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Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12275
ORIGINAL RESEARCH
Bioequivalence of 0.1% mometasone furoate lotion to 0.1% mometasone furoate hydrogel Kerryn A. Greive and Tanya M. Barnes Ego Pharmaceuticals, Braeside, Victoria, Australia
ABSTRACT used for Background/Objectives: Vehicles topical therapy can affect drug delivery and patient adherence. This study compared the bioequivalence of 0.1% mometasone furoate lotion (reference) and 0.1% mometasone furoate hydrogel (test). Moisturising capacity and sensitivity/irritancy potential were also determined. Methods: Bioequivalence was assessed by vasoconstriction assay and analysis of area under the effect curve (AUEC0–24) according to the Food and Drug Administration (FDA) guidance. In total, 131 individuals were screened in a pilot dose duration-response study, and 90 responders enrolled. For the pivotal study, lotion and hydrogel (5 mg/cm2) were applied in a double-blind manner. Vasoconstriction was evaluated by chromameter at 0, 2, 4, 6, 19 and 24 h following lotion and hydrogel removal. Barrier function was measured by assessment of transepidermal water loss (TEWL) and skin hydration. Sensitivity/irritancy potential was assessed by repeat insult patch tests. Results: The mean AUEC0–24 of the test hydrogel and reference lotion were −18.200 and −18.953, respectively, with test/reference = 96%, with 90% confidence interval (0.81, 1.12), which was within FDA guidance limits. TEWL was found to significantly decrease by 43 and 29% after 2 and 24 h, respectively, while skin hydration significantly increased by 38% after 24 h following a single application of hydrogel. The hydrogel was also found to be non-irritating and non-sensitising. No adverse events were observed.
Correspondence: Dr Kerryn A. Greive, Ego Pharmaceuticals Pty Ltd, 21–31 Malcolm Road, Braeside, Vic 3195, Australia. Email: [email protected] Kerryn A. Greive, PhD. Tanya M. Barnes, PhD. Conflict of interest: Kerryn A. Greive and Tanya M. Barnes are employed by Ego Pharmaceuticals Pty. Ltd., the sponsor of the study and manufacturer of Zatamil Hydrogel Submitted 11 August 2014; accepted 14 October 2014.
Conclusions: Mometasone furoate hydrogel is bioequivalent to mometasone furoate lotion. This novel hydrogel formulation provides effective drug delivery, increases moisturisation and affords greater ease and tolerability of application, improving patients’ adherence to therapy. Key words: bioequivalence, blanching, corneometry, hydrogel, lotion, patient adherence, topical mometasone furoate, transepidermal water loss, vasoconstrictor assay.
INTRODUCTION Topical corticosteroids are commonly used for the treatment of a range of skin diseases, and are among the most commonly prescribed topical medications.1 Topical corticosteroids are commercially available in a variety of formulations including creams, ointments and lotions.2 The properties of vehicles used to deliver topical corticosteroid therapy may have a considerable impact on their efficacy.2,3 Vehicles must optimise drug–skin interactions and the stability and release of the active drug, as well as being compatible with the active drug.4 Furthermore, vehicles may also influence patients’ adherence to a prescribed topical treatment regimen.5,6 Adherence to topical corticosteroid therapy has been found to be poor in clinical practice, with adherence determined to be as low as 32% in children with atopic dermatitis over an 8-week period.5 Poor adherence to prescribed therapy may be a reason for topical treatment failure in many patients with various skin diseases, including atopic dermatitis.5–8 Abbreviations: AUEC FDA MF RIPT TEWL
area under the effect curve Food and Drug Administration mometasone furoate repeat insult patch test transepidermal water loss
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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Poor adherence may stem from several factors, including patients’ fears of medication side effects, inconvenience and their dislike of messy or greasy topical medications, and their frustration with the efficacy of the medication.8 Patients’ preferences vary and the importance of certain aesthetic attributes depend on the state of the disease, the site of application, and the length and extent of treatment, among other factors.9 Factors that influence patients’ preference for different vehicles include the ease of application, the time it takes to apply the medication, how well it is absorbed into the skin, how it feels to the touch (its greasiness), how it smells, how it feels on the skin and how much it stains.10 Mometasone furoate (MF), a synthetic 16α-methyl analogue of beclomethasone, is classified as a potent corticosteroid for dermatological use.11 MF is an effective and well tolerated topical corticosteroid which is approved for use in steroid-responsive dermatoses, including atopic dermatitis, seborrhoeic dermatitis and psoriasis.11 It exhibits anti-inflammatory, anti-pruritic and vasoconstrictor properties, with a rapid onset of action and low systemic bioavailability after topical application.11 In addition, MF offers the convenience of once-daily administration and has been shown to have a favourable safety profile compared with other potent corticosteroids.11,12 MF is one of the most commonly prescribed topical corticosteroids in Australia.13 In August 2012 a topical hydrogel formulation of MF was approved by the Therapeutic Goods Administration, in addition to the cream, ointment and lotion formulations already available. Hydrogels are swellable polymeric materials, which have been developed for use in pharmaceuticals, including the topical drug delivery of corticosteroids.14 Advances in formulation technology have resulted in the development of hydrogel vehicles which are water-based, alcohol free, non-irritating, have a non-greasy texture, and have been shown to have moisturising properties which reduce scaling and dryness.14 These key benefits may increase patients’ satisfaction and their adherence to topical corticosteroid treatment using hydrogel as a vehicle.14 This randomised, double-blind, single-centre study was designed to compare the bioequivalence of 0.1% MF lotion to 0.1% MF hydrogel using a vasoconstriction assay and analysis of area under the effect curve (AUEC0–24) according to the guidelines outlined by the Food and Drug Administration (FDA) guidance for industry.15 In addition, barrier function was assessed by measuring transepidermal water loss (TEWL), skin hydration was determined by corneometry and sensitivity/irritancy potential was assessed by repeat insult patch tests (RIPT) following the topical application of MF hydrogel.
MATERIALS AND METHODS Topical preparations The formulations studied were Zatamil Hydrogel AUST R 195415 (Ego Pharmaceuticals, Braeside, Victoria, Australia) containing 0.1% MF and Elocon Lotion AUST R 53472
(Schering-Plough, Baulkham Hills, New South Wales, Australia) containing 0.1% MF.
