Sensory Irritation Scale

Each minute for 10 to 60 minutes, depending on the study, subjects reported the magnitude of sensory irritation (stinging, burning, and itching) according to the following scale:

1 = slight Transient, barely perceptible irritation

Does not bother them

2 = mild Definite and continuous irritation

Bothers them

3 = moderate Distinctly uncomfortable irritation

Bothers them and interferes with concentration

4 = severe Continuous, intensely uncomfortable irritation

Intolerable and would interfere with daily routine

ACIDIC IRRITANTS

Lactic Acid (7.5%, pH = 1.9) Sensory Irritation on the Face

Alpha-hydroxyacids (AHAs) including lactic and glycolic acids are used in cosmetics and in professionally applied chemical peels to reduce the visible signs of skin aging. To maximize AHA efficacy, the formulation must be acidic, which increases the active ''free acid'' form of the AHA molecule and, unfortunately, directly contributes to their irritation potential [11,12]. To evaluate the ability of strontium salts to reduce lactic acid sensory irritation, either lactic acid alone (7.5% in 10% ethanol/water vehicle, pH = 1.9), or an identical vehicle at the same pH containing various concentrations of strontium nitrate or strontium chloride was applied (0.1 g) to cheek sites using cotton swabs (6 swipes) extending from the nasolabial fold to the outer cheek. Test materials were applied to the right or left side of subjects' faces sequentially followed by sensory irritation assessment on each side for 10 minutes. A typical time-response curve for lactic acid (7.5%, pH = 1.9) on the face is presented in Figure 1. When the areas under both irritation curves are compared, strontium nitrate inhibited sensory irritation by 68% (p <0.01). Both strontium nitrate and strontium chloride produced dose-dependent inhibition of sensory irritation when mixed with lactic acid (Table 1) [7]. In separate studies, the local anesthetic lidocaine (4%) was used as a positive control. When applied at the same time as the lactic acid, lidocaine did not produce significant inhibition (<10%), presumably because it requires time to be absorbed. When lidocaine (4%) was applied 5 minutes before the lactic acid, lidocaine inhibited by 51% (p <0.05, n = 10).

Strontium Pretreatment on the Face

Many cosmetics such as toners and skin conditioners, are applied immediately before application of potentially irritating products. Incorporation of strontium salts into such a pretreatment product from 1 minute to 15 minutes before the same lactic acid facial challenge produced a substantial level of sensory irritation inhibition (Table 1). In other studies, substantial anti-irritancy was also observed when strontium nitrate was applied several minutes after lactic acid was applied.

When the same lactic acid challenge was used in conjunction with ''conventional'' anti-irritants used in cosmetics such as green tea (3%), alpha-bisabolol (1%), and glycyr-rhizic acid (1%), no significant inhibition was observed (<10% difference from vehicle control).

Figure 1 Lactic acid alone (closed squares) or with strontium nitrate (250 mM) was applied to the faces of 23 subjects and sensory irritation was assessed every minute for 10 minutes (see text for scale). Each data point represents the mean ±SEM irritation at each minute for all subjects. Total cumulative irritation (area under the curve) was inhibited by 68% (p < 0.01).

Figure 1 Lactic acid alone (closed squares) or with strontium nitrate (250 mM) was applied to the faces of 23 subjects and sensory irritation was assessed every minute for 10 minutes (see text for scale). Each data point represents the mean ±SEM irritation at each minute for all subjects. Total cumulative irritation (area under the curve) was inhibited by 68% (p < 0.01).

To determine whether the strontium cation was necessary for the observed antiirritant activity, sodium chloride (250 mM) and sodium nitrate (250 mM) were mixed with the lactic acid and compared with strontium nitrate (250 mM) or strontium chloride (250 mM). In both instances, sodium nitrate or sodium chloride produced insignificant (< 10%) inhibition of sensory irritation proving that the nitrate or chloride anions did not produce the observed anti-irritant activity.

Lactic Acid (15%, pH = 3.0) Sensory Irritation on the Face

The anti-irritant activity of strontium salts is also evident for less acidic AHA irritants similar to what could be used in high-potency over-the-counter cosmetic products. When lactic acid (15% in a hydroxyethyl cellulose hydrogel, pH = 3.0) with or without 250 mM

(5.3%) strontium nitrate was applied to the faces of 33 subjects, the cumulative irritation inhibition by the strontium-containing solutions was 66% (p = 0.003) (Table 2). The g incidence of each of the four scores of lactic acid only versus lactic acid plus strontium was: severe: 25 vs. 1 = 96% inhibition; moderate: 59 vs. 2 = 97% inhibition; mild: 48 ^

vs. 5 = 90% inhibition; slight: 22 vs. 48 = 118% increase; and none: 44 vs. 142 = 223% ^

increase.

