Oxybutynin gel versus nanoemulgel for treating primary palmar hyperhidrosis: A pilot double‐blind randomized controlled trial

Palmar hyperhidrosis or excessive palmar sweating can reduce one's quality of life as it is associated with significant physical and occupational disabilities. We compared the gel and nanoemulgel of oxybutynin in treating these patients.


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SAKI et al. 6 months along with at least four of the following symptoms: excessive localized sweating in the axilla, palms, soles, or face; bilateral sweating; symmetrical sweating; lack of night sweating; sweating at least once a week; a positive family history; and the presence of sweating at the age of 25 years or less. [2][3][4][5] Due to the destructive effects of hyperhidrosis on a person's life, topical, systemic, and surgical treatments have been used to overcome this problem. Systemic anticholinergics such as glycopyrrolate and oxybutynin are effective in treating patients with hyperhidrosis because of the high levels of acetylcholine and nicotine receptors in their sympathetic ganglia. 4,[6][7][8][9] However, these treatments are associated with widespread side effects such as dry mouth and eyes and gastrointestinal and urinary complications, making their use practically in 30% of patients, difficult. 10 In recent years, efforts have been made to create transdermal formulations of drugs to eliminate side effects caused by oral consumption. 11 Topical gels can produce a faster release than creams and ointments, but they have difficulty transporting hydrophobic drugs.
To solve this problem, emulsions were produced, offering the benefits of gels while also transferring hydrophobic drugs. Among all topical compounds, a nanoemulgel is an ideal product as it is a gel-emulsion mixture, simultaneously exhibiting the advantages of both and offering the highest permeability. In fact, nanoemulgels can maximize drug efficacy while minimizing toxicity. 12 Accordingly, the present study was designed to evaluate and compare the topical effect of oxybutynin in the form of gel and nanoemulgel in treating palmar hyperhidrosis.

| Study design
This study was designed and conducted as a pilot, double-blind,

| Sample size
Due to the study's novelty, a pilot design was considered and confirmed using the NCSS software (NCSS, LLC®). Accordingly, the minimum sample size was determined as 15 in each of the two groups, with a total sample size of at least 30. The samples were selected by simple random sampling via the "completely random" method. The study population included patients with primary palmar hyperhidrosis referred to the Dermatology Clinic of Shahid Faghihi Hospital, Shiraz, Iran, between 2020 and 2021.

| Participants
Patients over 18 years old diagnosed with primary palmar hyperhidrosis by an attending dermatologist were considered for inclusion in this study. Secondary causes were ruled out through a detailed clinical history and physical examination. Exclusion criteria were hypersensitivity to topical oxybutynin, pregnancy, autonomic dysfunction, history of surgery, receiving oral or topical treatments in the last 4 weeks, or a Botox® injection in the last 12 weeks.

| Intervention
Patients were randomly assigned to receive either 1% oxybutynin topical gel or 1% oxybutynin topical nanoemulgel. Each patient applied half a fingertip (roughly 0.25 g) of the product to both palms every 12 h for 1 month. A demonstration of how to gently squeeze the tube and release this amount of the product was made for each participant. The products were prepared in similar packages (15 g tubes) labeled as A or B by a pharmacist external to the research group. The patients and study authors were blinded to the treatment groups, and the identity of the codes was not revealed until after statistical analysis.

| Product preparation
To prepare 1% oxybutynin gel, first, 0.8 g of sodium carboxymethyl cellulose was dispersed and mixed in 20 mL of distilled water until it was completely uniform and the structure of the gel network was formed. Then, 0.2 g of oxybutynin (equivalent to 1% by weight) dissolved in 1 mL of ethanol and water was added to the gel. The mixture was stirred for about an hour until a uniform gel was obtained.
We prepared the 1% oxybutynin nanoemulgel according to the procedure described in a previous study. 13

| Outcome assessment
At the beginning of the study, all patients filled out a questionnaire that asked for the following demographic data: name, age, sex, history of previous treatments, duration of disease, and duration of previous treatments. Outcomes were assessed at the beginning of the study and 1 month after treatment initiation. In these assessments, patients were clinically evaluated by an attending dermatologist using three standard questionnaires: Hyperhidrosis Disease Severity Scale (HDSS), Visual Analog Scale (VAS), and Dermatology Life Quality Index (DLQI). The HDSS and VAS were used to assess hyperhidrosis severity, while the DLQI was used to assess the quality of life.

