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Sexually Transmitted Diseases:
doi: 10.1097/OLQ.0b013e3181644669
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Mucosal Irritation Potential of Personal Lubricants Relates to Product Osmolality as Detected by the Slug Mucosal Irritation Assay

Adriaens, Els PhD; Remon, Jean Paul Professor

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Author Information

Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium

Supported, in part, by NICHD grant SBIR #1R43HD43593 to INGfertility.

Correspondence: Dr. Els Adriaens, Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. E-mail: Els.Adriaens@UGent.be.

Received for publication September 6, 2007, and accepted December 4, 2007.

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Abstract

Background: The slug mucosal irritation assay has recently been used as a sensitive measure of mucus membrane tolerance for vaginal microbicide products and carriers. In the current study, it was determined whether musosal irritation potency of personal lubricants is related to varying product osmolalities.

Methods: Five commercial lubricants with an osmolality range were evaluated using the previously validated slug mucosal irritation assay. Specifically, Arion lusitanicus were treated with lubricants over 5 days to quantify mucus production and tissue damage, allowing assignment of each product into an irritation potency category (none, mild, moderate, or severe).

Results: The irritation potency (assessed by the mucus production) of the lubricants showed a significant, quadratic relationship with the product osmolality (P = 0.001; R2 = 0.99). Femglide, a hypo-osmotic lubricant (32 mOsm/kg), caused a negative mucus production. Pré, an iso-osmotic lubricant (316 mOsm/kg), caused no changes. Two moderately hyperosmotic lubricants, Replens and K-Y jelly (2143 and 2463 mOsm/kg), induced mild and moderate irritation, respectively. The highly hyperosmotic lubricant Astroglide (5848 mOsm/kg) resulted in severe irritation and tissue damage.

Conclusions: Commonly used personal lubricants show a full range of mucosal irritation potential, which is related to product osmolality.

INSUFFICIENT LUBRICATION DURING INTERCOURSE is a common complaint for women at all life stages.1 Although often a topic of discussion with older patients, over 40% of reproductive age women also report intermittent episodes of vaginal dryness2 and occasional dyspareunia.3 Personal lubricants are commonly used to alleviate such dryness and discomfort at intercourse. Most personal lubricants are currently regulated as medical devices4 with little published information on product-specific vaginal tolerance or irritation potency, despite their frequent use by millions of women. Even for women with more severe vulvar pain disorders, such as vulvodynia, there is little empirical data to base palliative lubricant choice on other than the generic “nonirritating, water-soluble” recommendation.5

In contrast, newly developed vaginal drug formulations are thoroughly evaluated for irritation potential, because inflammation can increase disease transmission.6–10 Historically, the standard assay for assessing vaginal tolerance has been the rabbit vaginal irritation test (RVI). However, recent studies have demonstrated that slug mucosal irritation assay (SMI) is a more sensitive system to detect even mild mucosal irritation potency.11,12 For example, the SMI detected the irritation potency of a lubricant that manifest as clinical genital itching and discharge in women, even though RVI studies for irritation were negative.7,11,13 The SMI assay uses slugs (Arion lusitanicus) as the test organism.14 The body wall of slugs consists of a mucosal surface including mucus secreting cells covering a subepithelial connective tissue. Slugs that are placed on an irritant substance will actively produce mucus as a protective mechanism from noxious agents. Additionally, tissue damage of the slug's surface results in the release of proteins and enzymes. To date, more than 200 raw materials and formulations with known animal and clinical irritation outcomes have been used to optimize and validate the SMI assay for local mucosal tolerance testing of topical pharmaceuticals. Based on these results, a prediction model has been developed that can classify products into categories of potency: no, mild, moderate, or severe irritation potential.15

A major advantage of the SMI assay is that it can be used to predict genital burning and itching. An increase in the amount of mucus produced in the SMI has been associated with an increase in the number of patients complaining of genital heat, itching, or burning.15 Although not widely reported, genital itching and burning following personal lubricant use is not uncommon, with over 25% of women and men6,16 reporting symptoms during “control” lubricant use in vaginal microbicide development studies. However, few studies have compared mucosal irritation potential of common personal lubricants to determine whether a range of tolerance can be identified. Such information is important to assist the clinician and patient in appropriate product choice.

Several recent studies suggest that osmolality differences in personal care products, including lubricants, may impact local tolerance. For example, itching and burning of the sensitive eyelid skin has been related to product osmolality of make-up removers.17 Also, the osmolality of personal lubricants has been associated with cellular toxicity, as shown by loss of sperm motility and DNA integrity after lubricant contact in vitro18 and epithelial sloughing of anal tissue after contact in men.19

The current study was done to determine whether common personal lubricants differed in mucosal irritation potency using the SMI, and to evaluate whether any such differences in mucosal tolerance could be predicted by a product's osmolality.