Vasoconstrictor assay This study was approved by the Zenith Biomedical Ethics Committee which operates in accordance with the National Health and Medical Research Council of Australia’s National Statement on Ethical Conduct in Research Involving Humans and according to the International Conference on Harmonisation guidelines of Good Clinical Practice, the US Code of Federal Regulations and the Declaration of Helsinki. The study protocol adopted and followed the recommendations as set out in the FDA ‘Guidance on topical dermatologic corticosteroids: In vivo bioequivalence’, issue date: 2 June 1995.15 Eligible participants were: healthy men and nonpregnant, non-lactating women, as determined by their medical history, physical examination, 12-lead electrocardiograms, blood pressure and laboratory tests; aged between 18 and 55 years; responders to MF lotion (Elocon); weighing between 50 and 120 kg; non-HIV carriers and hepatitis A, B and C negative; alcohol, caffeine and chocolate free for 48 h prior to and throughout the study; had not consumed grapefruit or oranges and/or grapefruit or orange products for 1 week prior to and throughout the study; drug free including substances of abuse and herbal stimulants for 2 weeks prior to and throughout the study; non-smokers for at least 6 months; available for the entire study period and willing to adhere to the protocol requirements as evidenced by a signed consent to participate form. Exclusion criteria included: clinically significant hypertension or circulatory disease or any clinically significant illness during the 4 weeks prior to the study; a caffeine intake greater than 500 mg per day; on a special diet, especially a low salt or fluid restricted diet during the 2 weeks prior to the first study day; a clinically significant history of alcoholism or drug abuse; the use of topical dermatological drug therapy on the ventral forearms, including prior dosing of a topical corticosteroid in a pharmacodynamic study within 1 month prior to the study; adverse reactions to topical or systemic corticosteroids; any current or past medical condition including active dermatitis or any other dermatological condition which might significantly affect the pharmacodynamic response to the administered drug; persons who would require shaving to ventral forearms; the use of any vasoactive medication, prescription or over the counter medication that could modulate blood flow for 2 weeks prior to the study; the use of any prescription medication within 2 weeks preceding entry into the study; any obvious difference in skin colour between arms or any scarring on the forearms; participants who did not consent to their GP being contacted about any adverse results or reactions; participants who did not, according to the trial physician, understand the information and procedures of the study, particularly the study restrictions and risks involved; women who were pregnant or lactating (female partici-
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
Mometasone lotion and hydrogel pants were permitted to take oral contraceptives throughout the study) and individuals who had participated in another clinical trial within 30 days prior to the first dose. Only responders were included in this study and they were selected by a pilot dose duration–response study. The inclusion of non responders reduces the ability of a study to detect a true difference between the test and reference products, should they exist. Responders were individuals who showed a vasoconstriction response to a single dose of the reference drug used in the study. To determine which individuals were responders, two sites were selected on each arm about 3 cm above the anticubital fossa. Approximately 10 mg (5 mg/cm2) of MF lotion was applied to one site and the other was left blank. The lotion was removed after 4 h and chromameter evaluations of vasoconstriction were made after a further 2 h with a Minolta CR300 chromameter set (Minolta Co, Osaka, Japan) on the luminosity a-scale (red-green) which was standardised to an external ceramic plate before each use. A responder was defined as having a reduction in a-scale data (baseline and blank corrected). In all, 131 individuals were screened to provide 90 responders, with the expectation of having 40–60 evaluable participants (individuals meeting both responder and detector criteria). Each participant was identified by a three-digit enrolment number and a two-digit study code. The three-digit number was issued on enrolment and the two-digit number after randomisation. Individuals determined to be responders who were enrolled in the study entered the clinical site at 10.00 am on study day 1, and at 7.30 am on study day 2. The participants were asked to refrain from showering for 10 to 12 h prior and during the study. Eight treatment sites were randomly assigned to the flexor surface of each forearm of each participant. Four strips of Micropore tape (3M, Saint Paul, MN, USA) with 2 × 2 cm diameter pre-punched circles were applied to each forearm allowing each participant to receive six dosed sites and two untreated control sites per arm. Participants were blinded from the identity of each treatment, as were the staff evaluating the blanching (vasoconstriction). Participants were provided water ad libitum throughout the study period. They were also provided with a standard lunch and dinner at approximately 12.00 pm and 6.00 pm, respectively, on study day 1, after all study activities had been completed. Lunch was provided at 12.00 pm on study day 2. All meals and beverages were free of grapefruit and orange products, caffeine and chocolate, and were identical between the study days. The application of the treatments on study day 1 began at approximately 12.00 pm. Ten milligrams (5 mg/cm2) of either the test MF hydrogel or the reference MF lotion was applied to each arm via a syringe and spread evenly, using the smooth conical end of 1.5 mL conical plastic centrifuge tube and protected from the environment with a nonoccluding tape guard. This dose was expected to be sufficient to provide measurable levels of blanching. The test (T) hydrogel and the reference (R) lotion were each in contact with two treatment sites on each arm at the dose duration corresponding approximately to ED50 (30 min), as determined from a pilot dose duration–response study for the
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lotion (data not shown). To determine which participants were detectors (and therefore evaluable), the reference formulation was also in contact with one treatment site on each arm for 15 min (D1) and with another treatment site on each arm for 60 min (D2). The remaining two sites on each arm were used as untreated controls. Staggered hydrogel and lotion application with synchronised removal methods were adopted in this study. Following the specified times, the residual hydrogel and lotion on the forearms was removed. The arms were gently washed, patted dry with paper towels and left uninterrupted for a further 30 min before blanching assessment. The degree of blanching (vasoconstriction) was determined with a Minolta CR300 chromameter set on the luminosity a-scale (red-green) which was standardised to an external ceramic plate before each use. Readings were taken at 0, 2, 4, 6, 19 and 24 h following hydrogel and lotion removal, and were expected to allow good characterisation of the vasoconstriction bioequivalence determination. Two readings per site were taken at each time point and the average readings were used for further processing. Haematology and biochemistry blood profiles were repeated prior to discharge at the completion of the study.
TEWL Measurement of TEWL were performed in a double-blind manner on 10 volunteers aged 18 to 70 years, as previously described.16 MF hydrogel was applied to the inner forearm at a rate of 4 mg/cm2. Measurements were taken at t = 0 (pre-application) and at 2, 4, 6 and 24 h post-application using a TEWA Meter (Model TM 210 TEWA Meter, Courage and Khazaka, Cologne, Germany) at five different points on the skin, giving a total of 50 points.
Skin hydration Corneometry was performed as previously described.16 The same participants who had enrolled into the TEWL study also participated in the skin hydration study. MF hydrogel was applied to the inner forearm at a rate of 4 mg/cm2. Measurements were taken in a double-blind manner at t = 0 (pre-application) and at 24 h post-application using a Corneometer (Model CM 825 PC Corneometer, Courage and Khazaka) at five different points on the skin, giving a total of 50 points.
Repeat insult patch test In all, 111 healthy participants were enrolled in the study. Participants were requested to bathe or wash as usual before the test. 0.2 mL of MF hydrogel was placed onto a semi-occlusive, hypoallergenic patch (20 × 20 mm Webril affixed to the centre of a 40 × 40 mm adhesive bandage) (Parke-Davis, Rochester, MI, USA). The patch was then affixed directly to the skin of the infrascapular regions of the back to the right or left of the midline, and the participant was allowed to return home with instructions not to wet or expose the test area to direct sunlight. After 24 h the patch
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
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Figure 1 The degree of blanching determined by chromameter (baseline adjusted, untreated control site corrected a-scale data; ΔRx − ΔCon) versus time (h) for participants found to be detectors (n = 49) following the removal of either , topical 0.1% mometasone furoate (MF) lotion after 15 min (D1); , topical 0.1% MF lotion after 30 min (ED50); , topical 0.1% MF lotion after 60 min (D2); or , topical 0.1% MF hydrogel after 30 min (ED50). Results are presented as mean ± SD.
was removed by the participant at home. This procedure was repeated until a series of nine consecutive 24 h exposures were made for every Monday, Wednesday and Friday for three consecutive weeks. In the event of an adverse reaction, the area of erythema and oedema was measured. Oedema was estimated by the evaluation of the skin with respect to the contour of the unaffected normal skin. Reactions were scored just before applications two to nine and the next test date following application nine. Participants were then given a 10 to 14-day rest period, after which a challenge or retest dose was applied once to a previously unexposed test site. The retest dose was equivalent to any one of the original nine exposures. Reactions were scored 24 and 48 h after application.
