to refer to the space located between the introitus of the
vagina (sometimes referred to as the sphincter of the vagina) and
the cervix and is not intended to include the interlabial space,
including the floor of vestibule. The externally visible genitalia
generally is not included within the term "vaginal cavity" as used
herein.
[0025] As used herein, the term "bound" means less than about 10%
of the biological activity associated with inhibiting toxin
production or growth of S. aureus in the tampon is lost by soaking
the tampon over an 8 hour period at 100.degree. F. in three times
the syngnya capacity of sterile physiologic saline solution. The
saline is removed from the tampon by compressing the tampon at 1
psi on a series of blotter paper until .ltoreq.0.5 grams of fluid
is absorbed by the blotter paper on the last compression/absorption
sequence and remeasuring the biological activity remaining in the
tampon. The extraction and testing should be conducted in the
absence of light. The ratio of initial biological activity of the
tampon pre-extraction to post extraction is >90%.
[0026] As used herein, the term "partially bound" means less than
about 50% of the biological activity associated with inhibiting
toxin production or growth of S. aureus in the tampon is lost by
soaking the tampon over an 8 hour period at 100.degree. F. in three
times the syngnya capacity of sterile physiologic saline solution.
The saline is removed from the tampon by compressing the tampon at
1 psi on a series of blotter paper until .ltoreq.0.5 grams of fluid
is absorbed by the blotter paper on the last compression/absorption
sequence and remeasuring the biological activity remaining in the
tampon. The extraction and testing should be conducted in the
absence of light. The ratio of initial biological activity of the
tampon pre-extraction to post extraction is >50%.
[0027] As used herein, the term "substantially bound" means less
than about 25% of the biological activity associated with the toxin
production organic growth associated with S. aureus of the tampon
is lost by soaking the tampon over an 8 hour period at 100.degree.
F. in three times the syngnya capacity of sterile physiologic
saline solution. The saline is removed from the tampon by
compressing the tampon at 1 psi on a series of blotter paper until
.ltoreq.0.5 grams of fluid is absorbed by the blotter paper on the
last compression/absorption sequence and remeasuring the biological
activity remaining in the tampon. The extraction and testing should
be conducted in the absence of light. The ratio of initial
biological extraction to post extraction is >75%.
[0028] As used herein, the term "biological activity" of a tampon
is measured by the method described by J. Parsonnet, et. Al. (J.
Infect. Dis. 1996, 173: 98-103).
[0029] As used herein, the term "encapsulation" means the
surrounding off or "caging" of a compound using a physical or
chemical component.
[0030] As used herein, the term "nonabsorbent" means a
non-absorbing component of an absorbent article, as distinct from
the absorbing article itself, and that individual component
(particle or fiber) will not swell or absorb fluid. Typically, this
means less than a 0.15% weight gain of the component when placed in
a saline solution for 10 minutes and then removed and compressed at
1 psi repeatedly against a series of blotter papers until less than
about 0.5 gram of saline is absorbed by the blotter paper on the
last compression/absorption sequence. As used herein an absorbent
material, as distinct from an absorbent component is a material
from which the absorbent core is made and may hold fluid in the
intercapillary fibers or voids and may itself be an absorbent or
non-absorbent component.
[0031] As used herein, the term "inhibitor" means any agent that
prevents the normal growth of an organism or the activity of an
enzyme or protein.
[0032] As used herein, the term "pre-toxin limiting agent" means
any agent that prevents the initiation or actual production of a
toxin.
[0033] As used herein, the term "deactivation" means to make less
toxic or nontoxic.
[0034] As used herein, the term "permeable structure" means any
article that selectively allows components of a particular size
less than or equal to the particular size to readily pass through
without substantial resistance. An overwrap is an example of a
permeable structure.
