M etronidazole 0.75% gel (MetroGel) is a treatment well known and often used by many dermatologists. The first topical agent approved by the FDA for the treatment of rosacea, this drug has been available for clinical use in the United States since 1989. Recently, a large community-based trial provided further information regarding the clinical impact of twice-daily application of topical metronidazole 0.75% gel on inflammatory lesions, erythema and the telangiectasia index. A new 1% gel formulation of topical metronidazole has been developed and evaluated in clinical trials using once-daily application. This article reviews specialized vehicle technology allowing for aqueous gel solubilization of metronidazole at a higher concentration and current data from recent clinical trials evaluating topical metronidazole, including the new 1% gel formulation. History of Metronidazole 0.75% Aqueous Gel The efficacy and safety of topical metronidazole has been evaluated in studies involving more than 2,200 patients, with data from all but a few of the most recent trials published elsewhere.1-3 All of the currently available topical metronidazole formulations — 0.75% gel, lotion, cream and 1% cream — have demonstrated statistically significant superior efficacy as compared to vehicle. In addition, all have well-established favorable safety and skin tolerability profiles.1-6 Since its launch in the marketplace as the first FDA-approved topical product for rosacea, metronidazole 0.75% gel has proven to be effective, safe and adaptable to multiple skin types and climates.1,2,6 A more recent multicenter, open-label, 12-week trial (CLEAR Trial) evaluated 582 patients treated with metronidazole 0.75% gel for papulopustular rosacea,8 whose severity ranged from mild (19%) to moderate (58%) to moderately severe (23%). Mean inflammatory lesion count reduction, erythema score, investigator global assessment score and telangiectasia index score all improved significantly (P<0.0001) at each evaluation point (weeks 4, 8 and 12), with consistency of results observed across age and gender subgroups. At study endpoint, mean inflammatory lesion count reduction was 44% at week 4, 61% at week 8, and 71% at week 12, with 42% of patients rated by the investigator as clear or almost clear at week 12. The reported adverse reaction rate in the trial was <2% at week 12, which was similar to rates observed in previous clinical trials with topical metronidazole, confirming the favorable tolerability profile of the aqueous gel vehicle.1,2,4,7 The results from this trial provided community-based experience from a wide geographic range of dermatologic practices in the United States and confirmed efficacy, safety and favorable tolerability.8 Topical metronidazole 0.75% gel has also demonstrated efficacy and a high degree of tolerability when used in combination with other prescription topical agents for rosacea, including therapeutic cleansers and leave-on products.3,4,6 A New Aqueous Gel Formulation of Metronidazole 1% It has been suggested, based on in vitro drug release and cutaneous penetration studies, that the vehicle may be more important than the active drug concentration in the skin delivery of metronidazole.8 A recent formulation advance has enabled the solubilization of metronidazole 1% into a novel aqueous-based gel formulation using hydrosolubilizing agents vehicle technology, referred to a HSA-3. Metronidazole 1% gel differs from the initial 1% cream because the latter incorporates the drug in suspension, which may predispose metronidazole to crystallization with filtering by the stratum corneum.8 The 1% HSA-3 formulation, which has successfully incorporated metronidazole into a 1% aqueous solution, has been shown to do the following: 1. provide enhanced cutaneous penetration of active drug 2. exhibit marked clinical efficacy 3. provide favorable skin tolerability based on both clinical trial results and 21-day cumulative irritancy testing9 4. improve results detected through cutaneous corneometry studies, reflecting enhanced skin hydration without impairing epidermal barrier function.10 SkinCare and Vehicle Formulation Considerations in Managing Rosacea It is well established that patients with rosacea commonly exhibit skin sensitivity, with signs and symptoms of irritation triggered by several exogenous factors including heat and skincare products.11-14 In a survey of 1,023 patients affected by rosacea, 58% reported sensitivity to skincare products.15 For females, the top-three culprits were the following: 1. astringents/toners (49.5%) 2. soap (40%) 3. exfoliants (34%). For men, the top culprits were: 1. shaving lotion (24%) 2. soap (24%) 3. cologne (19%). Other skincare products commonly reported to aggravate rosacea in the survey included makeup, perfume, hairspray, sunscreen and shampoo. A significant number of both