Calculations and statistical analysis A total of 90 responders were recruited with the expectation of having 40 to 60 evaluable participants, that is, participants who meet both the responder and detector criteria. The detectors were those participants who exhibited (AUEC0–24 at D2)/(AUEC0–24 at D1) ≥ 1.25 and in whom both AUEC0–24 at D1 and D2 were negative due to the blanching effect, that is, showing a reduction in the a-scale value of the treated sites compared to the baseline values. The degree of colour change of each treatment site x at time t (ΔRx) was calculated as the differences of the a-scale readings from time t and time zero at treatment site x (baseline adjusted a-scale data): ΔRx = (a-scale reading of site x at time t) – (a-scale reading of site x at time 0). The degree of blanching of each treatment site (baseline adjusted, untreated control site corrected a-scale data) was estimated by the following equation: degree of blanching = ΔRx − ΔCon, where ΔRx is defined above and ΔCon = average [(a-scale reading of the control site at time t) – (a-scale reading of the control site at time 0)]. The degree of blanching values (baseline adjusted, untreated control site corrected a-scale data) for the different treatment sites were calculated and plotted against time. The area under the effect curve of these profiles, AUEC0–24 versus dose duration were then used in the assessment of the value for ED50. The AUEC0–24 was used in the
study design in accordance with the FDA Guidance.15 The AUEC0–24 from time zero to the last determined time point was calculated using the trapezoidal rule for each evaluation time. Real evaluation time was used in the calculation. The 90% confidence interval for detectors only was calculated using Locke’s method.15 For TEWL and skin hydration studies, percentage change in each parameter was determined by the following equation: Percentage change = [(a–b)/b]*100, where a = individual value of either TEWL or water content at each individual time point and b = zero hour value of either TEWL or water content. The Student’s t-test was used to compare the mean values and % change in TEWL and water content for both test preparations at each time point compared to pre-application. A further analysis was used to compare any differences between the test preparations at each time point. P < 0.05 was considered statistically significant.
RESULTS Vasoconstrictor assay Of the 131 participants screened in the pilot study, 90 healthy male (41) and female (49) participants aged 18 to 33 years (21 ± 3 years), weighing 48.8 to 111.6 kg (72.6 ± 13.5 kg) and with a body height of 1.53 m to 1.94 m (1.75 ± 0.10 m) were found to be responders and enrolled in the pivotal study. A total of 89 participants completed the pivotal study with one participant withdrawing due to personal circumstances unrelated to the study. Of these 89 participants, 49 were found to meet both the responder and detector criteria in accordance with the protocol and FDA Guidance, and these participants were used for all subsequent calculations.15 One participant experienced a headache which was deemed to be unrelated to the study drugs. Figure 1 shows the mean degree of blanching of each treatment site (baseline adjusted, untreated control site corrected a-scale data) over the 24 h time period following hydrogel and lotion removal for the 49 detectors only. Individual plots were used to determine the AUE0–24 for each participant.
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
Mometasone lotion and hydrogel
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Table 1 Area under the effect curve from 0 to 24 h (AUEC0–24) for 0.1% mometasone furoate (MF) lotion at the dose durations of 15 min (D1) and 60 min (D2), and for both 0.1% MF hydrogel (test) and 0.1% MF lotion (reference) at the dose duration corresponding to the ED50 (30 min) for participants found to be detectors. Results are presented as mean ± SD, with ranges in parentheses
Parameter D1 (15 min) Test (30 min) Reference (30 min) D2 (60 min)
AUEC0–24 0.1% MF lotion n = 49
AUEC0–24 0.1% MF hydrogel n = 49
−15.284 ± 9.945 (−43.529 to −0.186) n/a
n/a
−18.953 ± 11.166 (−53.282 to −2,597) −35.744 ± 16.275 (−73.199 to −4.061)
−18.200 ± 12.943 (−55.382 to −3, 145) n/a n/a
Table 1 shows a summary for the average AUE0–24 results for the test (T) hydrogel and reference (R) lotion at the dose duration corresponding to the ED50 (30 min), and the reference lotion at the dose durations of 15 min (D1) and 60 min (D2) for the detectors only. These results indicate that both the reference lotion and test hydrogel have very similar mean AUEC0–24 for the 49 detectors; AUEC0–24(T) = −18.200, AUEC0–24(R) = −18.953 and AUEC0–24 (T/R) = 96.03%. The 90% confidence interval calculated for the ratio of the average AUEC0–24 response due to the test product to the average AUEC0–24 response due to the reference product, using Locke’s method, was (0.8141, 1.1221). This is within the acceptance criteria of 0.8 and 1.25 according to the FDA guidance.15 Therefore, it can be concluded that MF hydrogel is bioequivalent to MF lotion.
Figure 2 Mean percentage change in transepidermal water loss (TEWL) measurements for 0.1% mometasone furoate hydrogel over time (h). The maximum response at each time point is also shown. Results are presented as mean ± SEM. *P < 0.001 vs t = 0. Table 2 Mean water content measurements (arbitrary units) for 0.1% mometasone furoate hydrogel over time (h). The percentage of change in water content post-application is given in parentheses Time (h)
0.1% mometasone furoate hydrogel
0 24
29.9 ± 1.2 41.0 ± 1.4 (38.3 ± 5.7)† Results are presented as mean ± SEM. †P < 0.001 vs t = 0.
over time. The pre-application mean water content value was 29.9 ± 1.2. Following a single application of MF hydrogel, water content and therefore moisturisation was significantly increased by 38.3 ± 5.7% to 41.0 ± 1.4 (P < 0.001) 24 h post-application.
TEWL
RIPT
Ten participants completed the study with an average age of 49.3 ± 4.0 years. No adverse reactions were observed. The pre-application mean TEWL value was 7.23 ± 0.27 g/hm2. Figure 2 illustrates the mean percentage decrease in TEWL over time. Two hours post-application TEWL significantly decreased by 42.7 ± 1.9% to 4.14 ± 0.21 g/hm2 (P < 0.001 vs t = 0), by 41.7 ± 2.3% at t = 4 h to 4.23 ± 0.26 g/hm2 (P < 0.001 vs t = 0), by 40.8 ± 1.4% at t = 6 h to 4.27 ± 0.16 g/ hm2 (P < 0.001 vs t = 0) and by 29.4 ± 2.2% at t = 24 h to 4.57 ± 0.63 g/hm2 (P < 0.001 vs t = 0) post-application. These results show that a significant reduction in water loss was observed 2 h following the topical application of MF hydrogel, which was maintained up to 6 h post-application, and was still significantly reduced up to 24 h of the study duration.