[0035] B. Phase I: Reduce and/or Prevent Colonization of the Tampon
by Vaginal Microorganisms
[0036] To reduce the risk of TSS, antimicrobial agents are
incorporated within an absorptive product such as a tampon to
prevent the colonization of the tampon by bacterial species. If the
bacterial species colonize, the bacteria can create toxin. If S.
aureus is present and the toxin is created, the woman is at risk
for TSS. The tampon represents a new ecological niche within the
vaginal environment for the indigenous bacterial species of the
vagina to colonize. New understandings of this indigenous
population point toward the hypothesis that the greatest diversity,
especially of minor species, in the vaginal biofilm/colony occurs
at the surface of the vaginal mucosa. The highest probability of S.
aureus initial colonization occurs at this vaginal mucosa
surface/tampon interface. Components secreted by other species of
vaginal bacteria can amplify toxin production by S. aureus.
Therefore, to reduce the risk of an increase in population of S.
aureus, via growth in the tampon, and extracellular components
secreted by other organisms from affecting the potential rate of
toxin produced, the present invention incorporates inhibitors that
inhibit colonization into the tampon's design and construction.
Section i. discusses the incorporation of antimicrobial agents into
the absorptive product. Section ii. discusses the incorporation of
antifouling agents into the absorptive product. Section iii.
discusses the incorporation of biostatic agents into the absorptive
product. Section iv. discusses the incorporation of negatively
charged molecules. Finally, Section v. discusses the encapsulation
of antimicrobial agents and biostatic agents.
[0037] i. Antimicrobial Agents
[0038] Antimicrobial agents may be incorporated into the
construction of the absorptive, non-absorptive, and/or overwrap
components of the tampon. Antimicrobial agents are agents which
inhibit growth or kill bacteria. Controlling the localization of
these antimicrobial agents is important. If the localization of the
antimicrobial agents is not controlled, disruption and/or depletion
of the indigenous microflora covering the vaginal mucosa would
potentially be harmful to the overall health of the vaginal canal.
The antimicrobial activities of many antimicrobial agents are
dependent upon solubilization and uptake by the microorganisms of
interest.
[0039] The antimicrobial agents may be covalently linked to the
non-absorbent material of the tampon, either directly or through
modification. The presence and detection of the antimicrobial
agents by the vaginal microorganisms would be sufficient to delay
or decrease the potential overall colonization of the tampon during
typical wear. Modification of the antimicrobial agent to allow the
antimicrobial to be immobilized, for example via --CH.sub.2-- or
--CH.sub.2--CH.sub.2-- etc. linker, while not obstructing their
active sites would allow for increased availability and
effectiveness against colonization of the tampon. However, linking
the antimicrobial agents to the absorbent component of the tampon
may decrease the tampon's overall effectiveness.
[0040] Antimicrobial agents that can be utilized for this purpose
may include but are not limited to Clindamycin, Lysostaphin, PHMB,
Triclosan, and quaternary ammonia compounds. Clindamycin and
Lysostaphin are discussed in more detail below.
[0041] An additional benefit of using Clindamycin is that this
agent depresses toxin production by S. aureus. Clindamycin
hydrochloride, or CLEOCIN.RTM. HCl, is currently used to treat
vaginal infections. It is a semisynthetic antibiotic produced by
7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent
compound lincomycin. Clindamycin inhibits bacterial protein
synthesis at the level of the bacterial ribosome. It binds
preferentially to the 50S ribosomal subunit and affects the process
of peptide chain initiation. Although clindamycin phosphate is
inactive in vitro, rapid in vivo hydrolysis converts this compound
to the antibacterially active form. Clindamycin has been shown to
be an effective antimicrobial agent for a number of organisms
reported to be associated with bacterial vaginosis, such as
Bacteroides spp., Prevotella spp., Gardnerella vaginalis,
Mycoplasma hominis and Peptostreptococcus spp.