females and males reported that they had eventually found skincare products that did not aggravate their rosacea. Skin cleansing using a mild synthetic detergent bar instead of a true bar soap has been shown to further reduce clinical signs and symptoms of rosacea in patients stabilized on topical metronidazole.11 It has also been confirmed that rosacea is innately associated with impaired epidermal barrier function, which is often characterized by increased transepidermal water loss predominantly involving the central face.14 Additionally, almost two-thirds (62.5%) of patients with rosacea were shown to exhibit positive lactic acid stinging, compared to 5% to 20% of the general population.16 Factors such as the common presence of baseline signs and symptoms of rosacea related to the underlying disease, innate epidermal barrier impairment with increased transepidermal water loss, and increased skin sensitivity with propensity for irritation after use of multiple skincare products warrants use of topical therapies and vehicle formulations that do not exacerbate irritation or barrier dysfunction.17 Some advanced vehicles are designed to include components that may contribute to reducing the signs and symptoms of rosacea and may help to restore epidermal barrier function. Correlation of HSA-3 Vehicle Technology and Topical Metronidazole 1% Gel HSA-3 imparts the capability of solubilizing metronidazole into a 1% aqueous solution comprised of 92% water.9 Before the inception of HSA-3, a maximum concentration of metronidazole 0.75% could be placed into aqueous solution, with a suspension of the drug needed to formulate a 1% cream. As noted above, drug delivery and skin penetration of metronidazole is optimized by formulation in an aqueous solution, not simply by increasing concentration of active drug.8 The HSA-3 gel formulates metronidazole into an aqueous vehicle that utilizes a unique combination of niacinamide (Vitamin B3), beta-cyclodextrin (also known as Betadex), and propylene glycol (Table 1). The concentration of propylene glycol is significantly lower than what may be associated with skin irritation or allergy. The use of propylene glycol, a hydrophilic solvent, has been shown to be a significant vehicle component for maximizing penetration of metronidazole into the skin.8 In a Phase II study, the percutaneous absorption of metronidazole 1% gel (HSA-3 vehicle) and metronidazole 1% cream (suspension) were compared. The results demonstrated optimal penetration into the epidermis and dermis with the 1% gel formulation. (See Table 2 for the results.) In a Phase II, 2-week study of adult females (n=25) with mild to moderate rosacea, transepidermal water loss (TEWL) and corneometry were evaluated after weeks 1 and 2 of treatment with metronidazole 1% gel (HSA-3) applied twice daily (although once daily is the recommended application frequency based on Phase III clinical trials).10 (Evaluation of TEWL allows for the assessment of the effect of a given drug formulation or vehicle on epidermal barrier function. An increase in TEWL as compared to baseline indicates impairment of barrier function. Corneometry is a measure of skin hydration with an increase as compared to baseline reflective of an increase in skin water content.) The results of this Phase II study demonstrated increased skin hydration based on corneometry testing and no increase in TEWL, indicating that metronidazole 1% gel (HSA-3) does not impair epidermal barrier function.10 Statistically significant reductions from baseline were noted by patients for symptoms of stinging (P=0.02) and burning (P=0.02) and signs of erythema (P<0.001) and roughness (P<0.001) at study endpoint; similar improvements in clinical signs of rosacea were also observed by the investigator. **sub*Clinical Data Review of Metronidazole 1% Gel (HSA-3) Efficacy. A multicenter, double-blind, randomized, investigator-blinded, 10-week trial evaluated efficacy, safety and skin tolerability of metronidazole 1% formulated in the HSA-3 gel vehicle (n=557) compared to vehicle alone (n=189) in patients with rosacea.18 Efficacy parameters included reduction in inflammatory lesion counts, reduction in erythema score, and investigator global assessment. Metronidazole 1% gel (HSA-3) demonstrated statistically significant superiority over vehicle in mean percentage reduction of inflammatory lesions (P=0.0001), reduction in combined erythema severity score (P=0.033), and improvement based on investigator global assessment (P=0.033). Skin Tolerability. At study endpoint, the percentage of patients reported to experience cutaneous adverse reactions determined to be related to the study product were 2.2% in the actively treated group and 3.7% in the vehicle study arm. Both the metronidazole 1% gel (HSA-3) and vehicle produced reductions in facial dryness, scaling, stinging/burning