Glycolic Acid (70%, pH = 0.6) Sensory Irritation on the Arms 2

High-concentration, low-pH glycolic acid formulations are used by physicians to reduce the visible signs of skin photoaging and to treat moderately severe acne. To maximize

Table 1 Inhibition of Sensory Irritation Scores from 7.5% Lactic Acid (pH = 1.9)

15-Minute pretreatment strontium Strontium chloride* Strontium nitrate* nitrate*

Table 1 Inhibition of Sensory Irritation Scores from 7.5% Lactic Acid (pH = 1.9)

Strontium salt

Inhibitionf

Inhibition

Inhibition

(mM)

% ± SEM

(# subjects, p)

% ± SEM

(# subjects, p)

% ± SEM

(# subjects, p)

500

75 ± 7

(n = 16, p < 0.005)

68 ± 6

(n = 24, p < 0.01)

58 ± 12

(n = 16, p < 0.01)

250

65 ± 12

(n = 17, p < 0.01)

74 ± 7

(n = 23, p < 0.01)

48 ± 11

(n = 18, p < 0.01)

125

64 ± 5

(n = 15,p < 0.01)

42 ± 14

(n = 15,p < 0.01)

28 ± 16

(n = 15,p < 0.01)

63

30 ± 6

(n = 8, p < 0.01)

34 ± 8

(n = 16, p < 0.01)

17 ± 10

(n = 18, p < 0.01)

* Strontium nitrate or strontium chloride hexahydrate was either mixed with the lactic acid vehicle (1.5%, pH = 1.9, 10% ethanol/water) or preapplied to the face in a 10%

ethanol/water vehicle 15 minutes before the application of the lactic acid vehicle, t The total cumulative irritation in each study (scores of 1 + 2 + 3 + 4) for the lactic acid-treated side of the face was compared with the lactic acid + strontium-treated side of the face (areas under the curves) and irritation inhibition was calculated as a percent difference.

* Strontium nitrate or strontium chloride hexahydrate was either mixed with the lactic acid vehicle (1.5%, pH = 1.9, 10% ethanol/water) or preapplied to the face in a 10%

ethanol/water vehicle 15 minutes before the application of the lactic acid vehicle, t The total cumulative irritation in each study (scores of 1 + 2 + 3 + 4) for the lactic acid-treated side of the face was compared with the lactic acid + strontium-treated side of the face (areas under the curves) and irritation inhibition was calculated as a percent difference.

Copyright © Marcel Dekker, Inc. All rights reserved.

Table 2 Inhibition of Sensory Irritation Scores by Strontium Nitrate

% Inhibition of sensory irritation scores*

Table 2 Inhibition of Sensory Irritation Scores by Strontium Nitrate

Capryloyl

Calcium

Irritation

Lactic acid

Glycolic acid

salicylic acid

Ascorbic acid

thioglycolate

score

(15%, pH = 3.0)

(70%, pH = 0.6)

(1%, pH = 3.5)

(30%, pH = 1.7)

(4%, pH = 12)

Subjects (#)

33

19

24

20

23

Total scores

363

209

312

110

506

None

(0)

-223f

-381

-74

-260

-65

Slight

(1)

-118

-6

-8

63

40

Mild

(2)

90

43

71

91

76

Moderate

(3)

97

92

31

100

71

Severe

(4)

96

100

58

100

* Sensory irritation was induced by lactic acid (15%, pH = 3.0) application to the face, glycolic acid (70%, pH = 0.6) application to arms, capryloyl salicylic acid (1%, pH = 3.5) application to face, ascorbic acid (30%, pH = 1.7) application to the face, and calcium thioglycolate (4%, pH = 12) depilatory application to the legs. For each study, the incidence of each of the four sensory irritation scores (0-4) for the irritant alone and the irritant plus strontium nitrate treatment was compared. Each number represents the percent inhibition of each irritation score incidence induced by strontium nitrate, t Negative inhibition values represent an increase in the score incidence.

Copyright © Marcel Dekker, Inc. All rights reserved.

potency, unneutralized glycolic acid solutions are used (e.g., 20%, pH = 1.5 to 70%, pH = 0.6) but all produce potentially severe irritation. For this reason, most patients are exposed to increased concentrations and exposure times over a multimonth period until they reach a ''maintenance'' exposure (e.g., 70% glycolic acid, pH = 0.6 for 4-6 min) [13]. With strontium nitrate added to such formulations, patients can immediately obtain the benefits of the most potent glycolic acid formulations with very little or no irritation.