[0042] The antimicrobial agent lysostaphin (a zinc dependent,
25-kDa glycyl-glycine endopeptidase isolated from S. simulans) is a
specific peptidoglycan hydrolase ("PGH") enzyme for Staphylococcus
bacteria. PGH enzymes are incorporated and coordinated with the use
of absorbent articles to reduce the risk of colonization of the
absorbent article by Staphylococcus. PGH enzymes are naturally
present in small amounts in bacteria where they are essential for
cell wall re-modeling that must occur with cell growth and
division. Because bacterial peptidoglycan structures differ
significantly, PGHs can be found to target specific bacterial
species or groups of related organisms. Specifically, the action of
lysostaphin is hydrolysis of the --Gly+Gly-- bond in the
pentaglycine inter-peptide link joining Staphylococcal cell wall
peptidoglycans, thereby, digesting the peptidoglycan "structural
barrier" of the bacterial cell walls. Added in excess they rapidly
digest peptidoglycan resulting in cell rupture. Therefore,
lysostaphin, which is a specific PGH enzyme to Staphylococcal
organisms, would prevent S. aureus and other Staphylococcal
organisms from colonizing the tampon without adversely affecting
the non-Staphylococcal dominate species of the vaginal canal.
Lysostaphin's N-terminal of the enzymatic protein is the
enzymatically active region and the C-terminal is what confers
target cell specificity and allows it to distinguish between S.
aureus and its parent cells S. simulans (Baba & Schneewind,
EMBO J. 1996). Crosslinking the protein to a matrix via its
C-terminal region would anchor the protein and still allow it to
some degree to be enzymatically active against Staphylococcal
spp.
[0043] ii. Antifouling Agents
[0044] Antibiofilm formation agents may be incorporated into an
absorbent product such as a tampon to prevent the colonization of
the absorbent product. Antifouling agents are an antibiofilm
formation agent which may also be incorporated into the tampon's
construction. The antifouling agents can be incorporated into the
tampon's construction by binding. The binding of the antifouling
agents is important because of the non impact or influence upon an
environment external to its current environment. For example, an
anti-microbial agent located in the tampon should not impact or
influence the growth of bacteria outside the tampon.
[0045] The two types of antifouling agents which may be
incorporated are Furanones and L-acyl homoserine lactones.
Furanones are halogenated compounds that are known to depress
gram-negative bacterial growth and kill gram-positive bacteria.
L-acyl homoserine lactones are specific to gram-negative bacteria
and are also known to control virulence factors. These agents need
to be immobilized to the components of the tampon and prohibited
from coming into direct contact with the microflora of the vaginal
canal. Furthermore, quorum sensing signals are active biofilm
forming signals for gram-positive organisms and may be employed to
inhibit colonization of a tampon. Quorum signals will be discussed
in depth in Section C of the Phase II discussions.
[0046] iii. Biostatic Agents
[0047] Biostatic agents decrease bacterial growth. Biostatic agents
such as the common histochemical dyes, methylene blue, and gentian
violet can be cross-linked to cellulose fibers and other potential
absorptive materials. Methylene blue is a redox dye that raises the
oxygen consumption of cells. This means that the protons
(hydrogens) of the materials to be oxidized are passed on to the
oxygen molecules present in the environment. Methylene blue in an
unbound state acts as an electron carrier short circuiting the
electron transport process which is responsible for ATP (adenosine
triphosphate) production within the cell (as shown in FIG. 1). A
similar mechanism is hypothesized when methlene blue is bound to a
fiber structure.
[0048] iv. Negatively Charged Molecules
[0049] Coating the absorbent article and its components with
negatively charged molecules prevents the colonization of the
absorbent product/tampon. Negatively charged tampon and/or its
components electrostatically repel bacterial cell surfaces which
are negatively charged. If the materials of the absorbent product
were negatively charged via the use of PO.sub.4 or SO.sub.4 etc.,
bacteria would be repelled from forming biofilm and or rapidly
dividing in this negatively charged environment.
[0050] v. Encapsulation of Antimicrobial Agents and Biostatic
Agents
[0051] Incorporating the encapsulation of enzymes and or active
agents with an absorptive product such as a tampon prevents the
colonization of S. aureus. Antimicrobial and/or biostatic agents
can be encapsulated by the use of hydrophilic isocyanate polymers.