and pruritus throughout the study, with greater reductions noted in dryness and scaling in the actively treated group as compared to vehicle. The favorable tolerability profile appears to correlate with the relative lack of irritation of the metronidazole compound, enhanced by the lack of epidermal barrier impairment and the skin hydrating properties of the HSA-3 aqueous gel vehicle. Recounting the Main Points • More recent clinical trials confirm the efficacy and favorable tolerability of topical metronidazole for rosacea. • Hydrosolubilizing agent vehicle technology (HSA-3) incorporates niacinamide, beta-cyclodextrin and propylene glycol in low concentration. This vehicle provides enough solubilization of metronidazole to allow for production of a 1% solution formulated in an aqueous gel. The HSA-3 gel vehicle promotes enhanced percutaneous absorption of metronidazole as compared to 1% cream, which incorporates the drug as a suspension. • Metronidazole 1% gel (HSA-3) does not increase transepidermal water loss in patients with rosacea, indicating no impairment of epidermal barrier function, and improves skin hydration based on corneometry testing. • Clinical study indicates that metronidazole 1% gel (HSA-3) is effective in reducing inflammatory lesions and facial erythema in patients with rosacea. Signs and symptoms of disease such as dryness, scaling, stinging/burning and pruritus were shown to improve progressively from the initiation of the trial through study endpoint. Disclosure: Dr. Del Rosso is a consultant/advisor and speaker for Galderma, Medicis, Intendis and Stiefel.
A Closer Look at Topical Metronidazole 1% Gel
M etronidazole 0.75% gel (MetroGel) is a treatment well known and often used by many dermatologists. The first topical agent approved by the FDA for the treatment of rosacea, this drug has been available for clinical use in the United States since 1989. Recently, a large community-based trial provided further information regarding the clinical impact of twice-daily application of topical metronidazole 0.75% gel on inflammatory lesions, erythema and the telangiectasia index. A new 1% gel formulation of topical metronidazole has been developed and evaluated in clinical trials using once-daily application. This article reviews specialized vehicle technology allowing for aqueous gel solubilization of metronidazole at a higher concentration and current data from recent clinical trials evaluating topical metronidazole, including the new 1% gel formulation. History of Metronidazole 0.75% Aqueous Gel The efficacy and safety of topical metronidazole has been evaluated in studies involving more than 2,200 patients, with data from all but a few of the most recent trials published elsewhere.1-3 All of the currently available topical metronidazole formulations — 0.75% gel, lotion, cream and 1% cream — have demonstrated statistically significant superior efficacy as compared to vehicle. In addition, all have well-established favorable safety and skin tolerability profiles.1-6 Since its launch in the marketplace as the first FDA-approved topical product for rosacea, metronidazole 0.75% gel has proven to be effective, safe and adaptable to multiple skin types and climates.1,2,6 A more recent multicenter, open-label, 12-week trial (CLEAR Trial) evaluated 582 patients treated with metronidazole 0.75% gel for papulopustular rosacea,8 whose severity ranged from mild (19%) to moderate (58%) to moderately severe (23%). Mean inflammatory lesion count reduction, erythema score, investigator global assessment score and telangiectasia index score all improved significantly (P<0.0001) at each evaluation point (weeks 4, 8 and 12), with consistency of results observed across age and gender subgroups. At study endpoint, mean inflammatory lesion count reduction was 44% at week 4, 61% at week 8, and 71% at week 12, with 42% of patients rated by the investigator as clear or almost clear at week 12. The reported adverse reaction rate in the trial was <2% at week 12, which was similar to rates observed in previous clinical trials with topical metronidazole, confirming the favorable tolerability profile of the aqueous gel vehicle.1,2,4,7 The results from this trial provided community-based experience from a wide geographic range of dermatologic practices in the United States and confirmed efficacy, safety and favorable tolerability.8 Topical metronidazole 0.75% gel has also demonstrated efficacy and a high degree of tolerability when used in combination with other prescription topical agents for rosacea, including therapeutic cleansers and leave-on products.3,4,6 A New Aqueous Gel Formulation of Metronidazole 1% It has been suggested, based on in vitro drug release and cutaneous penetration studies, that the vehicle may be more important than the active drug concentration in the skin delivery of