Tacrolimus and paclitaxel co-loaded O/O ointment without surfactant: Synergistic combinations for the treatment of psoriasis

Psoriasis is an immune-mediated inflammatory disease characterized by differentiation coupled with scaly, itchy, erythematous plaques [1]. This disease affects about 0.5–1 % of children and 2–3 % of the global population [2]. Due to psoriasis being hardly curable completely and likely to invade multiple organs during its late course, it is termed as immortal cancer with a tremendous negative impact on the patients’ quality of the life [3]. Disease etiology is multifactorial with a combination of environmental, microbial and complex cellular interactions triggering the induction and maintenance of psoriatic plaques [4]. Due to its multi-factorial etiology, a series of treatment options are provided. For instance, mild psoriasis is typically treated with topical therapy and moderate to severe psoriasis is usually treated with phototherapy and systemic immunosuppressive therapy but topical therapy in combination with these therapies may be more effective [5]. Systemic immunosuppressive therapy can be accompanied by severe adverse events. Therefore, to reduce the burden of drugs on healthy bodies, topical administration is usually adopted [6]. However, corticosteroids are used as the topical therapeutic agents in clinical practice commonly, which also have the risk of cutaneous atrophy and the rebound of psoriasis [7]. Accordingly, it is desirable to develop an effective topical treatment system for psoriasis.

Tacrolimus (TAC), a calcineurin inhibitor, acts on the signal transduction pathways inside T cells and inhibits gene transcription, leading to decrease the responsiveness of T cells to the antigens, which has proved effective in the clinical treatment of psoriasis [8], [9]. There has been a significant amount of research conducted by far not only clinical studies such as double-blind and open studies but also mechanisms of action [10], [11]. Essentially, tacrolimus not only inhibits the dephosphorylation of the transcription factor nuclear factor of activated T-cells by calcineurin, leading to suppress activity of the genes that code for IL-2 in the nucleus, but also causes decreased transcription and release of other T-cell-derived cytokines such as IL-3, IL-4, IL-8, TNF-α, INF-γ, and granulocyte–macrophage colony-stimulating factor [10]. It is commercially available as a topical ointment, and observational data from post marketing surveillance studies have shown no serious safety concerns, so there are reports that the current warning of the Japanese labeling or the boxed US FDA for tacrolimus is not appropriate based on available scientific evidence [12]. But the TAC ointment has been reported with low and highly variable absorption and doesn’t ensure adequate topical delivery of the drug into deeper skin layers [13].

Paclitaxel (PTX), a mitotic inhibitor, which induces tubulin polymerization and forms extremely stable and nonfunctional microtubules, leading to cell death eventually, is commonly adopted in certain cancer treatments to inhibit the proliferation of cancer cells [14]. Paclitaxel's unique mechanism of action to inhibit cell division could also address the hyperproliferative pathophysiologic process in psoriasis. To our knowledge, micellar paclitaxel can be applied to treat severe psoriasis and most important is reasonably well tolerated at the doses used in the study [15]. Despite the data indicating that it is effective as an injection administered systemically, adverse events such as fatigue, alopecia and infusion reactions also appear simultaneously [15]. To further reduce the risk of unpredictable adverse reactions after treatment, a skin-targeted formulation for topical treatment system needs to be developed. Kilfoyle et al. developed paclitaxel-TyroSphere, which proved paclitaxel skin-targeted topical delivery system was feasible [16].

Classically, synergy is defined as greater than the additive therapeutic effects compared with the therapeutic efficacy of each drug alone [17]. Now synergistic combinations are talking more about involving the use of two or more therapeutically relevant molecules, acting through different mechanisms to achieve and maintain the maximum therapeutic effect by providing a multi-target treatment approach [18]. Tacrolimus combined with paclitaxel have been used to enhance the therapeutic effect of drug-resistant ovarian cancer [19]. Therefore, we mainly use different mechanisms to achieve better psoriasis treatment effect. Ointment system has been used to co-deliver multiple drugs to their action site [20]. The oil-in-oil (O/O) ointment was widely used to develop a topical, skin-targeted preparation, in which a drug was dispersed or dissolved in an internal oil phase to form stable droplets [21]. O/O TAC ointment, trade name PROTOPIC®, is mainly used for non-immunocompromised patients with moderate to severe atopic dermatitis who are not immune compromised due to potential dangers and are not suitable for traditional therapy. O/O PTX ointment can improve skin thickening and inflammation in psoriasis mice [22]. O/O ointment has several advantages over other systems such as stability, low cost of reagent and ease of manufacture.

The current research work aimed at evaluating the potential of TAC and PTX coloaded ointment for the treatment of psoriasis. TAC induced calcineurin inhibition and the action of PTX on cell mitosis can provide a multi-target treatment approach to maximize therapeutic effect. The preparation without any surfactant possessed the feature of ease of application and slow release of the drug with less irritation. In vitro studies and in vivo studies were applied to optimize formulations and the anti-psoriatic efficacy has been evaluated using the imiquimod (IMQ) induced psoriatic plaque model. This study reports the novel combination of TAC and PTX coloaded ointment for the treatment of psoriasis for the first time.

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