These polymers are water-soluble and a variety of molecules can be
incorporated into these hydrophilic urethane type polymers. During
the polymerization of hydrophilic isocyanate prepolymers, carbon
dioxide is typically generated keeping the oxygen levels in the
immediate environment low. This low oxygen environment aides in the
overall stability of any enzyme added to the prepolymer emulsion
which becomes an integral part of the resultant copolymer. The
enzyme(s) or other chemical antimicrobial/biostatic agent(s)
participates in the polymerization and is typically chemically
attached at multiple points within the resulting isocyanate
copolymer matrix essentially becoming caged within the isocyanate
polymer. As described previously, the overall availability and
effectiveness of the caged enzyme may be increased by first
modifying the attachment site of the enzyme to the polymer matrix
via the addition of a "linker" molecule. Within this copolymer
matrix a variety of enzymes have been shown to be thermally stable
over time. Since this is an aqueous polymerization event, upon
hydration of the copolymer matrix the enzyme or microbial agent
becomes "active" and can exhibit a retention of specific activity
as high as 80% of "uncaged" activity. This solubilization of the
isocyante polymer allows for a controlled release of the enzyme as
fluid triggers the solubilization of the urethane like gel. The
components, which exhibit antimicrobial or biostatic activity, are
covalently bound to the polymer. Upon hydration, the polymer is
eroded to release the active material at the preferred site of
action.
[0052] It is preferred to keep antimicrobial and biostatic agents
isolated from the vaginal mucosa. This may be accomplished by the
use of appropriate overwraps that cover the absorbent core. For
example, formed film overwraps may be used or nonwoven overwraps
made of rayon, cotton, polyesters, polyolefins that provide
separation where the core is isolated from the surrounding vaginal
tissue preventing destruction and/or alteration to the vaginal
flora. The overwrap may also act in combination with the absorbent
core to provide a one-way valve such that fluid enters the tampon
and is irreversibly trapped. This tampon exhibits the one-way
property when it is loaded with saline at 75% of syngyna capacity,
allowed to equilibrate for fifteen minutes and then placed on
blotter paper, the tampon is then rolled over the blotter paper
without pressure applied to remove free fluid on the surface of the
tampon. The tampon is then placed on a fresh blotter paper and
compressed with a force of 1 psi. If the squeeze out on the blotter
paper is less than 0.1 grams the tampon is considered to be a
one-way valve.
[0053] Physical separation of the inhibitor or antimicrobial agent
can be demonstrated by adding sterile saline solution (at syngyna
capacity) gently blot the surface to remove free fluid and place
the tampon containing the inhibitor onto an agar place colonized
with a lawn of Lactobacillas. If the Lactobacillas lawn is not
disturbed/killed at the contact point between the tampon and the
agar plate physical separation is demonstrated.
[0054] C. Phase II: Prevent Toxin from Being Produced by TSST-1
Producing
[0055] Extensive in vitro work describes the environmental and
genetic conditions required for S. aureus to produce TSST-1 toxin.
Current in vivo physiological understanding of the dynamics of
dissolved oxygen and carbon dioxide in the tampon during menstrual
wear indicate that optimum conditions for toxin production by S.
aureus must exist within the tampon. The oxygen required for
potential toxin production within the tampon is believed to come
from the inherent air within the tampon and the oxygen carried by
the menstrual fluid absorbed by the tampon. The inherent oxygen of
the tampon is essentially unutilized by the facultative
microorganisms of the vaginal canal in the absence of blood/menses.
However, in the presence of a heavy loading of blood/menses
virtually all of the oxygen in the tampon can be consumed, while
the dissolved carbon dioxide levels within the tampon rise
significantly above that present in the vaginal environment.
[0056] As shown in FIG. 2A, during non-menstrual wear, carbon
dioxide levels of the tampon rose to be essentially equivalent to
those observed in the vagina. However, as shown in FIG. 2A, the
oxygen levels within a non-menstrual tampon remained essentially at
atmospheric levels.