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Materials and Methods

Experiment A. Personal Lubricants Evaluated for Irritation Potency and Osmolality

The first experiment evaluated 2 controls (a negative and a positive); along with 5 commercially available personal lubricants (or “vaginal moisturizers”) covering a relative range of osmolalities based on product composition: Hypo-osmotic (32 mOsm/kg) lubricant, Femglide (WalMed Inc., Puyallup, WA), contains water, polyoxyethylene, methylparaben, and sodium carbomer. Iso-osmotic (314 mOsm/kg) lubricant, Pré (INGfertility, Valleyford, WA), contains water, hydroxyethylcellulose (HEC), Pluronic 127, sodium chloride, arabinogalactan, sodium phosphate, carbomer, methylparaben, sodium hydroxide, and potassium phosphate. Deemed as “iso-osmotic” for the vaginal environment based on a range consistent with normal osmolality of female secretions 260 to 290 mOsm/kg and human semen 250 to 380 mOsm/kg.20,21 Moderately hyperosmotic (2143 mOsm/kg) lubricant, Replens (Columbia Laboratories, Hitchin, UK), contains water, carbomer, polycarbophil, glycerin, paraffin, hydrogenated palm oil glyceride, sorbic acid, and sodium hydroxide. Moderately hyperosmotic (2463 mOsm/kg) lubricant, K-Y jelly (Johnson & Johnson Inc., MTreal, Canada), contains water, chlorhexidine gluconate, hydroxyethyl cellulose, gluconodeltalactone, glycerin, methylparaben, and sodium hydroxide. Highly hyperosmotic (5848 mOsm/kg) lubricant, Astroglide (BioFilm Inc., Vista, CA) contains water, glycerin, propylene glycol, polyquaternium 15, methylparaben, and propylparaben.

The negative control, known to not cause mucosal irritation, consisted of an isotonic HEC gel, used as the “universal placebo” gel in microbicide efficacy and safety trials.22,23 The HEC gel consisted of 5% (w/w) HEC (377 mPa·S), 2% glycerol, 0.068% (w/w) methylparaben, 0.017% (w/w) propylparaben, and water. The positive control, known to induce mucosal irritation and tissue damage in the SMI and the RVI,12,22 was Conceptrol (Ortho-McNeil Pharmaceutical Inc., Raritan, USA), a vaginal contraceptive gel containing 4.0% nonoxynol-9 (N-9), sodium carboxymethylcellulose, propylene glycol, methylparaben, povidone, sorbic acid, sorbitol solution, lactic acid, and water.

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Experiment B. Evaluation of Changing Osmolality on Irritation Potency

In this second experiment, a direct effect of changing osmolality on subsequent mucosal irritation potency was evaluated by adding increasing amounts of glycerol to the HEC gel, the negative control formula (as in Experiment A). Final glycerol concentrations in the HEC gel were: 0%, 2%, 4%, 6%, 8%, 10%, 20% or 40% (w/w) glycerol.

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Osmolality Measurement

Osmolalities of commercial lubricants in Experiment A and HEC/glycerol test gels in Experiment B were measured using an advanced Micro Osmometer Model 3300 (Advanced Instruments, Norwood, MA) by the freezing-point method. The device was calibrated with a Clinitrol 290 reference solution (Advanced Instruments). The measurements were performed in triplicate (on 20-μL aliquots) and mean values used for analysis. Samples with an osmolality >1200 mOsm/kg were diluted for measurement, and a linearity check was performed on the dilutions (R2 > 0.99) to confirm accuracy.

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Slug Mucosal Irritation Assay

Detailed procedures for completion and validation of the SMI are described elsewhere.11,12,14 The irritation and tissue damaging potency of the formulations was evaluated by placing 5 slugs per treatment for a 30-minutes contact period, on 100 mg of the gel in a petri dish, for 5 consecutive days. Test exposures consisted of: Experiment A—2 controls and 5 lubricants; and Experiment B—8 treatments with varying percents of glycerol and subsequent osmolality. Because of the nature of the test organism (invertebrate), this study was not subject to Institutional Review.

The protein concentration in the collected samples was determined with a NanoOrange protein quantitation kit (Molecular Probes, Leiden, The Netherlands) and expressed as microgram per milliliter per gram body weight. The LDH activity (EC 1.1.1.27) and ALP activity (EC 3.1.3.1) were measured with an enzyme kit (LDH/HBDH 2.8 and ALP 6, ABX diagnostics, MTpellier, France) and expressed as international unit per liter per gram body weight.