In all, 107 participants aged between 19 and 71 years completed the study. No adverse reactions of any kind were observed during the course of the study for MF hydrogel. Therefore, MF hydrogel was found to be non-irritating and non-sensitising to the skin, as determined by RIPT.
Skin hydration Ten participants with an average age of 49.3 ± 4.0 years completed the study with no adverse reactions observed. Table 2 shows the mean corneometry measurements and the percentage increase in water content for MF hydrogel
DISCUSSION This study has shown that 0.1% MF hydrogel is bioequivalent to 0.1% MF lotion as assessed by skin blanching using a chromameter set on the a-scale, according to the requirements of the US FDA guidance for industry.15 Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. Novel formulations that are bioequivalent offer additional treatment options for physicians and patients. This study has also demonstrated that MF hydrogel produces an improvement in barrier function following a single application of hydrogel, with a significant decrease in TEWL by 43% observed after 2 h, which was still significantly decreased by 29% after 24h, while skin hydration
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
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significantly increased by 38% after 24 h. Advances in formulation technology have enabled the development of MF into a novel aqueous hydrogel that is free from alcohol and other harsh surfactants or fragrances, and which disappears quickly without leaving a greasy residue. It contains purified water, hexylene glycol as a humectant moisturiser, hydroxypropyl cellulose to form a barrier on the skin and citric acid to adjust pH. As has been shown in this study, a hydrogel based on water with humectants can provide moisturising properties, unlike older alcohol-based gels, which can be drying to the skin.4,17 Since the stratum corneum is typically compromised in patients with various skin diseases, including atopic dermatitis, it is important that treatments should provide moisture to the skin as well as restoring impaired barrier function.18,19 Desonide hydrogel is the only other topical corticosteroid available in an alcohol-free and surfactant-free hydrogel formulation at present.20 It is currently unavailable in Australia. This hydrogel vehicle contains purified water, glycerine and propylene glycol as humectants, edetate disodium dehydrate, methylparaben, propylparaben, sodium hydroxide and Carbopol 981.21 Studies using this hydrogel vehicle have demonstrated an increase in epidermal moisturisation measured by corneometry, both after a single application to healthy participants4 and following repeated twice daily application to patients with atopic dermatitis over 221 and 4 weeks.4 Epidermal barrier function, as demonstrated by the measurement of TEWL, was also significantly improved in patients with atopic dermatitis following repeated application over a 4-week period.4 Similarly, twice daily application of desonide hydrogel to patients with atopic dermatitis was found to significantly improve TEWL measurements and corneometry over a 4-week period compared to baseline measurments.17 MF hydrogel would provide at least similar, if not better hydration to the skin of patients given that there is significantly more humectant in MF hydrogel than in desonide hydrogel. MF hydrogel was found to be non-irritating and nonsensitising, as determined by RIPTs in this study. A very low sensitisation potential has also been found for the desonide hydrogel vehicle.4 Historically, ointment formulations have been preferred for the treatment of various dermatoses for their presumed hydrating effects, yet studies have found that patients have a low satisfaction with ointments, which can be messy and uncomfortable.21,22 Cream formulations come in a variety of weights and feels, depending on how they are formulated; for example, oil in water versus water in oil emulsions, each with either a high or low fat content. Hydrogel formulations offer an alternative for patients if they are not happy with the feel or residual nature of their cream. Vehicle attributes are rated as 4 out of 5 of the most important qualities of a topical medicine by patients, along with side-effects, which rated 3 out of 5.6 Patients’ perceptions and attitudes to treatment can impact on their adherence to treatment regimens, which is a major reason for treatment failure in patients with skin diseases.5,6 Importantly, formulations that offer aesthetic advantages over traditional vehicles may improve patients’ willingness to apply therapy as directed.
Patients’ preference studies have indicated a high preference for the desonide hydrogel vehicle.9,23 Similar results would be expected for MF hydrogel due to the similarities between the vehicles. Aesthetic attributes of desonide hydrogel rated highly by patients with atopic dermatitis include: easy to apply/use/spread, disappear quickly, easy to use on hair-bearing skin, comfortable to wear under clothes, comfortable to use under make-up or cosmetics, feels soothing, they are suitable for use on various body areas, and are non-greasy and stain free.4,9 Participants’ satisfaction was evident from the high satisfaction ratings for all attributes as well as from the fact that most participants indicated an intention to use the product again, a willingness to follow the prescribed treatment regimen and a willingness to recommend the product to others.4,9 In addition, topical steroid therapy using the desonide hydrogel vehicle was found to be significantly preferred to the cream, foam and ointment formulations.6 The development of a MF hydrogel formulation which is bioequivalent to MF lotion, and is significantly moisturising compared with alcohol-based hydrogels, as well as being non-sensitising and non-irritating, offers patients and physicians an alternative to traditional formulations for the treatment of common steroid-responsive dermatoses. The novel MF hydrogel formulation provides effective drug delivery plus greater ease and tolerability of application, which may further increase effectiveness by improving patients’ adherence to therapy. Further, hydrogels, including MF hydrogel, may replace the use of many formulations since it can be used simultaneously on the skin and on hirsute areas such as the scalp, thus providing a versatile, simplified treatment option for some patients.24
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Trookman NS, Rizer RL, Ho ET et al. The importance of vehicle properties to patients with atopic dermatitis. Cutis 2011; 88: 13–17. Feldman SR, Housman TS. Patients’ vehicle preference for corticosteroid treatments of scalp psoriasis. Am. J. Clin. Dermatol. 2003; 4: 221–4. Prakash A, Benfield P. Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs 1998; 55: 145– 63. Samson C, Peets E, Winter-Sperry R et al. Mometasone furoate – Elocon® A medium potency topical corticosteroid with favorable efficacy/safety profile. In: Maibach HI, Surber C (eds). Topical Corticosteroids. Basel: Karger, 1992; 462–79. IMS Data Moving Annual Total. IMS Health, CT, USA. April 2014. Amin S, Rajabnezhad S, Kohli K. Hydrogels as potential drug delivery systems. Sci Res Essay 2009; 3: 1175–83. US Food and Drug Administration. Guidance for industry: topical dermatological corticosteroids: in-vivo bioequivalence. Rockville MD: 1995. Greive KA, Barnes TM. Increased bioavailability of hydrocortisone dissolved in a cream base. Australas. J. Dermatol. 2013; doi: 10.1111/ajd.12128. (epub ahead of print).
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24.
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Trookman NS, Rizer RL, Ho ET et al. Moisturizing advantages of desonide hydrogel in treating atopic dermatitis. Cutis 2011; 88: 7–12. Kim DW, Park JY, Na GY et al. Correlation of clinical features and skin barrier function in adolescent and adult patients with atopic dermatitis. Int. J. Dermatol. 2006; 45: 698–701. Gupta J, Grube E, Ericksen MB et al. Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity. J. Allergy Clin. Immunol. 2008; 121: 725–30. Gelbard CM, Hebert AA. Desonide hydrogel: advances in vehicle technology. Expert Rev. Dermatol. 2009; 4: 23–7. Kircik LH. Transepidermal water loss (TEWL) and corneometry with hydrogel vehicle in the treatment of atopic dermatitis: a randomized, investigator-blind pilot study. J. Drugs Dermatol. 2012; 11: 180–4. Kircik LH. The effect of desonide hydrogel on pruritus associated with atopic dermatitis. J. Drugs Dermatol. 2014; 13: 725–8. Kerney DL, Ford RO, Gotz V. Self-reported participant experience with desonide hydrogel in the treatment of mild to moderate atopic dermatitis. Cutis 2011; 88: 18–24. Kircik L. Treatment of scalp and facial seborrheic dermatitis with desonide hydrogel 0.05%. J. Clin. Aesthetic Dermatol. 2009; 2: 32–6.