[0057] As shown in FIG. 2B, during menstruation, the mean levels of
carbon dioxide in about 50% of the tampons exceed the carbon
dioxide levels of the vaginal environment. The mean levels of
oxygen within the tampon decrease with apparent loading of the
menses such that about 50% of the menstrual tampons reached an
oxygen level near the ranges of oxygen levels observed in the
vagina after 8 hours of wear. The decline of oxygen and the
increase of carbon dioxide within a menstrual tampon may be at
least partially related to microbial metabolic activity. Since
menses is a mixture of venous and arterial blood, some of the
oxygen may be "lost" due to partitioning from the gas phase to the
liquid phase where it binds to un-oxygenated heme molecules present
in the menses. The oxygen and carbon dioxide levels observed in a
menstrual tampon after prolonged wear are consistent with in vitro
data showing high levels of toxin production by S. aureus under
similar O.sub.2/CO.sub.2 conditions.
[0058] Phase II provides several approaches to prevent toxin from
being produced by the TSST-1 producing strains of S. aureus.
Particularly, pre-toxin limiting agents are used to retard the
production of bacteria produced toxins. Part i. discusses oxygen
scavengers incorporated into the construction of the tampon. Part
ii. discusses the alteration of the heme in menses. Part iii.
discusses the encapsulation of antimicrobial agents via hydrophilic
isocyanate polymers. Part iv. discusses the construction and/or
additive to an absorbent structure, which either moderates (i.e.
reduces) the thermal energy released during expansion of a tampon
and/or cools the absorbent article. Part v. discusses the blockage
of either the production of the octapeptide (Quorum Signal) or the
binding of the peptide to the cell membrane receptor.
[0059] i. Oxygen Scavengers
[0060] In a number of in vitro experiments, oxygen has been shown
to be essential for toxin production by S. aureus. An oxygen
scavenger incorporated into the construction of a tampon would
significantly reduce, if not entirely prohibit, toxin production
within the product. Examples of oxygen scavengers, which could be
employed, are antioxidants such as ascorbic acid, tocopherol and
retinal. Compounds such as the antioxidants used in food substances
such as butylated hydroxyanisole, di-tertiary-butyl-patacresol,
propyl gallate, phenylenethiourea, and aldoalpha-napthylamine could
also be used. Other oxygen scavenging agents employed may be
composed of transition metal complexes, chelates of a salicyclic
acid, salicylate salt, metal complex, and/or chelate of an organic
polycarboxylic acid preferably an amino polycarboxylic acid wherein
the transition metal could be supplied via the iron present in
menses from the degraded heme molecules present in this body fluid.
This type of oxygen scavenging molecule is typically activated by
contact with water or water vapor.
[0061] These same oxygen-scavenging agents have the additional
benefit of moderating the pH of the tampon. Because optimum toxin
production occurs at a neutral pH, any agent which will lower the
pH of the internal environment of the tampon into the acidic range
could effectively reduce toxin production. Such agents are organic
acids, for example ascorbic acid, polycarboxylic acid, etc. Not
only does ascorbic acid act as a means to lower the pH and/or
scavenge oxygen, but the ascorbic acid also deactivates the toxin.
While the mechanism of deactivation is unknown, the present
application includes the use of ascorbic acid in a tampon to
deactivate the potential presence of TSST-1 toxin to the point of
rendering it non-toxic, i.e. not lethal in animal experiments.
[0062] ii Alteration of the Heme in Menses
[0063] Another approach is to alter the heme in menses such that it
has a lower affinity for oxygen. This may be accomplished by
placing BPG (2,3-bisphosphoglycerate) within the tampon. BPG lowers
the affinity of oxygen for hemoglobin by a factor of 26. This is
the compound used to dissociate oxygen from the heme enabling the
unloading of oxygen to tissue capillaries in the body. If the
oxygen can not associate with heme, it is probable that it will no
longer be bioavailable to the microorganisms potentially colonizing
the tampon such as S. aureus and therefore, avoid the perceived
required conditions for toxin production within the tampon during
menstruation.
