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AIDS Behav (2010) 14:600606

DOI 10.1007/s10461-009-9655-6

BRIEF REPORT

Acceptability of a Non-Woven Device for Vaginal Drug Delivery


of Microbicides or Other Active Agents
Carol L. Joanis Catherine W. Hart

Published online: 5 January 2010


 Springer Science+Business Media, LLC 2010

Abstract Vaginal microbicides could reduce incidence of


HIV. However, the current method of delivering gel formulations (standard applicator) can result in acceptability
concerns/issues. This study evaluated the concept of using
a non-woven textile material (modified tampon) for vaginal
drug delivery. The study was nested within a Phase I randomized safety trial of lime juice concentrations used intravaginally. Of 47 women completing the safety trial, 16
were interviewed about their experiences. Overall, women
found the concept of non-woven materials for vaginal drug
delivery acceptable for use in delivering yeast medications
(13 of 16) and STI/HIV preventives (10 of 16).
Keywords Vaginal drug delivery  Non-woven device 
Lime juice  Microbicide  HIV

Introduction
In 2007, women accounted for 46% of the 33.2 million
people living with human immunodeficiency virus (HIV).
The estimated number of people newly infected with HIV
in 2007 was 2.5 million.[1] Male and female condoms
remain the only methods proven to reduce risk of sexually
transmitted diseases (STDs) and HIV, but negotiating their
use is not always possible. [2, 3] Researchers believe that
the use of a vaginal microbicide could substantially reduce
the number of new cases of STD/HIV. Numerous research
studies have examined the perceived acceptability of gel

C. L. Joanis (&)  C. W. Hart


Behavioral and Biomedical Research Department, Family Health
International, P.O. Box 13950, Research Triangle Park,
NC 27709, USA
e-mail: cjoanis@fhi.org

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microbicides. A recurrent acceptability theme centers on


messiness in use. Coggins et al. conducted an international
study to determine the safety and acceptability of microbicides. [4] Participants in the study inserted 5 mL of a
placebo gel vaginally once a day for 7 days. The participants were then asked about the acceptability of the gel.
Women reported excessive wetness, leakage, and messiness after the gel was inserted. The researchers concluded
that using less gel may be more acceptable.
While some microbicides show promise, the most
common method of microbicide delivery (standard applicator) is not without problems. Standard applicators are
inexpensive, but drug effectiveness can be contingent on
proper placement in the vagina, spread of the microbicide
throughout the vagina, and minimizing drug leakage after
placement. Barnhart et al. compared vaginal coating (gel
spread) among women using 2.5 and 3.5 mL doses of a
contraceptive gel. The researchers found greater coverage
with increased gel volume and greater gel spread over time.
[5] However, higher gel volume increased the likelihood of
messiness and reduced acceptability. Efficacy and user
satisfaction may be further compromised by human error,
e.g. not applying gel deeply in the vagina, which may result
in rapid leakage and/or inadequate spreading of the drug.
[5] Also, evidence points toward the cervix as one of the
main ports of entry for HIV. A mechanical barrier placed
at/near the cervix may have additional prophylactic benefit
[6].
Mauck, et al. conducted a Phase I safety study of three
concentrations of lime juice (25, 50% and undiluted) and
bottled water applied intra-vaginally either by douching or
by use of a saturated tampon. The study utilized a parallel
design and women were randomized to bottled water or a
specific lime juice concentration. A crossover design was
employed whereby women used both application methods

