The transdermal drug delivery system offers several advantages, such as avoiding first-pass metabolism effects, preventing gastrointestinal irritation, maintaining constant drug concentration levels in the plasma, and, in some cases, increasing bioavailability. Non-invasive formulation approaches can enhance patient compliance for long-term treatment against inflammation. The skin barrier plays a crucial role in the transdermal delivery of drugs across the skin. Additionally, developing a transdermal formulation can impact the physicochemical properties of the active pharmaceutical ingredient. Various formulation strategies for transdermal drug delivery systems can be employed to enhance bioavailability, including the use of drug release or permeation enhancers [[1], [2], [3]], microneedles [[4], [5], [6]], or nanoparticle technology [7,8]. Among these strategies, the use of permeation enhancers is a preferred option for improving drug permeation through the cutaneous barrier.

Cannabis sativa has been utilized for centuries, serving multiple purposes, including its use as an active pharmaceutical ingredient in folk medicine, as a psychoactive substance in religious ceremonies or for recreational purposes, and as a source of textile fiber [9]. The plant's major active pharmaceutical ingredients are cannabinoids, known for their anti-inflammatory, neuroprotective, anxiolytic, and antipsychotic properties [9]. The primary cannabinoids found in the fiber-type plant are cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). CBDA and THCA have previously been studied for their antitumor effects [10,11], anti-inflammatory properties [[12], [13], [14]], and analgesic effects [15]. Therefore, cannabinoid-loaded transdermal patches (CLTPs) may offer an alternative approach for localized anti-inflammatory and pain relief treatments.

The transdermal delivery of cannabinoids presents a promising frontier in medicinal therapeutics, leveraging the systemic benefits while mitigating the gastrointestinal and first-pass metabolism challenges associated with oral administration [16]. Particularly, Cannabis sativa plant material, characterized by its higher concentrations of non-psychoactive cannabinoids such as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA), provides a compelling alternative to the hot processed and decarboxylated extracts containing cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Furthermore, plant varieties are nowadays cultivated which have much higher cannabinoid content [17]. The cold extraction of cannabis is necessitated by the distinct therapeutic profiles of these acidic cannabinoids, which exhibit reduced psychoactivity compared to their decarboxylated counterparts, thereby offering significant advantages for patients requiring long-term treatments without cognitive impairments [18,19].

However, the utilization of cannabis plant material is accompanied by several limitations when extracted conventionally. Concerns regarding the stability of cannabinoid acids, which are prone to decarboxylation, highlight the necessity for meticulous control throughout the extraction and formulation processes. Such control is critical to maintain the therapeutic efficacy and safety profile of the cannabinoids [20,21]. It is essential to establish standardization protocols that ensure the integrity and consistency of the active pharmaceutical ingredients derived from these cannabinoids [22,23]. Additionally, the chemical composition of Cannabis sativa L. aerial parts has been shown to be consistent across different growth stages, suggesting that harvesting prior to the flowering stage could contribute to the standardization of the source material [24]. The variability in the phytochemical profile of the source material can significantly affect the reproducibility and efficacy of the final cannabis-derived medicinal product. In fact, this study used standardized extracts, of CBDA, and THCA, as model drugs.

This study aimed to develop CLTPs and characterize their physicochemical properties and in vitro performance, including stability and release profile. Matrix-type transdermal patches for the cannabinoids were prepared using acrylic adhesives, and various types of release enhancers were screened and optimized for the cannabinoids. Subsequently, the physicochemical and mechanical properties of optimized CLTPs were investigated.