[0064] iii. Encapsulation of Antimicrobial Agents via Hydrophilic
Isocyanate Polymers
[0065] In Phase I, there was a discussion of encapsulation of
antimicrobial agents via hydrophilic isocyanate polymers to prevent
colonization of the tampon. This same technology can be utilized to
encapsulate agents which would prevent or decease the production of
toxin by S. aureus. An alternative method to the isocyanate polymer
encapsulation would be the use of alginates precipitated from
solution. Material that may be physically encapsulated includes but
is not limited to carbon black, antimicrobials, oxygen scavengers
(i.e. ascorbic acid), quorum signal analogs and/or blockers,
methylene blue, chitosan malate, etc. These same compounds can be
added to absorbent foams either pre- or post-polymerization. Other
agents which can be added include but are not limited to ascorbic
acid, tocopherol, glycerol, etc., all of which have been shown to
reduce toxin production and/ or deactiviate the toxin TSST-1.
Algenic acid can also be made into fibers via reaction with
cellulosic fibers and provides a matrix for the additional
cross-linking of a number of compounds such as chitosan malate,
which is known to depress microbial growth of S. aureus and
significantly reduce its ability to produce the TSST-1 toxin. Thus,
alginate particles/fibers act as an active agent carrier that can
be used with or in a component of the construction of an absorbent
article such as a tampon to depress microbial growth of S. aureus
and significantly reduce its ability to produce the TSST-1.
[0066] iv. Construction and/or Additive to an Absorbent Structure
which either Moderates or Reduces the Thermal Energy Released
during Expansion of a Tampon and/or Cools the Absorbent Article
[0067] A potential risk factor for toxin production in vivo is
believed to be elevated temperature. In an attempt to moderate or
depress any tendency the tampon may have to exist at an elevated
temperature in vivo, a number of compounds could be used. As shown
in FIG. 3A, in in vitro experiments a one degree Fahrenheit
increase in temperature can result in a 50% increase in TSST-1
production by S. aureus.
[0068] This patent application claims any technique of construction
and/or additive to an absorbent structure, which either moderates
(i.e. reduces) the thermal energy released during expansion of a
tampon and/or cools the absorbent article (either of compressed or
non-compressed construction) such that it preferably remains at or
below typical body temperature of 98.6.degree. F. If the internal
tampon temperature does rise above the ambient body temperature of
98.6.degree. F., it returns to 98.6.degree. F. within 30
minutes.
[0069] A number of currently marketed products are tested for their
potential change in internal temperatures upon hydration, i.e. a
measure of their absorbent material's heat of dissolution. The
experimental design involves the use of non-lubricated condoms
submerged with the open end above water into a 98.6.degree. F.
water bath. A thermocouple is placed in a small hole drilled
through the middle of a tampon, which is inserted into the condom
such that it too is submerged into the water bath. A second
thermocouple is placed between the tampon and the surrounding
condom. The condom-surrounded tampon is then allowed to come to the
temperature of 98.6.degree. F. Sterile saline is also allowed to
come to a temperature of 98.6.degree. F. in the same water bath. A
gush of the 98.6.degree. F. sterile saline (at syngyna capacity) is
then pumped in such that the tampon becomes saturated. The internal
and external tampon temperature is monitored. In addition to
commercially available products, a tampon constructed of a super
absorbent material as well as one constructed of foam absorbent
material (FAM) is tested. As shown in FIG. 3B, no changes were
observed for the tampons "external" temperature.
[0070] As shown in FIG. 3B, currently marketed products that are
constructed as a compressed "plug" of absorbent material exhibited
a sharp rise in internal temperature upon hydration with fresh
menses. The thermal energy is a result of the release of expansion
energy upon hydration of the compressed absorbent plug structure.
Referring to FIG. 3B, note that the temperature of the commercially
available products quickly returned to water bath temperature after
the action of hydration. The tampon composed of super absorbent
material exhibited an internal temperature of over 2.degree. F.
above that of the water bath and sustained this temperature for a
prolonged period of time of 7 hours. Temperature increase of the
super absorbent tampon may be related to the heat of dissolution of
the materials used in its construction, a phenomena previously not
considered in tampon construction. The foam absorbent material
("FAM") constructed tampon's internal temperature rose only
slightly and quickly returned to the original ambient temperature
of 98.6.degree. F.