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12275
ORIGINAL RESEARCH
Bioequivalence of 0.1% mometasone furoate lotion to 0.1% mometasone furoate hydrogel Kerryn A. Greive and Tanya M. Barnes Ego Pharmaceuticals, Braeside, Victoria, Australia
ABSTRACT used for Background/Objectives: Vehicles topical therapy can affect drug delivery and patient adherence. This study compared the bioequivalence of 0.1% mometasone furoate lotion (reference) and 0.1% mometasone furoate hydrogel (test). Moisturising capacity and sensitivity/irritancy potential were also determined. Methods: Bioequivalence was assessed by vasoconstriction assay and analysis of area under the effect curve (AUEC0–24) according to the Food and Drug Administration (FDA) guidance. In total, 131 individuals were screened in a pilot dose duration-response study, and 90 responders enrolled. For the pivotal study, lotion and hydrogel (5 mg/cm2) were applied in a double-blind manner. Vasoconstriction was evaluated by chromameter at 0, 2, 4, 6, 19 and 24 h following lotion and hydrogel removal. Barrier function was measured by assessment of transepidermal water loss (TEWL) and skin hydration. Sensitivity/irritancy potential was assessed by repeat insult patch tests. Results: The mean AUEC0–24 of the test hydrogel and reference lotion were −18.200 and −18.953, respectively, with test/reference = 96%, with 90% confidence interval (0.81, 1.12), which was within FDA guidance limits. TEWL was found to significantly decrease by 43 and 29% after 2 and 24 h, respectively, while skin hydration significantly increased by 38% after 24 h following a single application of hydrogel. The hydrogel was also found to be non-irritating and non-sensitising. No adverse events were observed.
Correspondence: Dr Kerryn A. Greive, Ego Pharmaceuticals Pty Ltd, 21–31 Malcolm Road, Braeside, Vic 3195, Australia. Email: [email protected] Kerryn A. Greive, PhD. Tanya M. Barnes, PhD. Conflict of interest: Kerryn A. Greive and Tanya M. Barnes are employed by Ego Pharmaceuticals Pty. Ltd., the sponsor of the study and manufacturer of Zatamil Hydrogel Submitted 11 August 2014; accepted 14 October 2014.
Conclusions: Mometasone furoate hydrogel is bioequivalent to mometasone furoate lotion. This novel hydrogel formulation provides effective drug delivery, increases moisturisation and affords greater ease and tolerability of application, improving patients’ adherence to therapy. Key words: bioequivalence, blanching, corneometry, hydrogel, lotion, patient adherence, topical mometasone furoate, transepidermal water loss, vasoconstrictor assay.
INTRODUCTION Topical corticosteroids are commonly used for the treatment of a range of skin diseases, and are among the most commonly prescribed topical medications.1 Topical corticosteroids are commercially available in a variety of formulations including creams, ointments and lotions.2 The properties of vehicles used to deliver topical corticosteroid therapy may have a considerable impact on their efficacy.2,3 Vehicles must optimise drug–skin interactions and the stability and release of the active drug, as well as being compatible with the active drug.4 Furthermore, vehicles may also influence patients’ adherence to a prescribed topical treatment regimen.5,6 Adherence to topical corticosteroid therapy has been found to be poor in clinical practice, with adherence determined to be as low as 32% in children with atopic dermatitis over an 8-week period.5 Poor adherence to prescribed therapy may be a reason for topical treatment failure in many patients with various skin diseases, including atopic dermatitis.5–8 Abbreviations: AUEC FDA MF RIPT TEWL
area under the effect curve Food and Drug Administration mometasone furoate repeat insult patch test transepidermal water loss
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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Poor adherence may stem from several factors, including patients’ fears of medication side effects, inconvenience and their dislike of messy or greasy topical medications, and their frustration with the efficacy of the medication.8 Patients’ preferences vary and the importance of certain aesthetic attributes depend on the state of the disease, the site of application, and the length and extent of treatment, among other factors.9 Factors that influence patients’ preference for different vehicles include the ease of application, the time it takes to apply the medication, how well it is absorbed into the skin, how it feels to the touch (its greasiness), how it smells, how it feels on the skin and how much it stains.10 Mometasone furoate (MF), a synthetic 16α-methyl analogue of beclomethasone, is classified as a potent corticosteroid for dermatological use.11 MF is an effective and well tolerated topical corticosteroid which is approved for use in steroid-responsive dermatoses, including atopic dermatitis, seborrhoeic dermatitis and psoriasis.11 It exhibits anti-inflammatory, anti-pruritic and vasoconstrictor properties, with a rapid onset of action and low systemic bioavailability after topical application.11 In addition, MF offers the convenience of once-daily administration and has been shown to have a favourable safety profile compared with other potent corticosteroids.11,12 MF is one of the most commonly prescribed topical corticosteroids in Australia.13 In August 2012 a topical hydrogel formulation of MF was approved by the Therapeutic Goods Administration, in addition to the cream, ointment and lotion formulations already available. Hydrogels are swellable polymeric materials, which have been developed for use in pharmaceuticals, including the topical drug delivery of corticosteroids.14 Advances in formulation technology have resulted in the development of hydrogel vehicles which are water-based, alcohol free, non-irritating, have a non-greasy texture, and have been shown to have moisturising properties which reduce scaling and dryness.14 These key benefits may increase patients’ satisfaction and their adherence to topical corticosteroid treatment using hydrogel as a vehicle.14 This randomised, double-blind, single-centre study was designed to compare the bioequivalence of 0.1% MF lotion to 0.1% MF hydrogel using a vasoconstriction assay and analysis of area under the effect curve (AUEC0–24) according to the guidelines outlined by the Food and Drug Administration (FDA) guidance for industry.15 In addition, barrier function was assessed by measuring transepidermal water loss (TEWL), skin hydration was determined by corneometry and sensitivity/irritancy potential was assessed by repeat insult patch tests (RIPT) following the topical application of MF hydrogel.
MATERIALS AND METHODS Topical preparations The formulations studied were Zatamil Hydrogel AUST R 195415 (Ego Pharmaceuticals, Braeside, Victoria, Australia) containing 0.1% MF and Elocon Lotion AUST R 53472
(Schering-Plough, Baulkham Hills, New South Wales, Australia) containing 0.1% MF.
