Innovative Topical Patches for Non-Melanoma Skin Cancer: Current Challenges and Key Formulation Considerations.

Non-melanoma skin cancer (NMSC) is the most prevalent malignancy worldwide, with approximately 6.3 million new cases worldwide in 2019. One of the key management strategies for NMSC is a topical treatment usually utilised for localised and early-stage disease owing to its non-invasive nature. However, the efficacy of topical agents is often hindered by poor drug penetration and patient adherence. Therefore, various research groups have employed advanced drug delivery systems, including topical patches to overcome the problem of conventional topical treatments. This review begins with an overview of NMSC as well as the current landscape of topical treatments for NMSC, specifically focusing on the emerging technology of topical patches. A detailed discussion of their potential to overcome the limitations of existing therapies will then follow. Most importantly, to the best of our knowledge, this work unprecedentedly combines and discusses all the current advancements in innovative topical patches for the treatment of NMSC. In addition to this, the authors present our insights into the key considerations and emerging trends in the construction of these advanced topical patches. This review is meant for researchers and clinicians to consider utilising advanced topical patch systems in research and clinical trials toward localised interventions of NMSC.

Development and Optimization of Imiquimod-Loaded Nanostructured Lipid Carriers Using a Hybrid Design of Experiments Approach.

Background: Imiquimod (IMQ) is an immunomodulating drug that is approved for the treatment of superficial basal cell carcinoma, actinic keratosis, external genital warts and perianal warts. However, IMQ cream (Aldara®) has several drawbacks including poor skin permeation, local toxicity, and compromised patient compliance as a topical pharmacological option. Methods: Our research aimed to develop and optimize nanostructured lipid carriers (NLCs) containing IMQ for the first time using a hybrid design of experiments approach. The optimized formulation was then incorporated into a matrix-type topical patch as an alternative dosage form for topical application and evaluated for IMQ deposition across different skin layers in comparison to the performance of the commercial product. Additionally, our work also attempted to highlight the possibility of implementing environment-friendly practices in our IMQ-NLCs formulation development by reviewing our analytical methods and experimental designs and reducing energy and solvent consumption where possible. Results: In this study, stearyl alcohol, oleic acid, Tween® 80 (polysorbate 80), and Gelucire® 50/13 (Stearoyl polyoxyl-32 glycerides) were selected for formulation development. The formulation was optimized using a 2k factorial design and a central composite design. The optimized formulation achieved the average particle size, polydispersity index, and zeta potential of 75.6 nm, 0.235, and - 30.9 mV, respectively. Subsequently, a matrix-type patch containing IMQ-NLCs was developed and achieved a statistically significant improvement in IMQ deposition in the deeper skin layers. The IMQ deposition from the patch into the dermis layer and receptor chamber was 3.3 ± 0.9 µg/cm2 and 12.3 ± 2.2 µg/cm2, while the commercial cream only deposited 1.0 ± 0.8 µg/cm2 and 1.5 ± 0.5 µg/cm2 of IMQ, respectively. Conclusion: In summary, IMQ-NLC-loaded patches represent great potential as a topical treatment option for skin cancer with improved patient compliance.

Formulation Development and Pharmaceutical Evaluation of Lysiphyllum strychnifolium Topical Patches for Their Anti-inflammatory Potential.

Topical drug delivery systems are interesting and popular dosage forms for formulation development. Thai herbs are used in alternative medicine to treat patients suffering from severe illnesses. They have significant economic and cultural value in Thailand. This work prepared Thai herbal topical patches of Lysiphyllum strychnifolium stem extracts using pectin and Eudragit® NM 30D, and glycerin as a plasticizer. Astilbin was selected as a chemical marker in L. strychnifolium stem extracts. The L. strychnifolium stem extracts showed a statistically significant decrease in nitrate accumulation. The various properties of Thai herbal topical patches were not significantly different from blank patches. However, the trends of the properties depended on the amount of Eudragit® NM 30D. All ingredients were homogeneously mixed in Thai herbal topical patches and showed a smooth and compact film. The astilbin content was found in a range of 52.72-63.36 µg/cm2. The in vitro release of astilbin depended on the amount of Eudragit® NM 30D. The kinetics of astilbin release were fitted to the Korsmeyer-Peppas model. The astilbin showed low permeation; thus, polyethylene glycol 400 was used as a permeation enhancer. Polyethylene glycol 400 could increase the permeation rates of astilbin and the cumulative amount of astilbin in pig skin. This would be suitable for preparing the Thai herbal topical patches and could be developed for pharmaceutical and herbal products.

Effect of plasticizers on drug-in-adhesive patches containing 5-fluorouracil.

Topical patches containing 5-fluorouracil (5-FU) are a feasible alternative to overcome the shortcomings of commercial cream for the treatment of non-melanoma skin cancer (NMSC). Plasticizers are a critical component of drug-in-adhesive (DIA) patches as they can significantly affect the mechanical, adhesive and drug release characteristics of the patches. Eudragit® E (EuE) is a methacrylate-based cationic copolymer capable of producing flexible and adhesive films for topical application. In this study, the effect of plasticizers on the mechanical, adhesive and 5-FU release characteristics of EuE-based patches was comprehensively evaluated. While the elongation at break (%) and adhesion of the films were significantly increased with increasing triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) concentrations, the tensile strength showed an inverse relationship. EuE plasticized with 40% triacetin, 30% DBS or 40% w/w TEC produced elastic and adhesive films most suitable for topical application. In vitro release studies of the 5-FU-loaded patches demonstrated an initial burst release pattern during the first 10 min followed by a slow release over 120 min. In summary, this study provides important information on effect of plasticizers for preparation of EuE-based patches with desired mechanical, adhesive and release characteristics of 5-FU towards their potential application in the treatment of NMSC.

Artificial neural network for modeling formulation and drug permeation of topical patches containing diclofenac sodium.

In this work, topical matrix patches of diclofenac sodium (DS) were formulated by the solvent casting method using different ratios of chitosan (CTS) and kappa carrageenan (KC). Propylene glycol and tween 80 were used as a plasticizer and permeation enhancer, respectively. The drug matrix film was cast on a polyvinyl alcohol backing membrane. All the patches were evaluated for their physicochemical characteristics (thickness, folding endurance, flatness, drug content, tensile strength, bioadhesion, moisture content, and moisture uptake), along with their in vitro release and in vitro skin permeation studies. Franz diffusion cells were used to conduct the in vitro permeation studies. The artificial neural network (ANN) model was applied to simultaneously predict the DS release and the ex vitro skin permeation kinetics. The formulated patches showed good physicochemical properties. Out of all the studied patches, F6 presented sustained permeation in 32 h and was selected as the best formulation. The ANN model accurately predicted both the kinetic release and the skin permeability of DS from each formulation. This performance was demonstrated by the obtained R2 = 0.9994 and R2 = 0.9798 for release and permeation kinetics modeling, respectively, with root mean square error (RMSE) = 3.46 × 10-5.

Safe-by-design development of a topical patch for drug delivery

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.