[0071] The Epson Salt or magnesium sulfate hepta-hydrate
(MgSO.sub.4--H.sub.2O) is somewhat endothermic in nature and could
be employed to counteract any physical reactions to elevate
temperature within the tampon. Epsom Salt or magnesium sulfate
hepta-hydrate (MgSO.sub.4--H.sub.2O) has a low energy of
dissolution. Certain absorbent materials such as psyllium husk and
certain FAMs have been shown to moderate the temperature of a
tampon under the experimental conditions outlined above such that
the temperature of the tampon is not significantly elevated (as
shown in FIG. 3A and FIG. 3B). Other agents that possess zero or
less than zero heats of dissolution include but are not limited to
NaCl, Ca(NO.sub.3).sub.2-4H.sub.2O, Na.sub.2CO.sub.3-10H.sub.2O,
CaCl.sub.2-6H.sub.2O and various other magnesium salts.
[0072] An absorbent foam such as FAM or another absorbent may be
saturated with a solution of salt such as CaC12, MgC12, or sodium
ascorbate or absorbic acid and then dried leaving a residual salt
or acid content within the foam. It has been found that
concentrations of these materials on a weight percent of foam
between 0.1% and 10% can inhibit TSS-1 production The architecture
of the tampon being either a compressed plug or a loose sack has
been demonstrated to impact the internal temperature of the tampon
upon hydration. The loose sack design moderates the temperature of
the tampon such that its internal environment does not exceed the
temperature of the body during absorption of bodily fluids. In this
design cellulose could also be employed in the construction of the
product to act to establish a less dense product to allow for
better temperature control, i.e. body temperature or less.
[0073] v. Blockage of either the Production of the Octapeptide
(Quorum Signal) or the Binding of the Peptide to the Cell Membrane
Receptor
[0074] This patent application claims the use of such signals
and/or signal analogs/antagonist, either natural or artificial in
origin to repress the signal for the ultimate production of TSST-1
by S. aureus in an absorbent article and or menstrual cup,
diaphragm or other like devices. Likewise any agent that can either
prevent the production of the octapeptide, bind up the octapeptide
after its production such that it is no longer available to "feed
back" to the cell or occupy the binding sites on the cell membrane
such that the cyclic peptide--signaling molecule octapeptide (agr
D/autinducing peptide) can not bind and signal for toxin production
in the absorbent articles.
[0075] The gene cluster or operon that regulates the expressions of
the toxin designated TSST-1 is an example of Quorum Sensing. When
an infectious agent such as S. aureus invades a host, it first
attaches and attempts to grow and form a biofilm. The agr system
controls the production of many secreted proteins: positively
regulating enterotoxins, epidermolytic toxins and enzymes produced
by staphylococci, and negatively controls such proteins such as
Protein A, fibronectin-binding protein and coagulase. During this
time signals are sent out into the immediate environment where the
biofilm is forming. When enough of this signal is present, it binds
to a membrane receptor on the S. aureus cells to indicate that a
critical density of bacteria has been reached and cells of S.
aureus may be released into the environment to continue the process
of infection. Therefore, when the population of the cells is dense
enough and the concentration of signal is high enough such that an
individual bacterial cell can detect the signal toxin synthesis is
initiated. This high level of signal is referred to, as a "Quorum"
of signal, the signal compound in the case of TSST-1 is an
octapeptide auto inducing peptide. Toxin production occurs due to a
cascade of phosphorylation events in response to the quorum signal
within the cell that brings about the activation of the promoter
region, which controls the expression of the genes encoded for the
toxin. After the biofilm "burst", the S. aureus cells adhere to a
new site within the host and the "Quorum Sensing" process begins
again. FIG. 4 depicts the production of the octapeptide, its
release into the environment and its signaling for the production
of the toxin. (Arvidson, S. European Conference on Toxic Shock.