AIDS Behav (2010) 14:600606

(douche and tampon) with a 3-week wash out period


between methods. Women were instructed to use their
respective lime juice concentration and application methods twice daily for 6 days (12 doses). Required wear times
for the tampon ranged from 1 h (first usage) to six to 10 h
in subsequent uses. Further, they were to abstain from
sexual intercourse during the study period. Results showed
a dose response relationship, with higher concentrations of
lime juice associated with more frequent and severe
adverse events. Genital pain and itching occurred in both
tampon and douching arms, but metrorrhagia was noted
only in the tampon arm, a result of the effect of lime juice
dosage combined with the 610 h wear time of the tampon.
Further, lime juice compromised the vaginal epithelia and
would not likely protect against HIV [7].
Non-woven textile materials are widely used to make
consumer products, including tampons, menstrual pads,
diapers, vaginal wipes, and baby wipes. To evaluate the
concept of using a non-woven textile material as a drug
delivery system, we nested our research within the aforementioned lime juice safety study. Based on the results of
that research, we believe that the ideal vaginal drug
delivery system would include features that a soft, prewetted non-woven textile material could provide, notably:
ease of insertion and removal; comfort in use; reduction of
leakage and messiness; and less irritation. The availability
of a drug-delivery system that is inexpensive, easy to use,
assists in drug retention and delivery, and could be worn
during multiple acts of intercourse would increase use
effectiveness and drug efficacy. Given these considerations, an improved device for vaginal drug delivery should
be of interest.

Materials and Methods


Materials
The clinical study utilized a repackaged tampon as a
delivery device for three different solutions of lime juice
and bottled water. Women were provided with fresh limes
and/or bottled water and instructed in the preparation and
use of their randomly assigned solutions. The repackaged
tampon consisted of a regular tampon (Tampax Compak
Regular, Procter and Gamble, Cincinnati, OH) which was
contained within the applicator of a super tampon (Kotex
Security Plus, Kimberly-Clark, Dallas, TX). The larger
applicator allowed space for absorption of the fluid and
resultant expansion of the smaller tampon when the women
placed the device in a vessel containing their lime juice
solution or water. The repacked tampons were assembled
in a clean room environment under Good Manufacturing
Practice (GMP) conditions.

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Methods
This study was a qualitative assessment of the acceptability
and function of a non-woven substrate (modified tampon)
used to dispense water or lime juice solutions.
The researchers collected information through use of indepth telephone interviews with a 16-woman subset of the
47 women who completed the Contraceptive Research
and Development Program (CONRAD) sponsored study
6-Day Safety Trial of Intravaginal Lime Juice (in 3 concentrations) versus Water, Applied Twice Daily. [7] Participation in this sub-study was voluntary and women were
enrolled from each of the four study groups (three lime
juice concentrations and water) until four women from
each group were interviewed. Eligible women were
required to use their assigned solution of lime juice or
water as a douche and in the saturated tampon, be at least
18 years old, have used at least one of the saturated,
modified tampons and have provided oral informed consent. Women completing only the douching condition of
the aforementioned lime juice study were not eligible to
participate. Participants were enrolled from two clinical
study sites: East Virginia Medical School (EVMS), Norfolk, VA, and the Magee Womens Hospital (MWH),
Pittsburgh, PA.
The primary objective of this sub-study was to determine the feasibility and potential acceptability of using a
non-woven textile material (similar to the wetted tampon)
to deliver drugs intra-vaginally. Further, we described a
device prototype during the interview process and participants were asked their opinions about using such a device.
After oral informed consent, researchers from Family
Health International (FHI) interviewed the 16 women
individually by telephone. The interviews were conducted
using a semi-structured survey instrument that included
fixed-response questions linked to open-ended questions
and probes. The survey instrument was designed to move
toward more precise questioning as information emerged
throughout the interview. Women were interviewed within
one week of last study product use and each interview
lasted approximately 45 min. The interviews were taped
and transcribed verbatim.
Prior to participant recruitment, this sub-study was
reviewed and approved by the ethics committees of
CONRAD (East Virginia Medical School) and FHIs Protection of Human Subjects Committee (PHSC).
Data Analysis
Demographic data were entered into a Microsoft Excel
spreadsheet and quantified. Qualitative data analysis was
performed manually. We used the research questions from
the survey instrument to group the data and then looked for