Vasoconstrictor assay This study was approved by the Zenith Biomedical Ethics Committee which operates in accordance with the National Health and Medical Research Council of Australia’s National Statement on Ethical Conduct in Research Involving Humans and according to the International Conference on Harmonisation guidelines of Good Clinical Practice, the US Code of Federal Regulations and the Declaration of Helsinki. The study protocol adopted and followed the recommendations as set out in the FDA ‘Guidance on topical dermatologic corticosteroids: In vivo bioequivalence’, issue date: 2 June 1995.15 Eligible participants were: healthy men and nonpregnant, non-lactating women, as determined by their medical history, physical examination, 12-lead electrocardiograms, blood pressure and laboratory tests; aged between 18 and 55 years; responders to MF lotion (Elocon); weighing between 50 and 120 kg; non-HIV carriers and hepatitis A, B and C negative; alcohol, caffeine and chocolate free for 48 h prior to and throughout the study; had not consumed grapefruit or oranges and/or grapefruit or orange products for 1 week prior to and throughout the study; drug free including substances of abuse and herbal stimulants for 2 weeks prior to and throughout the study; non-smokers for at least 6 months; available for the entire study period and willing to adhere to the protocol requirements as evidenced by a signed consent to participate form. Exclusion criteria included: clinically significant hypertension or circulatory disease or any clinically significant illness during the 4 weeks prior to the study; a caffeine intake greater than 500 mg per day; on a special diet, especially a low salt or fluid restricted diet during the 2 weeks prior to the first study day; a clinically significant history of alcoholism or drug abuse; the use of topical dermatological drug therapy on the ventral forearms, including prior dosing of a topical corticosteroid in a pharmacodynamic study within 1 month prior to the study; adverse reactions to topical or systemic corticosteroids; any current or past medical condition including active dermatitis or any other dermatological condition which might significantly affect the pharmacodynamic response to the administered drug; persons who would require shaving to ventral forearms; the use of any vasoactive medication, prescription or over the counter medication that could modulate blood flow for 2 weeks prior to the study; the use of any prescription medication within 2 weeks preceding entry into the study; any obvious difference in skin colour between arms or any scarring on the forearms; participants who did not consent to their GP being contacted about any adverse results or reactions; participants who did not, according to the trial physician, understand the information and procedures of the study, particularly the study restrictions and risks involved; women who were pregnant or lactating (female partici-
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
Mometasone lotion and hydrogel pants were permitted to take oral contraceptives throughout the study) and individuals who had participated in another clinical trial within 30 days prior to the first dose. Only responders were included in this study and they were selected by a pilot dose duration–response study. The inclusion of non responders reduces the ability of a study to detect a true difference between the test and reference products, should they exist. Responders were individuals who showed a vasoconstriction response to a single dose of the reference drug used in the study. To determine which individuals were responders, two sites were selected on each arm about 3 cm above the anticubital fossa. Approximately 10 mg (5 mg/cm2) of MF lotion was applied to one site and the other was left blank. The lotion was removed after 4 h and chromameter evaluations of vasoconstriction were made after a further 2 h with a Minolta CR300 chromameter set (Minolta Co, Osaka, Japan) on the luminosity a-scale (red-green) which was standardised to an external ceramic plate before each use. A responder was defined as having a reduction in a-scale data (baseline and blank corrected). In all, 131 individuals were screened to provide 90 responders, with the expectation of having 40–60 evaluable participants (individuals meeting both responder and detector criteria). Each participant was identified by a three-digit enrolment number and a two-digit study code. The three-digit number was issued on enrolment and the two-digit number after randomisation. Individuals determined to be responders who were enrolled in the study entered the clinical site at 10.00 am on study day 1, and at 7.30 am on study day 2. The participants were asked to refrain from showering for 10 to 12 h prior and during the study. Eight treatment sites were randomly assigned to the flexor surface of each forearm of each participant. Four strips of Micropore tape (3M, Saint Paul, MN, USA) with 2 × 2 cm diameter pre-punched circles were applied to each forearm allowing each participant to receive six dosed sites and two untreated control sites per arm. Participants were blinded from the identity of each treatment, as were the staff evaluating the blanching (vasoconstriction). Participants were provided water ad libitum throughout the study period. They were also provided with a standard lunch and dinner at approximately 12.00 pm and 6.00 pm, respectively, on study day 1, after all study activities had been completed. Lunch was provided at 12.00 pm on study day 2. All meals and beverages were free of grapefruit and orange products, caffeine and chocolate, and were identical between the study days. The application of the treatments on study day 1 began at approximately 12.00 pm. Ten milligrams (5 mg/cm2) of either the test MF hydrogel or the reference MF lotion was applied to each arm via a syringe and spread evenly, using the smooth conical end of 1.5 mL conical plastic centrifuge tube and protected from the environment with a nonoccluding tape guard. This dose was expected to be sufficient to provide measurable levels of blanching. The test (T) hydrogel and the reference (R) lotion were each in contact with two treatment sites on each arm at the dose duration corresponding approximately to ED50 (30 min), as determined from a pilot dose duration–response study for the
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lotion (data not shown). To determine which participants were detectors (and therefore evaluable), the reference formulation was also in contact with one treatment site on each arm for 15 min (D1) and with another treatment site on each arm for 60 min (D2). The remaining two sites on each arm were used as untreated controls. Staggered hydrogel and lotion application with synchronised removal methods were adopted in this study. Following the specified times, the residual hydrogel and lotion on the forearms was removed. The arms were gently washed, patted dry with paper towels and left uninterrupted for a further 30 min before blanching assessment. The degree of blanching (vasoconstriction) was determined with a Minolta CR300 chromameter set on the luminosity a-scale (red-green) which was standardised to an external ceramic plate before each use. Readings were taken at 0, 2, 4, 6, 19 and 24 h following hydrogel and lotion removal, and were expected to allow good characterisation of the vasoconstriction bioequivalence determination. Two readings per site were taken at each time point and the average readings were used for further processing. Haematology and biochemistry blood profiles were repeated prior to discharge at the completion of the study.
TEWL Measurement of TEWL were performed in a double-blind manner on 10 volunteers aged 18 to 70 years, as previously described.16 MF hydrogel was applied to the inner forearm at a rate of 4 mg/cm2. Measurements were taken at t = 0 (pre-application) and at 2, 4, 6 and 24 h post-application using a TEWA Meter (Model TM 210 TEWA Meter, Courage and Khazaka, Cologne, Germany) at five different points on the skin, giving a total of 50 points.
Skin hydration Corneometry was performed as previously described.16 The same participants who had enrolled into the TEWL study also participated in the skin hydration study. MF hydrogel was applied to the inner forearm at a rate of 4 mg/cm2. Measurements were taken in a double-blind manner at t = 0 (pre-application) and at 24 h post-application using a Corneometer (Model CM 825 PC Corneometer, Courage and Khazaka) at five different points on the skin, giving a total of 50 points.