September 1997)
[0076] As shown in FIG. 4, blockage of either the production of the
octapeptide auto inducing peptide (Quorum Signal) or the binding of
the peptide to the cell membrane receptor, could essentially lock
the door to toxin production. With the use of natural repressors
for TSST-1 production such as competing analogs or antagonists
peptides. Therefore, this patent application claims the application
of such an analog or antagonist peptide/compound to the
construction of and/or as an additive to an absorbent article such
as a tampon to reduce the expression of TSST-1 toxin by S. aureus
during the absorbent articles use.
[0077] D. Phase III: Disrupt Toxin Binding Sites and/or Prevent
Toxin from Contacting Vaginal Mucosa
[0078] Phase III of this patent application claims any technique
(i.e. application of technique to an absorbent article) or tampon
construction that acts to retain/adsorb the toxin into/on the
tampon preventing the toxin and/or toxin producing strains of S.
aureus from coming into contact with the vaginal mucosa. To prevent
any TSST-1 toxin production from contacting the vaginal mucosa, the
tampon will be designed to specifically attract and bind TSST-1
toxin from and within the tampon from the immediate environment
around the tampon or from blood/menses entering the tampon.
[0079] Several ways have been developed to retain the toxin in the
tampon by a variety of ligand binding sites. The binding of the
specific toxins onto the fiber surfaces of the tampon prevents them
from contacting vaginal mucosal tissue, and thereby, is expected to
provide some degree of protection to the wearer against the toxin.
The toxin can be retained by a direct affinity to its own antibody
or antibody fragment or a chemical hapten resembling its own
binding site. Specific polypeptides or fragments of polypeptides
which show an affinity for the toxin can also be employed to
directly link the toxin. Toxins may also adhere to specific
oligonucleotide sequences which create direct or combinatorial
libraries and screen them for binding activity to the toxin that
can identify these oligonucleotides. Indirectly the toxin can be
linked by saturating the environment with protein A.
[0080] There are a variety of methods to attach ligands to fibers
and/or materials, such as: 1) solid matrix support though
cullulosic fibers: 2) activation coupling chemistry with the use of
sodium periodate: 3) site directed antibody coupling though
carbohydrates: 4) coupling of antibody fragments with sulfhydral
residues: and 5) amplification of antibody binding sites such as
avidin coupled matrixes or biotinylated antibodies or
fragments.
[0081] The above-described ligands need not only be linked to the
tampon's absorptive fibers/particles and/or overwrap and/or
materials (i.e. psyllium, FAM, etc.). The toxin binding ligands may
also be attached to non-absorptive/or absorptive glass beads,
zeolites and charcoal as examples. In addition, the ligands may be
attached to the inner surface of the tampon overwrap composed of
formed film topsheet, 3-D films, high loft structures, low
capillary force gradients (hollow fibers, etc.). These materials
act not only as one-way flow valves, allowing flow into the tampon
but not out, but also as the final "net" to catch the toxin before
coming into contact with the vaginal mucosa.
[0082] In order for the toxin to remain in the tampon once it
becomes linked to a particular ligand, the ligand must be anchored
to the particular absorbent or non-absorbent material composing the
tampon. If the biologically active molecules is not bound or
partially bound to the internal matrix of the tampon there may be a
risk of the toxin coming into contact with the vaginal mucosa. Here
again, the one-way flow valve overwrap structure can be
incorporated to the final "safety net" to catch any toxin or toxin
complex from coming into contact with the vaginal mucosa.
[0083] Overwraps that isolate or trap fluid in the tampon by
providing a physical separation between the fluid in the core and
the top surface of the tampon or vaginal membrane are defined as
"one way valves."
[0084] All documents cited in the Detailed Description of the
Invention are, in relevant part, incorporated herein by reference;
the citation of any document is not construed as an admission that
it is prior art with respect to the present invention
[0085] While particular embodiments of the present invention have
been illustrated and described, it would be obvious to those
skilled in the art that various other changes and modifications can
be made without departing from the spirit and scope of the
invention. It is therefore intended to cover in the appended claims
all such changes and modifications that are within the scope of
this invention.
* * * * *