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Data Analysis

The irritation potency was predicted based on the total amount of mucus produced (total MP) during the repeated 30-minute contact periods. Total MP is expressed as a percent of the body weight of the slugs. For each slug, total MP is calculated by adding up the mucus produced during each 30-minute contact period, and a mean value for the slugs in each treatment was calculated. Four categories of irritation potency can be defined based on total MP:

* <15% = nonirritant

* between 15% and 20% = mild irritation

* between 20% and 25% = moderate irritation; and

* >25% = severe irritation.

Tissue damage is predicted by: the number of slugs in each treatment (out of the 5 per treatment) that show ALP release; the mean LDH release of all the samples; and the mean protein release excluding the samples taken on day 1.

The SMI was considered valid when the following criteria are met: (1) the negative control (5% HEC, 2% glycerol gel) is classified as a nonirritant (total MP <15%) with no tissue damage found (no ALP release, mean protein release <25 μg/mL·g, and mean LDH release <1 IU/L·g); (2) the positive control (Conceptrol) was classified as an irritant (total MP >20%) with severe tissue damage induced (ALP release in 4 of the 5 slugs or mean protein release >100 μg/mL·g).

The relationship between osmolality and the irritation potential (predicted by the total mucus production) in both experiments was determined by least squares regression analysis using SPSS (version 15.0).

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Results

Experiment A. Irritation Potency of Personal Lubricants

There was a significant quadratic relationship between increasing osmolality of the lubricants evaluated in this study and the total MP (measure of irritation potency) (R2 = 0.99; F = 167.2, df = 5; P = 0.001) as shown in Table 1 and Figure 1. Specifically, neither the hypo-osmotic Femglide, nor the iso-osmotic Pré caused mucosal irritation. In fact, the hypo-osmotic lubricant resulted in a negative mucus production value (total MP −4.3%), as the slugs absorbed water from the product. The moderately hyperosmotic lubricants resulted in mild irritation (total MP between 15% and 20%) for Replens, and moderate irritation (total MP between 20% and 25%) for K-Y jelly. The highly hyperosmotic Astroglide resulted in the most mucus production (total MP of 38%) and was classified as a severe irritant, with mucus production being higher than that observed in the positive control. Slugs treated with this lubricant produced high amounts of yellow colored mucus, whereas their mucus is normally colorless. The positive control Conceptrol also induced severe irritation (total MP of >25%), although irritation for this product is known to be due primarily to the nonoxynol-9 present and not the osmolality.

Table 1
Table 1
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Fig. 1
Fig. 1
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Only slugs treated with the highly hyperosmotic lubricant and the positive control (Conceptrol) showed tissue damage, with the protein release increasing after repeated treatment (Fig. 2) and both formulations inducing LDH release after the second contact period (Fig. 3). Only slugs treated with the positive control (Conceptrol) showed ALP release from the third contact period. No other lubricants caused tissue damage, with mean protein release staying below 25 μg/mL·g and no enzyme release occurring. As shown in Figure 2, the protein release profiles after exposure to these other lubricants were comparable to those observed after negative control (5% w/w HEC gel with 2% w/w glycerol) exposure.

Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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Experiment B. Effect of increasing Osmolality on the Irritation Potency

Regression analysis demonstrated a significant positive quadratic relationship between the irritation potency (total MP) of the HEC base gel and the osmolality (and percentages of glycerol) as seen in Table 2 and Figure 4 (F = 268.5, df = 7; P <0.001), and 99% of the variation in total MP can be attributed to changes in osmolality (R2 = 0.99). Although total MP increased as the osmolality rose, irritation and tissue damage did not occur until glycerol concentrations reached 20% and osmolality rose above 2000 mOsm/kg. The hypo-osmotic HEC gel without glycerol (34 mOsm/kg) resulted in a negative mucus production value (total MP −1.9%). The iso-osmotic HEC gel with 2% glycerol (304 mOsm/kg) resulted only in minimal mucus production (total MP 1.9%). The HEC gels with 4%, 6%, 8%, and 10% glycerol resulted in rising total MP to 12% (below the 15% cut off for mild irritation) and a high end osmolality of 1493 mOsm/kg. However, at concentrations of 20% and 40% glycerol (2206 and 4376 mOsm/kg, respectively), moderate irritation occurred (total MP 20% and 23%), as well as tissue damage with increased protein release. Additionally, the 40% glycerol gel induced LDH release after the third contact period and the release increased with repeated treatment.