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AIDS Behav (2010) 14:600606

similarities and differences in responses among participants. There were two sources of data: the transcripts from
the audiotapes and notes from each interview. A codebook
was developed and periodically reviewed to ensure consistency of coded definitions. Two people coded each
transcript and the field notes. Differences in coding decisions were negotiated and reconciled. Coded comments
were sorted by main and emergent themes and quantified.
Though seven main themes were identified, data were
reduced to commonly cited ideas/opinions and essential
points of interest relevant to the issue of acceptability of a
non-woven device. Five key themes emerged: ease of
insertion; ease of removal; comfort in use; leakage/messiness; and, physical effects. The interviewers discussed
impressions/opinions about participant responses to assist
in the evaluation and interpretation of the data.

Results
Ten sexually-active participants were recruited from MWH
and six from EVMS. Participants ranged in age from 20 to
49 years (mean = 34). Twelve were Caucasian and four
were African-American. Nine were married and seven
were single. The length of their relationships ranged from
less than 1 year to more than 22 years. Only one participant had less than 12 years of education, the remaining
reporting between two and 4 years of college. Their
occupations were: nurses; social worker; sales representatives; administrative assistants; students; a homemaker and
a domestic worker. Since the investigators found that
women in the 50 and 100% lime juice groups reported
irritation more frequently than those in the water and 25%

Table 1 Number of
participants experiencing
problems/difficulties by
category and future positive
interest in using a device for
vaginal drug delivery

lime juice groups, some results have been stratified by


these groupings (Table 1).
Ease of Insertion
Nine participants did not have problems or difficulties
inserting the wetted tampon. Insertion problems were
evenly spread across the four study groups. Problems with
insertion included: the tampon expanded fully giving the
perception of a tampon that was larger than participants
normally used during menstruation (n = 2); the wetted
tampon extended outside the applicator barrel causing
resistance (drag) during insertion (n = 3); and, the applicator barrel and plunger separated during product preparation (n = 2). In one case, the pre-cut edges of the
applicator barrel opened fully causing tearing or scratching
of vaginal tissue during insertion. Three women indicated
that the applicator itself was larger than they normally used
during menstruation.
Ease of Removal
Of the 16 participants, 14 reported no problems removing
the tampon. The two participants reporting problems
attributed those difficulties to resistance and/or vaginal
irritation. These women were assigned to the 50 and 100%
lime juice groups.
Comfort in Use
The participants were asked if they experienced any
discomfort while wearing the modified tampon. Half
reported no discomfort. Of the eight participants reporting

Category*

Water and lime juice concentrations


Water
n=4

25%
n=3

50%
n=4

100%
n=5

Total
n = 16

Difficulties preparing tampon for use

Difficult insertion

Difficult removal
Applicator problem

0
1

0
0

1
1

1
1

2
3

Wet string problem

Adverse medical event

Difficulty or complaint during use

10

STI/HIV

10

Contraception

Yeast treatment

13

Positive interest in device for Rx:


* Participants may have
mentioned more than one
category

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AIDS Behav (2010) 14:600606

discomfort, seven were from the 50 and 100% lime juice


groups (3 in the 50% lime juice group and 4 in 100% lime
juice group). The discomfort was described as wearing a
tampon that was heavier than those normally worn
during menstruation, i.e. they could feel the device after
insertion.
Leakage and/or Messiness
All participants (n = 16) experienced leakage on insertion
of the wetted tampon and most (n = 14) reported that
leakage was minimal and manageable. Two women found
the leakage problematic. Both participants reporting problems with leakage and/or messiness were from the 50%
lime juice group. All women managed leakage by using a
panty liner or using tissue to swab excess juice/water
immediately after insertion.
Physical Effects/Adverse Medical Events
Of the 16 participants, seven reported a physical effect (e.g.
dryness, cold feeling) or adverse medical event (three in
the 50% lime juice group and four in 100% lime juice
group). The negative physical effects reported were postwear dryness and discomfort (rubbing sensation) while
walking. These participants (n = 2) had never experienced
this discomfort while wearing a tampon during menstruation. The participants were asked if they felt the dryness
was caused by the tampon, the lime-juice solution, or the
combination of the two. The participants attributed the
dryness to the combination of the tampon and the lime
juice solution. One participant in the 50% lime juice group
stated, I think it was both because I did it with the douche
and had no problems. So I think it was the lime juice and
the tampon together. One participant in the 100% lime
juice group concluded that the lime juice seemed to
increase the absorbency of the tampon, so that it drew
most of the natural vaginal fluid into the tampon, thereby
reducing vaginal lubrication and causing dryness.
Regarding the discomfort while walking and wearing the
modified tampon, one participant in the water group stated,
The first time [I wore the modified tampon] was
uncomfortable, but after I got practice with it, it was better. A participant in the 100% lime juice group stated, I
work in a clinic and do a lot of walking around. I found it
difficultit was really raw around the outside of the vaginal area. One participant in the 25% group reported a
positive physical effect of feeling clean and fresh.
Adverse medical events reported included one or a
combination of the following: resultant yeast infection
from the assigned treatment, lesions, abrasions, bleeding,
burning, itching, irritation, genital pain, rash, and redness.
The physician investigator attributed these events to the

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long wear time of the saturated tampon and the higher


dosages of lime juice which disrupted the vaginal epithelium and/or lowered the vaginal pH.
Participant Interest in Future use of a Non-woven Drug
Delivery Device
The design concept for a prototype non-woven vaginal
drug delivery device was described to the study participants during the interviews. The device was described as
being smaller, thinner and softer than a tampon, diskshaped, with a longer string [than a tampon] for removal,
and containing a microbicide, spermicide, or a therapeutic
agent for yeast infection. Ten participants stated that they
would consider using such a device during sexual intercourse to prevent HIV/STI and eight would consider using
it for pregnancy protection, assuming that it did not
interfere with intercourse and was effective. Women who
would not use a vaginal drug delivery device for STI/HIV
protection were those in relationships of 8 years or longer.
Women who stated that they would not consider using the
device for pregnancy prevention were older ([35 years),
surgically sterile and in long term relationships, or they
were young (\25 years), fecund women desiring a method
of contraception they perceived as more reliable. Thirteen
participants stated that they would use such a device for
administration of yeast medications instead of current
messy, over-the-counter creams or suppositories. The
three women who would not use the vaginal drug delivery
system for treatment of vaginal yeast infection were
African-American, randomized to the water, 25 and 50%
lime juice groups, and were aged 38, 45 and 26,
respectively.
All participants were asked what would motivate them
to use or not use a non-woven vaginal drug delivery device.
The comments, listed by emergent themes, are representative of women of varying ages and ethnicity and in each
of the four lime juice/water groups. In some cases, a single
participant may be quoted in different theme categories.
Illustrative comments were as follows:

Small size of device (n = 3): Because it would be


more compact [than a sponge or tampon]. It would
be smaller.more like a bullet.
Disease prevention (n = 6): I would think that,
especially if it was going to prevent disease, I do not
see how anyone would not want to use that. I do not
have to protect myself [from disease]but if I was
younger, I would definitely use it. If it would block
HIV, I would use it.
Female controlled (n = 4): There is something that
you know yourselfthat you have taken care of. I
am protecting [my partner] one way or the other.

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AIDS Behav (2010) 14:600606

High efficacy rating (n = 5): Something that had a


good rating I would assume that if that were
something that my doctor prescribed, or that it was
found to have a certain percentage of effectiveness [I
would use it.].