metronidazole.8 A recent formulation advance has enabled the solubilization of metronidazole 1% into a novel aqueous-based gel formulation using hydrosolubilizing agents vehicle technology, referred to a HSA-3. Metronidazole 1% gel differs from the initial 1% cream because the latter incorporates the drug in suspension, which may predispose metronidazole to crystallization with filtering by the stratum corneum.8 The 1% HSA-3 formulation, which has successfully incorporated metronidazole into a 1% aqueous solution, has been shown to do the following: 1. provide enhanced cutaneous penetration of active drug 2. exhibit marked clinical efficacy 3. provide favorable skin tolerability based on both clinical trial results and 21-day cumulative irritancy testing9 4. improve results detected through cutaneous corneometry studies, reflecting enhanced skin hydration without impairing epidermal barrier function.10 SkinCare and Vehicle Formulation Considerations in Managing Rosacea It is well established that patients with rosacea commonly exhibit skin sensitivity, with signs and symptoms of irritation triggered by several exogenous factors including heat and skincare products.11-14 In a survey of 1,023 patients affected by rosacea, 58% reported sensitivity to skincare products.15 For females, the top-three culprits were the following: 1. astringents/toners (49.5%) 2. soap (40%) 3. exfoliants (34%). For men, the top culprits were: 1. shaving lotion (24%) 2. soap (24%) 3. cologne (19%). Other skincare products commonly reported to aggravate rosacea in the survey included makeup, perfume, hairspray, sunscreen and shampoo. A significant number of both females and males reported that they had eventually found skincare products that did not aggravate their rosacea. Skin cleansing using a mild synthetic detergent bar instead of a true bar soap has been shown to further reduce clinical signs and symptoms of rosacea in patients stabilized on topical metronidazole.11 It has also been confirmed that rosacea is innately associated with impaired epidermal barrier function, which is often characterized by increased transepidermal water loss predominantly involving the central face.14 Additionally, almost two-thirds (62.5%) of patients with rosacea were shown to exhibit positive lactic acid stinging, compared to 5% to 20% of the general population.16 Factors such as the common presence of baseline signs and symptoms of rosacea related to the underlying disease, innate epidermal barrier impairment with increased transepidermal water loss, and increased skin sensitivity with propensity for irritation after use of multiple skincare products warrants use of topical therapies and vehicle formulations that do not exacerbate irritation or barrier dysfunction.17 Some advanced vehicles are designed to include components that may contribute to reducing the signs and symptoms of rosacea and may help to restore epidermal barrier function. Correlation of HSA-3 Vehicle Technology and Topical Metronidazole 1% Gel HSA-3 imparts the capability of solubilizing metronidazole into a 1% aqueous solution comprised of 92% water.9 Before the inception of HSA-3, a maximum concentration of metronidazole 0.75% could be placed into aqueous solution, with a suspension of the drug needed to formulate a 1% cream. As noted above, drug delivery and skin penetration of metronidazole is optimized by formulation in an aqueous solution, not simply by increasing concentration of active drug.8 The HSA-3 gel formulates metronidazole into an aqueous vehicle that utilizes a unique combination of niacinamide (Vitamin B3), beta-cyclodextrin (also known as Betadex), and propylene glycol (Table 1). The concentration of propylene glycol is significantly lower than what may be associated with skin irritation or allergy. The use of propylene glycol, a hydrophilic solvent, has been shown to be a significant vehicle component for maximizing penetration of metronidazole into the skin.8 In a Phase II study, the percutaneous absorption of metronidazole 1% gel (HSA-3 vehicle) and metronidazole 1% cream (suspension) were compared. The results demonstrated optimal penetration into the epidermis and dermis with the 1% gel formulation. (See Table 2 for the results.) In a Phase II, 2-week study of adult females (n=25) with mild to moderate rosacea, transepidermal water loss (TEWL) and corneometry were evaluated after weeks 1 and 2 of treatment with metronidazole 1% gel (HSA-3) applied twice daily (although once daily is the recommended application frequency based on Phase III clinical trials).10 (Evaluation of TEWL allows for the assessment of the effect of a given drug formulation or vehicle on epidermal barrier function. An increase in TEWL as compared to baseline indicates impairment of barrier function. Corneometry is a measure of skin hydration with an increase as compared to