Table 2
Table 2
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Fig. 4
Fig. 4
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Discussion

Personal lubricants in this study showed varying levels of mucosal irritation potency, which significantly correlated with product osmolality. Formulations with osmolalities, markedly lower than the normal physiologic range for fluids from the female reproductive tract (280–290 mOsm/kg), resulted in negative mucus production (and a drier membrane surface). Whereas, the hyperosmotic lubricants in this study all contained glycerin (i.e., glycerol) and all induced some mucosal irritation in the SMI. The second experiment also found changes in total MP from slugs in response to changes in osmolality, as mucus secretions increased to counteract any dehydration effect of the hyperosmotic gels. Except for the highly hyperosmotic formulations Astroglide (5848 mOsm/kg) and the HEC gel with 40% glycerol (4376 mOsm/kg), the response on the mucus production induced by the commercial lubricants and the HEC gels with a similar osmolality was comparable. This is an indication that the observed mucus production is directly related with the osmolality of the compound. The difference in the curves of Figures 1 and 4 were mainly caused by the difference in mucus production that was observed between Astroglide and the HEC gel with 40% glycerol.

These results are similar to those found by Debbasch et al.17 where 66% of the variation in adverse clinical signs (including itching and burning) from makeup removers applied to the eyelid could be predicted by the glycol concentrations in the formulation and the osmolality of the solution. Additionally, the severity of the clinical symptoms was proportional to the concentrations of glycols and osmolality. Of course, other ingredients in any topical agent can also cause irritation in some individuals, but it is interesting to note that Debbasch found no relationship between preservative type and clinical signs. In our study, the difference in mucus production between Astroglide and the HEC gel with 40% glycerol may be explained by the presence of propylene glycol in Astroglide. In a previous study with the SMI assay, a concentration dependent increase in the mucus production was observed for propylene glycol.24 These observations are consistent with reports of nasal and throat irritation attributed to propylene glycol when present as a component of nasal spray and of acute ocular and upper airway irritation in subjects briefly exposed to propylene glycol mist used in artificial smoke generators.25,26 The irritating and tissue damaging effect of Conceptrol observed in the first experiment was also not related to the products osmolality but it was caused by the presence of nonoxynol-9. In a previous study, it was shown that a 4% w/v dilution of nonoxynol-9 induced an increased mucus production and tissue damage that was comparable with Conceptrol.27 The repeated vaginal application of N-9 in humans has been associated with irritation or disruption of the vaginal and cervical epithelia.9

In the current study, the severity of irritation potency and tissue damage was also greater for increasing levels of glycerol and osmolality in both the commercial lubricants (Experiment A) and the de novo formulated gel (Experiment B). It is interesting to note that endogenous glycerol concentrations increase vaginal secretions during sexual arousal, and glycerol is thought to provide the lubricating aspects of these fluids in vivo,20 although likely never at the 10-fold plus increases seen in the hyperosmotic lubricants reported here.

A review of the literature suggests that the irritation potency found for these hyperosmotic lubricants is reflective of tissue irritation or damage that can occur with these products. For example, the glycerol containing lubricants used in this study have been reported to cause sloughing of uterine and rectal epithelium in mice after direct contact.28,29 In-vitro cell contact studies with these products have also confirmed cell toxicity with significant reductions in cell viability seen after their culture with human cervical cells28 and sperm.18 In particular, the sperm toxicity of the hyperosmotic lubricants in this study have been especially well reported18,30,31; whereas, the isotonic product used in this study, recently received the first indications of use as a lubricant during fertility interventions, based on its lack of gamete toxicity.

Clinical genital symptoms with hyperosmotic lubricants used in this study have also been documented during microbicide safety studies, with burning, itching, or discharge occurring in 17% to 27% of women and mild colposcopic findings (predominantly erythema) in 16% to 47% of women.6,8,29 A high percentage of men (42%), using one of the moderately hyperosmotic lubricants once daily for a week, also reported burning and itching after penile contact.16 A recent study found that hyperosmotic lubricants applied anally to men resulted in significant denudation of the epithelium, with most damage occurring at the site of the deposition (area of greatest concentration).19

The use of the SMI in this study provided detailed data to assess local mucosal tolerance and irritation potency of commercial personal lubricants. These data showed a continuum of physiologic interactions between the slug's mucosa and the lubricants based, at least in part, on their osmolality, from decreasing secretions (hypo-osmotic products); to minimal impact of any type (iso-osmotic products); to severe irritation and frank tissue damage (highly hyperosmotic products). Such empirical data can assist patients and clinicians in personal lubricant choice for a variety of settings and life stage needs.

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