To demonstrate the anti-irritant efficacy of strontium in glycolic acid peel solutions, 70% glycolic acid (pH = 0.6) with or without strontium nitrate (20% [945 mM]) was applied to the forearms of 19 subjects on 2 inch by 4 inch rectangular sites and sensory irritation was evaluated every minute for 10 minutes, followed by neutralization with sodium bicarbonate. Within seconds after glycolic acid application (time 0 in Fig. 2), sensory irritation differences were apparent between the two groups (mean ± SEM = 0.53 ± 0.16 for glycolic only vs. 0.16 ± 0.09 for glycolic plus strontium) indicating that strontium had an immediate onset of action. Throughout the remainder of the exposure, strontium strongly inhibited irritation at all time points, and cumulative irritation was inhibited by 75% (p = 0.005). The data in Table 2 presents the percent inhibition of each of the four sensory irritation scores induced by strontium nitrate. During the study, the 19 subjects reported 209 irritation scores. The incidence of each of the four scores of the glycolic acid only versus the glycolic acid plus strontium was: severe: 41 vs. 0 = 100% inhibition; moderate: 50 vs. 4 = 92% inhibition; mild: 44 vs. 25 = 43% inhibition; slight: 47 vs. 50 = 6% increase; none: 27 vs. 130 = 381% increase. In other studies, measurement of skin turnover using the dansyl chloride technique [14] showed that strontium nitrate did not affect the stimulatory effect of glycolic acid on skin turnover.

Figure 2 Glycolic acid (70%, pH = 0.6) only (closed squares) or with strontium nitrate (20%) (open circles) was applied to the forearms of 19 subjects and sensory irritation was measured every minute for 10 minutes. Each data point represents the mean ±SEM irritation at each minute for 19 subjects. Total cumulative irritation (areas under the curve) was inhibited by 75% (p < 0.005).

Figure 2 Glycolic acid (70%, pH = 0.6) only (closed squares) or with strontium nitrate (20%) (open circles) was applied to the forearms of 19 subjects and sensory irritation was measured every minute for 10 minutes. Each data point represents the mean ±SEM irritation at each minute for 19 subjects. Total cumulative irritation (areas under the curve) was inhibited by 75% (p < 0.005).

Clinical studies of a 70% glycolic acid (pH = 0.6) chemical peel solution with strontium nitrate applied to the whole face in over 150 human subjects demonstrated substantially reduced sensory irritation and erythema without reducing the expected benefits of the peel as judged by clinical response [15,16]. Histological analysis of punch biopsies from skin exposed to AHA formulations containing strontium nitrate (70% glycolic acid, pH = 0.6) every 2 weeks for 8 weeks and 15% lactic acid lotion (pH = 3.2) twice daily at the same facial sites) demonstrated that there was slightly less inflammation in the AHA and strontium-treated sites compared with untreated skin in the same individuals [16], thus demonstrating that strontium not only reduced irritation symptoms, but also protected the skin from cryptic damage.

Capryloyl Salicylic Acid-Induced Sensory Irritation

Capryloyl salicylic acid is a covalently modified derivative of salicylic acid with enhanced lipophylicity attributable to the 8 carbon caprylic acid moiety. It is used as a cosmetic exfoliant and is reported to have utility as an acne therapeutic [17]. A cream emulsion base containing capryloyl salicylic acid (1%) with or without strontium nitrate (500 mM) was applied to cheek sites 2 inches by 4 inches extending from the nasolabial fold to the outer cheek of 24 female subjects and sensory irritation was evaluated every 5 minutes for 60 minutes. The data in Table 2 presents the percent inhibition of each of the four sensory irritation scores induced by strontium nitrate. During the entire study, subjects reported 312 sensory irritation scores. The incidence of each of the four scores of the capryloyl salicylic acid versus the capryloyl plus strontium was: severe: 19 vs. 8; moderate: 13 vs. 9; mild: 35 vs. 10; slight: 39 vs. 42; and none: 50 vs. 87. The mean sensory irritation score of the capryloyl salicylic acid reached approximately 0.8 5 minutes after application, peaked at approximately 1.0 from 20 minutes to 35 minutes, and remained at approximately 0.8 until 45 minutes, after which it declined to 0.4 at 60 minutes. Total irritation, calculated as the percent difference of the areas under the 60-minute irritation curves, was inhibited by 46% (p = 0.002).

Ascorbic Acid (30%, pH = 1.7) Sensory Irritation on the Face

Ascorbic acid (Vitamin C) is used in many cosmetic products because it is a potent water-soluble antioxidant and can protect the skin against damage from ultraviolet radiation [18]. In vitro studies also show that ascorbic acid can also stimulate collagen synthesis [19]. Because ascorbic acid is most stable and bioavailable in aqueous formulations at a highly acidic pH (e.g., pH < 3) a 30% aqueous solution of ascorbic acid (pH = 1.7) was evaluated for sensory irritation with or without strontium nitrate (250 mM). After application to the face of 20 subjects, the cumulative irritation inhibition by the strontium-containing solutions was 84% (p < 0.005) (Table 2). The incidence of each of the four scores of the | ascorbic acid only versus the ascorbic acid plus strontium was: severe: 1 vs. 0 = 100% inhibition; moderate: 13 vs. 0 = 100% inhibition; mild: 23 vs. 2 = 91% inhibition; slight: 48 vs. 18 = 63% inhibition; plus none: 25 vs. 90 = 260% increase).