Participants expressed the following objections to using


a non-woven vaginal drug delivery device:

Uncomfortable during intercourse/blocking the vagina


(n = 6): If it was so small that it was not going to be a
problem getting out, I would like to use it just for
protection. If it was difficult like my other experience
[sex with a tampon], then after trying it once, I would
never use it again.
Device could get stuck or lost in the vagina (n = 3): I
would be afraid that it would get lost. I would be
paranoid.
Difficult to insert or remove (n = 2): It could be
smaller, I would not object to it being smaller and
easier to get out [than the wetted tampon].

Discussion
Half of the women enrolled reported some discomfort or
adverse medical events associated with use of the wetted,
modified tampon. One woman in the water group complained
about tampon heaviness after insertion of the saturated
tampon. The remaining women complained about device
heaviness and discomfort (adverse events) associated with
use of the higher concentrations of lime juice (50 or 100%).
None expressed difficulties or problems using tampons during menstruation. When asked, the women attributed the
discomfort or adverse medical events to the combination of
the lime juice, the tampon, and the extended wear time
(610 h) of the device. Since 16 of 17 reports of discomfort
and adverse medical events occurred in the 50 and 100% lime
juice groups, and women did not report similar events during
the douching phase of study, it is likely that the tampon and
extended contact with a high concentration of an acidic
solution irritated the vaginal epithelium. Hemmerling, et al.
conducted the first safety study of diluted lime juice to assess
its potential as a candidate microbicide. [8] In that study, 10
and 20% concentrations of lime juice were delivered to the
vagina through a fully saturated tampon. Twenty-five sexually abstinent women participated. They were instructed to
use their randomly assigned dosage daily, during a 14-day
study period. Results showed that a 20% concentration of
lime juice exhibited an acceptable safety profile; however,
there was concern that use of lime juice at that concentration
would not be effective in killing HIV. Further, higher concentrations ([50%) may be toxic to tissue.

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Since women who reported adverse medical events in


this sub-study were in the 50 and 100% lime juice arms, we
assume that such toxicity may have played the greatest
role in the reported irritation. However, the impact of the
combined factors (lime juice, tampon, and extended wear)
cannot be excluded. In at least one participant, there was
damage to the vaginal epithelium based on her report of
lesions. [7] Since the intact vaginal epithelium is an
important barrier to infection, such lesions could actually
enhance transmission of STD/HIV. [9] Careful selection of
non-woven materials and use of less irritating active agents
in a drug delivery system should lessen the potential for
irritation and/or epithelial injury during extended wear.
An additional factor that could have contributed to the
reported discomfort and adverse medical events in the 50
and 100% lime juice groups is the osmolarity of lime juice,
estimated to be 600 mosmol. [10] The osmolarity of vaginal fluid is approximately 212 mosmol. [11] A solution
having osmolarity greater than vaginal fluid and in contact
with tissue will draw fluid from the tissue itself. Therefore,
it is possible that this difference in osmolarity resulted in
the drying of vaginal tissues. Because the osmolarity was
higher in the tampon in the two higher dose groups, and
especially in the 100% group, osmotic pressure might have
drawn vaginal fluid into the tampon. Thus, the comment by
one of the women in the 100% lime juice group that it
drew most of my natural vaginal fluid into the tampon,
thereby, reducing vaginal lubrication and causing dryness,
might have been fairly accurate. Further, this may have
contributed to the described heavier and larger feel of
the study tampon.
Three women complained about the process of preparing the tampon with their assigned liquid. Sometimes, the
procedure resulted in the separation of the applicator barrel
and plunger or expanded the tampon to such a degree that it
extended outside of the applicator opening. In this case,
insertion difficulty (resistance) was reported. In total, seven
women had complaints about the insertion of the wetted
tampon. Such complaints were spread across the study
groups.
Two women reported resistance (pressure) in removing
the wetted tampon from the vagina. Though these women
were in the 50 and 100% lime juice groups, similar pressure during removal of a tampon toward the end of menses,
when the vagina is likely to be drier, is a common complaint among women.
While only one participant reported previous experience
wearing a tampon during intercourse, all participants
expressed concern about the comfort of using a similar
product during intercourse. Their concerns centered on
ease of penetration and partner comfort. Several participants could not foresee ever using or having the need for
such a device given the trust in their marital/partner