Repeat insult patch test In all, 111 healthy participants were enrolled in the study. Participants were requested to bathe or wash as usual before the test. 0.2 mL of MF hydrogel was placed onto a semi-occlusive, hypoallergenic patch (20 × 20 mm Webril affixed to the centre of a 40 × 40 mm adhesive bandage) (Parke-Davis, Rochester, MI, USA). The patch was then affixed directly to the skin of the infrascapular regions of the back to the right or left of the midline, and the participant was allowed to return home with instructions not to wet or expose the test area to direct sunlight. After 24 h the patch
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
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Figure 1 The degree of blanching determined by chromameter (baseline adjusted, untreated control site corrected a-scale data; ΔRx − ΔCon) versus time (h) for participants found to be detectors (n = 49) following the removal of either , topical 0.1% mometasone furoate (MF) lotion after 15 min (D1); , topical 0.1% MF lotion after 30 min (ED50); , topical 0.1% MF lotion after 60 min (D2); or , topical 0.1% MF hydrogel after 30 min (ED50). Results are presented as mean ± SD.
was removed by the participant at home. This procedure was repeated until a series of nine consecutive 24 h exposures were made for every Monday, Wednesday and Friday for three consecutive weeks. In the event of an adverse reaction, the area of erythema and oedema was measured. Oedema was estimated by the evaluation of the skin with respect to the contour of the unaffected normal skin. Reactions were scored just before applications two to nine and the next test date following application nine. Participants were then given a 10 to 14-day rest period, after which a challenge or retest dose was applied once to a previously unexposed test site. The retest dose was equivalent to any one of the original nine exposures. Reactions were scored 24 and 48 h after application.
Calculations and statistical analysis A total of 90 responders were recruited with the expectation of having 40 to 60 evaluable participants, that is, participants who meet both the responder and detector criteria. The detectors were those participants who exhibited (AUEC0–24 at D2)/(AUEC0–24 at D1) ≥ 1.25 and in whom both AUEC0–24 at D1 and D2 were negative due to the blanching effect, that is, showing a reduction in the a-scale value of the treated sites compared to the baseline values. The degree of colour change of each treatment site x at time t (ΔRx) was calculated as the differences of the a-scale readings from time t and time zero at treatment site x (baseline adjusted a-scale data): ΔRx = (a-scale reading of site x at time t) – (a-scale reading of site x at time 0). The degree of blanching of each treatment site (baseline adjusted, untreated control site corrected a-scale data) was estimated by the following equation: degree of blanching = ΔRx − ΔCon, where ΔRx is defined above and ΔCon = average [(a-scale reading of the control site at time t) – (a-scale reading of the control site at time 0)]. The degree of blanching values (baseline adjusted, untreated control site corrected a-scale data) for the different treatment sites were calculated and plotted against time. The area under the effect curve of these profiles, AUEC0–24 versus dose duration were then used in the assessment of the value for ED50. The AUEC0–24 was used in the
study design in accordance with the FDA Guidance.15 The AUEC0–24 from time zero to the last determined time point was calculated using the trapezoidal rule for each evaluation time. Real evaluation time was used in the calculation. The 90% confidence interval for detectors only was calculated using Locke’s method.15 For TEWL and skin hydration studies, percentage change in each parameter was determined by the following equation: Percentage change = [(a–b)/b]*100, where a = individual value of either TEWL or water content at each individual time point and b = zero hour value of either TEWL or water content. The Student’s t-test was used to compare the mean values and % change in TEWL and water content for both test preparations at each time point compared to pre-application. A further analysis was used to compare any differences between the test preparations at each time point. P < 0.05 was considered statistically significant.
RESULTS Vasoconstrictor assay Of the 131 participants screened in the pilot study, 90 healthy male (41) and female (49) participants aged 18 to 33 years (21 ± 3 years), weighing 48.8 to 111.6 kg (72.6 ± 13.5 kg) and with a body height of 1.53 m to 1.94 m (1.75 ± 0.10 m) were found to be responders and enrolled in the pivotal study. A total of 89 participants completed the pivotal study with one participant withdrawing due to personal circumstances unrelated to the study. Of these 89 participants, 49 were found to meet both the responder and detector criteria in accordance with the protocol and FDA Guidance, and these participants were used for all subsequent calculations.15 One participant experienced a headache which was deemed to be unrelated to the study drugs. Figure 1 shows the mean degree of blanching of each treatment site (baseline adjusted, untreated control site corrected a-scale data) over the 24 h time period following hydrogel and lotion removal for the 49 detectors only. Individual plots were used to determine the AUE0–24 for each participant.
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
Mometasone lotion and hydrogel
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Table 1 Area under the effect curve from 0 to 24 h (AUEC0–24) for 0.1% mometasone furoate (MF) lotion at the dose durations of 15 min (D1) and 60 min (D2), and for both 0.1% MF hydrogel (test) and 0.1% MF lotion (reference) at the dose duration corresponding to the ED50 (30 min) for participants found to be detectors. Results are presented as mean ± SD, with ranges in parentheses
Parameter D1 (15 min) Test (30 min) Reference (30 min) D2 (60 min)
AUEC0–24 0.1% MF lotion n = 49
AUEC0–24 0.1% MF hydrogel n = 49
−15.284 ± 9.945 (−43.529 to −0.186) n/a
n/a
−18.953 ± 11.166 (−53.282 to −2,597) −35.744 ± 16.275 (−73.199 to −4.061)
−18.200 ± 12.943 (−55.382 to −3, 145) n/a n/a
Table 1 shows a summary for the average AUE0–24 results for the test (T) hydrogel and reference (R) lotion at the dose duration corresponding to the ED50 (30 min), and the reference lotion at the dose durations of 15 min (D1) and 60 min (D2) for the detectors only. These results indicate that both the reference lotion and test hydrogel have very similar mean AUEC0–24 for the 49 detectors; AUEC0–24(T) = −18.200, AUEC0–24(R) = −18.953 and AUEC0–24 (T/R) = 96.03%. The 90% confidence interval calculated for the ratio of the average AUEC0–24 response due to the test product to the average AUEC0–24 response due to the reference product, using Locke’s method, was (0.8141, 1.1221). This is within the acceptance criteria of 0.8 and 1.25 according to the FDA guidance.15 Therefore, it can be concluded that MF hydrogel is bioequivalent to MF lotion.
Figure 2 Mean percentage change in transepidermal water loss (TEWL) measurements for 0.1% mometasone furoate hydrogel over time (h). The maximum response at each time point is also shown. Results are presented as mean ± SEM. *P < 0.001 vs t = 0. Table 2 Mean water content measurements (arbitrary units) for 0.1% mometasone furoate hydrogel over time (h). The percentage of change in water content post-application is given in parentheses Time (h)
0.1% mometasone furoate hydrogel
0 24
29.9 ± 1.2 41.0 ± 1.4 (38.3 ± 5.7)† Results are presented as mean ± SEM. †P < 0.001 vs t = 0.
over time. The pre-application mean water content value was 29.9 ± 1.2. Following a single application of MF hydrogel, water content and therefore moisturisation was significantly increased by 38.3 ± 5.7% to 41.0 ± 1.4 (P < 0.001) 24 h post-application.