| Statistical analysis
Data were analyzed using SPSS version 25 (IBM Corp.). Mean, standard deviation (SD), and median were used to describe quantitative variables. The chi-squared test (Fisher's exact test if required) was used to compare qualitative variables, and the t-test was used to compare quantitative variables. p-Values less than 0.05 were considered statistically significant.

| RE SULTS
Thirty patients who met the inclusion criteria were enrolled in the study. Only one patient did not complete the follow-up and was ex- The intragroup analysis of the patients in the gel group revealed a significantly lower mean HDSS score at the end of the study compared with the beginning (p = 0.001); the mean HDSS score also fell significantly in the nanoemulgel group (p = 0.001) ( Table 1). The intragroup analysis revealed that the mean VAS score at the end of the study was significantly lower than at the beginning in both groups (p < 0.001 for both) ( Table 2). The same was true regarding the scores of the DLQI, which fell significantly in the gel group (p < 0.001) and in the nanoemulgel group (p = 0.001) ( Table 3). Both forms of oxybutynin effectively improved patients' quality of life without a significant difference between the groups (Table 4).
Anticholinergic side effects were observed in six patients. Three patients in the nanoemulgel group and two in the gel group transiently experienced a dry mouth during the first week of the study.
Urinary retention was experienced by one of the oxybutynin gel group patients in the initial days. All side effects disappeared within a few days without any particular interventions. There was no statistically significant difference between the two groups in terms of the occurrence of side effects (p = 0.983).

| DISCUSS ION
Hyperhidrosis is characterized by excessive sweating. This condition may be caused by a complex defect in both the sympathetic and parasympathetic components of the autonomic nervous system, leading to overstimulation of the eccrine glands. 14,15 The prevalence of hyperhidrosis is between 0.6% and 4.8%; the condition mostly affects individuals aged between 18 and 39 years, with an equal prevalence across both sexes. 5,16,17 In 93% of all cases of hyperhidrosis, the disease is primary, mostly affecting areas such as the palms, soles, and face. 18 [20][21][22][23][24][25][26] Hence, topical anticholinergics should be considered to reduce these side effects. Oxybutynin is an anticholinergic agent that undergoes hepatic and gastrointestinal metabolism when taken orally but has reduced first-pass metabolism and, thus, fewer anticholinergic side effects when used topically. [27][28][29] As there are few studies on topical treatments of hyperhidrosis, In the present study, we used oxybutynin gel and nanoemulgel to treat palmar hyperhidrosis. A nanoemulgel consists of two separate systems: an emulsion containing nanoscale droplets and a gel. In nanoemulgels, emulsions are used as physical or chemical carriers for drug delivery and are stabilized by emulsifiers. 31,32 The benefits of nanoemulgels include increasing the drug bioavailability, reducing the drug dose required, and increasing the skin permeability to the drug. 33 A previous study showed that simple oxybutynin gel did not have detectable amounts of oxybutynin permeation through skin layers, while oxybutynin nanoemulgel had 5% (36 μg/cm 2 ) and 12% (80 μg/cm 2 ) drug permeation after 12 and 24 h, respectively. 13 Despite the theoretical advantages, our study showed no significant difference between the topical use of oxybutynin in the form of gel and nanoemulgel; both methods had almost the same efficacy and side effects. Although both drugs had a favorable effect, the nanoemulgel does not seem economically justified due to its high production cost. Hence, we recommend the use of the simple form.
Reviewing different articles confirms the advantage of topical drugs in treating hyperhidrosis. Artzi et al. 30

FU N D I N G I N FO R M ATI O N
No funding or sponsorship was received for the conduction of this study.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that no conflict of or competing interests existed or occurred in the conduction of this manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The dataset supporting the conclusions of this article is available upon request to the corresponding author.