baseline reflective of an increase in skin water content.) The results of this Phase II study demonstrated increased skin hydration based on corneometry testing and no increase in TEWL, indicating that metronidazole 1% gel (HSA-3) does not impair epidermal barrier function.10 Statistically significant reductions from baseline were noted by patients for symptoms of stinging (P=0.02) and burning (P=0.02) and signs of erythema (P<0.001) and roughness (P<0.001) at study endpoint; similar improvements in clinical signs of rosacea were also observed by the investigator. **sub*Clinical Data Review of Metronidazole 1% Gel (HSA-3) Efficacy. A multicenter, double-blind, randomized, investigator-blinded, 10-week trial evaluated efficacy, safety and skin tolerability of metronidazole 1% formulated in the HSA-3 gel vehicle (n=557) compared to vehicle alone (n=189) in patients with rosacea.18 Efficacy parameters included reduction in inflammatory lesion counts, reduction in erythema score, and investigator global assessment. Metronidazole 1% gel (HSA-3) demonstrated statistically significant superiority over vehicle in mean percentage reduction of inflammatory lesions (P=0.0001), reduction in combined erythema severity score (P=0.033), and improvement based on investigator global assessment (P=0.033). Skin Tolerability. At study endpoint, the percentage of patients reported to experience cutaneous adverse reactions determined to be related to the study product were 2.2% in the actively treated group and 3.7% in the vehicle study arm. Both the metronidazole 1% gel (HSA-3) and vehicle produced reductions in facial dryness, scaling, stinging/burning and pruritus throughout the study, with greater reductions noted in dryness and scaling in the actively treated group as compared to vehicle. The favorable tolerability profile appears to correlate with the relative lack of irritation of the metronidazole compound, enhanced by the lack of epidermal barrier impairment and the skin hydrating properties of the HSA-3 aqueous gel vehicle. Recounting the Main Points • More recent clinical trials confirm the efficacy and favorable tolerability of topical metronidazole for rosacea. • Hydrosolubilizing agent vehicle technology (HSA-3) incorporates niacinamide, beta-cyclodextrin and propylene glycol in low concentration. This vehicle provides enough solubilization of metronidazole to allow for production of a 1% solution formulated in an aqueous gel. The HSA-3 gel vehicle promotes enhanced percutaneous absorption of metronidazole as compared to 1% cream, which incorporates the drug as a suspension. • Metronidazole 1% gel (HSA-3) does not increase transepidermal water loss in patients with rosacea, indicating no impairment of epidermal barrier function, and improves skin hydration based on corneometry testing. • Clinical study indicates that metronidazole 1% gel (HSA-3) is effective in reducing inflammatory lesions and facial erythema in patients with rosacea. Signs and symptoms of disease such as dryness, scaling, stinging/burning and pruritus were shown to improve progressively from the initiation of the trial through study endpoint. Disclosure: Dr. Del Rosso is a consultant/advisor and speaker for Galderma, Medicis, Intendis and Stiefel.
M etronidazole 0.75% gel (MetroGel) is a treatment well known and often used by many dermatologists. The first topical agent approved by the FDA for the treatment of rosacea, this drug has been available for clinical use in the United States since 1989. Recently, a large community-based trial provided further information regarding the clinical impact of twice-daily application of topical metronidazole 0.75% gel on inflammatory lesions, erythema and the telangiectasia index. A new 1% gel formulation of topical metronidazole has been developed and evaluated in clinical trials using once-daily application. This article reviews specialized vehicle technology allowing for aqueous gel solubilization of metronidazole at a higher concentration and current data from recent clinical trials evaluating topical metronidazole, including the new 1% gel formulation. History of Metronidazole 0.75% Aqueous Gel The efficacy and safety of topical metronidazole has been evaluated in studies involving more than 2,200 patients, with data from all but a few of the most recent trials published elsewhere.1-3 All of the currently available topical metronidazole formulations — 0.75% gel, lotion, cream and 1% cream — have demonstrated statistically significant superior efficacy as compared to vehicle. In addition, all have well-established favorable safety and skin tolerability profiles.1-6 Since its launch in the marketplace as the first FDA-approved topical product for rosacea, metronidazole 0.75% gel has proven to be effective, safe and adaptable to multiple skin types and climates.1,2,6 A more recent