TEWL
RIPT
Ten participants completed the study with an average age of 49.3 ± 4.0 years. No adverse reactions were observed. The pre-application mean TEWL value was 7.23 ± 0.27 g/hm2. Figure 2 illustrates the mean percentage decrease in TEWL over time. Two hours post-application TEWL significantly decreased by 42.7 ± 1.9% to 4.14 ± 0.21 g/hm2 (P < 0.001 vs t = 0), by 41.7 ± 2.3% at t = 4 h to 4.23 ± 0.26 g/hm2 (P < 0.001 vs t = 0), by 40.8 ± 1.4% at t = 6 h to 4.27 ± 0.16 g/ hm2 (P < 0.001 vs t = 0) and by 29.4 ± 2.2% at t = 24 h to 4.57 ± 0.63 g/hm2 (P < 0.001 vs t = 0) post-application. These results show that a significant reduction in water loss was observed 2 h following the topical application of MF hydrogel, which was maintained up to 6 h post-application, and was still significantly reduced up to 24 h of the study duration.
In all, 107 participants aged between 19 and 71 years completed the study. No adverse reactions of any kind were observed during the course of the study for MF hydrogel. Therefore, MF hydrogel was found to be non-irritating and non-sensitising to the skin, as determined by RIPT.
Skin hydration Ten participants with an average age of 49.3 ± 4.0 years completed the study with no adverse reactions observed. Table 2 shows the mean corneometry measurements and the percentage increase in water content for MF hydrogel
DISCUSSION This study has shown that 0.1% MF hydrogel is bioequivalent to 0.1% MF lotion as assessed by skin blanching using a chromameter set on the a-scale, according to the requirements of the US FDA guidance for industry.15 Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. Novel formulations that are bioequivalent offer additional treatment options for physicians and patients. This study has also demonstrated that MF hydrogel produces an improvement in barrier function following a single application of hydrogel, with a significant decrease in TEWL by 43% observed after 2 h, which was still significantly decreased by 29% after 24h, while skin hydration
© 2014 The Authors. Australasian Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of The Australasian College of Dermatologists.
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significantly increased by 38% after 24 h. Advances in formulation technology have enabled the development of MF into a novel aqueous hydrogel that is free from alcohol and other harsh surfactants or fragrances, and which disappears quickly without leaving a greasy residue. It contains purified water, hexylene glycol as a humectant moisturiser, hydroxypropyl cellulose to form a barrier on the skin and citric acid to adjust pH. As has been shown in this study, a hydrogel based on water with humectants can provide moisturising properties, unlike older alcohol-based gels, which can be drying to the skin.4,17 Since the stratum corneum is typically compromised in patients with various skin diseases, including atopic dermatitis, it is important that treatments should provide moisture to the skin as well as restoring impaired barrier function.18,19 Desonide hydrogel is the only other topical corticosteroid available in an alcohol-free and surfactant-free hydrogel formulation at present.20 It is currently unavailable in Australia. This hydrogel vehicle contains purified water, glycerine and propylene glycol as humectants, edetate disodium dehydrate, methylparaben, propylparaben, sodium hydroxide and Carbopol 981.21 Studies using this hydrogel vehicle have demonstrated an increase in epidermal moisturisation measured by corneometry, both after a single application to healthy participants4 and following repeated twice daily application to patients with atopic dermatitis over 221 and 4 weeks.4 Epidermal barrier function, as demonstrated by the measurement of TEWL, was also significantly improved in patients with atopic dermatitis following repeated application over a 4-week period.4 Similarly, twice daily application of desonide hydrogel to patients with atopic dermatitis was found to significantly improve TEWL measurements and corneometry over a 4-week period compared to baseline measurments.17 MF hydrogel would provide at least similar, if not better hydration to the skin of patients given that there is significantly more humectant in MF hydrogel than in desonide hydrogel. MF hydrogel was found to be non-irritating and nonsensitising, as determined by RIPTs in this study. A very low sensitisation potential has also been found for the desonide hydrogel vehicle.4 Historically, ointment formulations have been preferred for the treatment of various dermatoses for their presumed hydrating effects, yet studies have found that patients have a low satisfaction with ointments, which can be messy and uncomfortable.21,22 Cream formulations come in a variety of weights and feels, depending on how they are formulated; for example, oil in water versus water in oil emulsions, each with either a high or low fat content. Hydrogel formulations offer an alternative for patients if they are not happy with the feel or residual nature of their cream. Vehicle attributes are rated as 4 out of 5 of the most important qualities of a topical medicine by patients, along with side-effects, which rated 3 out of 5.6 Patients’ perceptions and attitudes to treatment can impact on their adherence to treatment regimens, which is a major reason for treatment failure in patients with skin diseases.5,6 Importantly, formulations that offer aesthetic advantages over traditional vehicles may improve patients’ willingness to apply therapy as directed.
Patients’ preference studies have indicated a high preference for the desonide hydrogel vehicle.9,23 Similar results would be expected for MF hydrogel due to the similarities between the vehicles. Aesthetic attributes of desonide hydrogel rated highly by patients with atopic dermatitis include: easy to apply/use/spread, disappear quickly, easy to use on hair-bearing skin, comfortable to wear under clothes, comfortable to use under make-up or cosmetics, feels soothing, they are suitable for use on various body areas, and are non-greasy and stain free.4,9 Participants’ satisfaction was evident from the high satisfaction ratings for all attributes as well as from the fact that most participants indicated an intention to use the product again, a willingness to follow the prescribed treatment regimen and a willingness to recommend the product to others.4,9 In addition, topical steroid therapy using the desonide hydrogel vehicle was found to be significantly preferred to the cream, foam and ointment formulations.6 The development of a MF hydrogel formulation which is bioequivalent to MF lotion, and is significantly moisturising compared with alcohol-based hydrogels, as well as being non-sensitising and non-irritating, offers patients and physicians an alternative to traditional formulations for the treatment of common steroid-responsive dermatoses. The novel MF hydrogel formulation provides effective drug delivery plus greater ease and tolerability of application, which may further increase effectiveness by improving patients’ adherence to therapy. Further, hydrogels, including MF hydrogel, may replace the use of many formulations since it can be used simultaneously on the skin and on hirsute areas such as the scalp, thus providing a versatile, simplified treatment option for some patients.24
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Stern RS. The pattern of topical corticosteroid prescribing in the United States, 1989–1991. J. Am. Acad. Dermatol. 1996; 35: 183–6. Tadicherla S, Ross K, Shenefelt PD et al. Topical corticosteroids in dermatology. J. Drugs Dermatol. 2009; 8: 1093–105. Hughes J, Rustin M. Corticosteroids. Clin. Dermatol. 1997; 15: 715–21. Kircik L, Del Rosso J. A novel hydrogel vehicle formulated for the treatment of atopic dermatitis. J. Drugs Dermatol. 2007; 6: 718–22. Krejci-Manwaring J, Tusa MG, Carroll C et al. Stealth monitoring of adherence to topical medication: adherence is very poor in children with atopic dermatitis. J. Am. Acad. Dermatol. 2007; 56: 211–16. Yentzer BA, Camacho FT, Young T et al. Good adherence and early efficacy using desonide hydrogel for atopic dermatitis: results from a program addressing patient compliance. J. Drugs Dermatol. 2010; 9: 324–9. Hebert AA, Cook-Bolden FE, Basu S et al. Safety and efficacy of desonide hydrogel 0.05% in pediatric subjects with atopic dermatitis. J. Drugs Dermatol. 2007; 6: 175–81. Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J. Am. Acad. Dermatol. 2006; 55: 607–13.
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