AIDS Behav (2010) 14:600606

relationships, but most women expressed approval only if it


was undetectable by their partners (i.e. the device would be
odorless, colorless, and not block the vaginal canal during
intercourse). The participants liked the idea of a womancontrolled method of disease prevention. Currently, the
only form of HIV prevention seemingly under a womans
control is the female condom.
Thirteen of the participants expressed interest in a nonwoven device for delivery of vaginal medications for yeast
or bacterial infections. The participants interest was in
minimizing messiness and leakage. Coggins, et al. reported
one-third of women in a study using 5 mL of carrageenan
gel recommended reducing gel volume due to messiness
However, less than 5 mL of gel might be less effective. [4]
Clearly, new female-controlled methods are needed for
disease prevention and treatment. Gel or cream formulations contained within a non-woven substrate would help to
minimize the messiness (leakage) associated with applicator-applied vaginal products. A device that could hold
larger volumes of an active agent and could be used for
multiple sexual acts would be a useful addition to methods
to protect and improve womens health.
Our study has several limitations. While the sample size
(n = 16) may be sufficient for a qualitative study, stratifying the analysis by treatment group provides for a limited
number (n = 4) of interviews per study condition. Data
saturation is generally not possible in such small samples;
however, we could find little variance in participant
responses with respect to age, ethnicity, occupation, education, marital status or duration of partnership within main
and emergent themes. Negative responses were generally
attributed to dose response (i.e. most complaints or problems occurring in the 50 and 100% lime juice groups). One
exception was African-American ethnicity which was
associated with a lack of interest in use of a non-woven
device for treatment of vaginal yeast infection.
Second, there is considerable difference in the physical
properties of liquids as compared to gels/creams. Use of a
gel saturated tampon may have resulted in a different
acceptability profile than the highly acidic lime juice.
Finally, the results of this research could be potentially
biased. Fifteen of 16 participants used tampons as their
primary method of menstrual hygiene. While this would
have little impact on introduction and use of a non-woven
vaginal drug delivery system in developed countries, the
concept may be difficult to accept among women in
countries where tampon exposure and use are limited.

Conclusions
The experience with the wetted tampons used in this
study, though different in construction from our proposed

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prototype device (US patent pending), provides useful


information for the development of vaginal drug delivery
systems. The selection of materials that desorb and
release rather than absorb fluids (e.g. a tampon) will
improve delivery of active agents and hold them in areas
of the vagina more susceptible to disease. Further, the
identification and selection of a gel that has similar
osmolar properties to vaginal fluid will minimize changes
in lubricity, ease insertion, and minimize vaginal irritation
or trauma. With the appropriate combination of a gel
formula and fiber properties, a device large enough to
hold a therapeutically effective dose, but small enough to
be comfortable may be found as an effective method for
delivering various type of drug formulations to the
vagina.
Acknowledgments The authors would like to thank Drs. David
Jenkins and David Sokal of Family Health International, Dr. G.A.M.
Butterworth of Butterworth Consulting, and Dr. Christine Mauck of
CONRAD for their advice and guidance during the study. We would
further like to acknowledge LaShawn Jones of Family Health International for her assistance during the interview process. Support for
this study was provided by Family Health International with support
from CONRAD and the United States Agency for International
Development (USAID) under USAID Cooperative Agreement HRNA-00-98-00020-00 (MSA-05-403, MSA-05-420, and MSA-06-450),
although the views expressed in this publication do not necessarily
reflect those of Family Health International, CONRAD or USAID.
The authors and others affiliated with the study have no financial
interests that would impact the conduct of the study or the integrity of
the research results.

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