multicenter, open-label, 12-week trial (CLEAR Trial) evaluated 582 patients treated with metronidazole 0.75% gel for papulopustular rosacea,8 whose severity ranged from mild (19%) to moderate (58%) to moderately severe (23%). Mean inflammatory lesion count reduction, erythema score, investigator global assessment score and telangiectasia index score all improved significantly (P<0.0001) at each evaluation point (weeks 4, 8 and 12), with consistency of results observed across age and gender subgroups. At study endpoint, mean inflammatory lesion count reduction was 44% at week 4, 61% at week 8, and 71% at week 12, with 42% of patients rated by the investigator as clear or almost clear at week 12. The reported adverse reaction rate in the trial was <2% at week 12, which was similar to rates observed in previous clinical trials with topical metronidazole, confirming the favorable tolerability profile of the aqueous gel vehicle.1,2,4,7 The results from this trial provided community-based experience from a wide geographic range of dermatologic practices in the United States and confirmed efficacy, safety and favorable tolerability.8 Topical metronidazole 0.75% gel has also demonstrated efficacy and a high degree of tolerability when used in combination with other prescription topical agents for rosacea, including therapeutic cleansers and leave-on products.3,4,6 A New Aqueous Gel Formulation of Metronidazole 1% It has been suggested, based on in vitro drug release and cutaneous penetration studies, that the vehicle may be more important than the active drug concentration in the skin delivery of metronidazole.8 A recent formulation advance has enabled the solubilization of metronidazole 1% into a novel aqueous-based gel formulation using hydrosolubilizing agents vehicle technology, referred to a HSA-3. Metronidazole 1% gel differs from the initial 1% cream because the latter incorporates the drug in suspension, which may predispose metronidazole to crystallization with filtering by the stratum corneum.8 The 1% HSA-3 formulation, which has successfully incorporated metronidazole into a 1% aqueous solution, has been shown to do the following: 1. provide enhanced cutaneous penetration of active drug 2. exhibit marked clinical efficacy 3. provide favorable skin tolerability based on both clinical trial results and 21-day cumulative irritancy testing9 4. improve results detected through cutaneous corneometry studies, reflecting enhanced skin hydration without impairing epidermal barrier function.10 SkinCare and Vehicle Formulation Considerations in Managing Rosacea It is well established that patients with rosacea commonly exhibit skin sensitivity, with signs and symptoms of irritation triggered by several exogenous factors including heat and skincare products.11-14 In a survey of 1,023 patients affected by rosacea, 58% reported sensitivity to skincare products.15 For females, the top-three culprits were the following: 1. astringents/toners (49.5%) 2. soap (40%) 3. exfoliants (34%). For men, the top culprits were: 1. shaving lotion (24%) 2. soap (24%) 3. cologne (19%). Other skincare products commonly reported to aggravate rosacea in the survey included makeup, perfume, hairspray, sunscreen and shampoo. A significant number of both females and males reported that they had eventually found skincare products that did not aggravate their rosacea. Skin cleansing using a mild synthetic detergent bar instead of a true bar soap has been shown to further reduce clinical signs and symptoms of rosacea in patients stabilized on topical metronidazole.11 It has also been confirmed that rosacea is innately associated with impaired epidermal barrier function, which is often characterized by increased transepidermal water loss predominantly involving the central face.14 Additionally, almost two-thirds (62.5%) of patients with rosacea were shown to exhibit positive lactic acid stinging, compared to 5% to 20% of the general population.16 Factors such as the common presence of baseline signs and symptoms of rosacea related to the underlying disease, innate epidermal barrier impairment with increased transepidermal water loss, and increased skin sensitivity with propensity for irritation after use of multiple skincare products warrants use of topical therapies and vehicle formulations that do not exacerbate irritation or barrier dysfunction.17 Some advanced vehicles are designed to include components that may contribute to reducing the signs and symptoms of rosacea and may help to restore epidermal barrier function. Correlation of HSA-3 Vehicle Technology and Topical Metronidazole 1% Gel HSA-3 imparts the capability of solubilizing metronidazole into a 1% aqueous solution comprised of 92% water.9 Before the inception of HSA-3, a maximum concentration of metronidazole 0.75% could be placed into aqueous solution, with a suspension