Aluminum Chloride Antiperspirant Application to Axilla |

Antiperspirants use aluminum salts alone or in combination with other agents to reduce perspiration. In the moist environment of the axilla, aluminum salts can cause sensory irritation and inflammation [20]. The axilla of 16 subjects was pretreated with 1.0 mL of 2

a strontium nitrate solution (500 mM, pH = 7.3 in 50% ethanol/water vehicle) followed 2 minutes later by a 1 mL application of the aluminum chloride (20%) antiperspirant solution. Sensory irritation was evaluated every 2 minutes for 20 minutes. The incidence of each of the four scores of the aluminum chloride versus the aluminum chloride plus strontium was: severe: 12 vs. 2; moderate: 22 vs. 9; mild: 30 vs. 13; slight: 60 vs. 41; and none: 52 vs. 111. Upon application, sensory irritation reached a mean score of 1 within the first minute and a plateau at approximately 1.5 from minutes 6 to 10, then gradually declined to a score of approximately 1 at 20 minutes. During the study, the 16 subjects reported 352 irritation scores. Total irritation caused by the aluminum chloride calculated as the percent difference of the areas under the 20-minute irritation curves was reduced by 56% when the areas under the irritation curves were compared (p < 0.005).

Aluminum/Zirconium Salt Erythema on the Arms

Aluminum salts, with or without zirconium salts, are FDA-approved antiperspirant ingredients and frequently cause both sensory irritation and inflammation [20]. Aluminum/ zirconium salt solution (25%) with or without strontium nitrate (500 mM) or strontium chloride (500 mM) was applied to the arms of 29 subjects using occluded patches for 21 days and the magnitude of visible inflammation was evaluated every day. Inflammation was visually measured according to the following scale:

0 = No evidence of erythema

1 = Minimal erythema

2 = Definite erythema

3 = Erythema and papules

Both stronium nitrate (500 mM) or strontium chloride (500 mM) caused nearly complete inhibition of erythema development during the first week and substantially inhibited erythema during the second and third weeks (Fig. 3). Total erythema caused by the aluminum/ zirconium salts, calculated as the percent difference of the areas under the 21 day irritation curves, was reduced by 64% (p < 0.0001) by strontium nitrate and by 66% (p < 0.0001) by strontium chloride.

BASIC IRRITANTS

Calcium Thioglycolate Sensory Irritation on the Legs

Chemical depilatories typically use calcium thioglycolate formulated at a basic pH (e.g., 9-12) to dissolve hair keratin [21]. Twenty-three subjects shaved their legs with a safety razor to enhance irritation, then strontium nitrate pretreatment solution (10% w/v, in 10% ethanol/water) or vehicle was applied to 2 inch by 4 inch sites on the lateral portions of the legs. After 2 minutes, 5 grams of depilatory lotion was applied to each leg followed by irritation evaluation every minute for 10 minutes. During the study, the 23 subjects reported 506 irritation scores (Table 2). The incidence of each of the four scores of the depilatory versus the depilatory plus strontium was: severe: 0 vs. 0; moderate: 7 vs. 2 = 71% inhibition; mild: 45 vs. 11 = 76% inhibition; slight: 88 vs. 53 = 40% inhibition; and none: 113 vs. 187 = 65% increase. Total irritation caused by the depilatory, calculated

Figure 3 Strontium nitrate (500 mM, open circles) or strontium chloride (500 mM, closed squares) was formulated with the aluminum/zirconium salt solution each day when a new patch was applied. Each data point represents the mean ±SEM for 29 subjects. Total cumulative irritation (areas under the curve) was inhibited by 64% (p < 0.0001) for strontium nitrate and 66% for strontium chloride (p < 0.0001).

Figure 3 Strontium nitrate (500 mM, open circles) or strontium chloride (500 mM, closed squares) was formulated with the aluminum/zirconium salt solution each day when a new patch was applied. Each data point represents the mean ±SEM for 29 subjects. Total cumulative irritation (areas under the curve) was inhibited by 64% (p < 0.0001) for strontium nitrate and 66% for strontium chloride (p < 0.0001).

as the percent difference of the areas under the 20-minute irritation curves, was reduced by 59% (p < 0.01).

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