of the drug needed to formulate a 1% cream. As noted above, drug delivery and skin penetration of metronidazole is optimized by formulation in an aqueous solution, not simply by increasing concentration of active drug.8 The HSA-3 gel formulates metronidazole into an aqueous vehicle that utilizes a unique combination of niacinamide (Vitamin B3), beta-cyclodextrin (also known as Betadex), and propylene glycol (Table 1). The concentration of propylene glycol is significantly lower than what may be associated with skin irritation or allergy. The use of propylene glycol, a hydrophilic solvent, has been shown to be a significant vehicle component for maximizing penetration of metronidazole into the skin.8 In a Phase II study, the percutaneous absorption of metronidazole 1% gel (HSA-3 vehicle) and metronidazole 1% cream (suspension) were compared. The results demonstrated optimal penetration into the epidermis and dermis with the 1% gel formulation. (See Table 2 for the results.) In a Phase II, 2-week study of adult females (n=25) with mild to moderate rosacea, transepidermal water loss (TEWL) and corneometry were evaluated after weeks 1 and 2 of treatment with metronidazole 1% gel (HSA-3) applied twice daily (although once daily is the recommended application frequency based on Phase III clinical trials).10 (Evaluation of TEWL allows for the assessment of the effect of a given drug formulation or vehicle on epidermal barrier function. An increase in TEWL as compared to baseline indicates impairment of barrier function. Corneometry is a measure of skin hydration with an increase as compared to baseline reflective of an increase in skin water content.) The results of this Phase II study demonstrated increased skin hydration based on corneometry testing and no increase in TEWL, indicating that metronidazole 1% gel (HSA-3) does not impair epidermal barrier function.10 Statistically significant reductions from baseline were noted by patients for symptoms of stinging (P=0.02) and burning (P=0.02) and signs of erythema (P<0.001) and roughness (P<0.001) at study endpoint; similar improvements in clinical signs of rosacea were also observed by the investigator. **sub*Clinical Data Review of Metronidazole 1% Gel (HSA-3) Efficacy. A multicenter, double-blind, randomized, investigator-blinded, 10-week trial evaluated efficacy, safety and skin tolerability of metronidazole 1% formulated in the HSA-3 gel vehicle (n=557) compared to vehicle alone (n=189) in patients with rosacea.18 Efficacy parameters included reduction in inflammatory lesion counts, reduction in erythema score, and investigator global assessment. Metronidazole 1% gel (HSA-3) demonstrated statistically significant superiority over vehicle in mean percentage reduction of inflammatory lesions (P=0.0001), reduction in combined erythema severity score (P=0.033), and improvement based on investigator global assessment (P=0.033). Skin Tolerability. At study endpoint, the percentage of patients reported to experience cutaneous adverse reactions determined to be related to the study product were 2.2% in the actively treated group and 3.7% in the vehicle study arm. Both the metronidazole 1% gel (HSA-3) and vehicle produced reductions in facial dryness, scaling, stinging/burning and pruritus throughout the study, with greater reductions noted in dryness and scaling in the actively treated group as compared to vehicle. The favorable tolerability profile appears to correlate with the relative lack of irritation of the metronidazole compound, enhanced by the lack of epidermal barrier impairment and the skin hydrating properties of the HSA-3 aqueous gel vehicle. Recounting the Main Points • More recent clinical trials confirm the efficacy and favorable tolerability of topical metronidazole for rosacea. • Hydrosolubilizing agent vehicle technology (HSA-3) incorporates niacinamide, beta-cyclodextrin and propylene glycol in low concentration. This vehicle provides enough solubilization of metronidazole to allow for production of a 1% solution formulated in an aqueous gel. The HSA-3 gel vehicle promotes enhanced percutaneous absorption of metronidazole as compared to 1% cream, which incorporates the drug as a suspension. • Metronidazole 1% gel (HSA-3) does not increase transepidermal water loss in patients with rosacea, indicating no impairment of epidermal barrier function, and improves skin hydration based on corneometry testing. • Clinical study indicates that metronidazole 1% gel (HSA-3) is effective in reducing inflammatory lesions and facial erythema in patients with rosacea. Signs and symptoms of disease such as dryness, scaling, stinging/burning and pruritus were shown to improve progressively from the initiation of the trial through study endpoint. Disclosure: Dr. Del Rosso is a consultant/advisor and speaker for Galderma, Medicis, Intendis and Stiefel.
