Design of colon-targeted drug delivery of dexamethasone: Formulation and in vitro characterization of solid dispersions

Colon-targeted drug delivery continues to generate increasing attention for its prospects in treating inflammatory bowel disease (IBD). This study aimed to develop and evaluate colon-targeted solid dispersions of dexamethasone (DEX-SDs) in vitro to reduce its systemic exposure. This would ultimately improve the therapeutic efficacy of DEX while minimizing its adverse effects. Different DEX-SDs formulations were prepared utilizing Eudragit S100 (EU S100) and a combination of hydroxypropyl methyl cellulose (HPMC) and EU S100 to tune its drug release profile suitable for colonic delivery. The fabricated formulations were extensively characterized via Attenuated Total Reflectance – Fourier Transform Infrared Spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and polarized light microscopy (PLM). The different characterization techniques strongly suggest preparing solid solution-type solid dispersions of DEX with the other polymers (DEX-SDs). In addition, the in vitro dissolution of DEX-SDs was evaluated using two dissolution media (pH 1.2 and 7.4). The in vitro release of DEX-SDs was low in the acidic media and higher and sustained in the basic medium, leading to the conclusion that the developed DEX-SDs may represent an effective technology can overcome challenges related to poor drug solubility and bioavailability.

Introduction

Chronic conditions, including Crohn’s disease and inflammatory bowel disease (IBD), are characterized by intestinal inflammation [1,2]. IBD prevalence in Western nations was 0.3 % in 2017, considered the highest prevalence. Additionally, it was shown that the prevalence of this condition is rising annually across the world [2,3]. IBD is currently treated with systemic drug delivery, which can result in side effects and decreased efficacy due to poor colonic drug exposure. To address these issues, there is a need to develop more efficient and targeted treatment approaches [4,5].

Several commercially available formulations that contain corticosteroids and immunomodulators have been used to treat IBD [6]. Corticosteroids (CSs) include cortisone, prednisone, budesonide, dexamethasone (DEX), and methylprednisolone used to treat IBD patients. They have a potent anti-inflammatory effect and are highly effective [7].

The purpose of the present study is to address the issues associated with the conventional delivery of DEX, particularly its limited bioavailability and adverse effects associated with systemic exposure. Dexamethasone (DEX) is a potent corticosteroid with an oral bioavailability of around 70 % [8]. The drug works by reducing inflammation in the digestive tract and suppressing the immune system. The drug is usually taken orally as tablets; the dose varies depending on the symptoms’ severity. DEX has extensive side effects such as acne and adrenal insufficiency; visual changes may occur due to steroid-induced hyperglycemia, osteoporosis, and high blood pressure [9]. In addition, DEX might cause immunosuppression. Since it inhibits T cell proliferation and differentiation by suppressing the CD28 co-stimulatory pathway [10].

Solid dispersions (SDs) are drug delivery systems that incorporate the drug into a polymeric carrier to improve its physical and biopharmaceutical properties [11,12]. One of well-known brand names for itraconazole and valsartan are Sporanox® and Entresto®, respectively, which are an example of approved medications that utilize solid dispersion (SD) technology. These approved formulations not only highlights how advanced pharmaceutical technologies can overcome challenges associated with poor solubility and bioavailability but also ensures more consistent therapeutic effects and better patient compliance [[13], [14], [15]].

In colon-targeted SDs, the drug is incorporated into a polymeric matrix along with a colon-specific targeting agent. Traditionally, solid dispersions could utilize either crystalline or amorphous polymeric matrices [16]. However, extensive studies confirmed that the ability of drugs to dissolve within crystalline polymeric carriers is restricted [[17], [18], [19]] and that the term “solid dispersions” has been recently more formalized to exclusively refer to systems in which the drug is maintained in an amorphous state within the carrier matrix [20,21]. Polyvinyl pyrrolidine (PVP), Eudragit S100 (EU S100), and hydroxymethyl cellulose-AS (HPMC-AS) are examples of amorphous polymeric carriers that are commonly employed in solid dispersions [17,19,[22], [23], [24]].

This study aims to develop and evaluate colon-targeted dexamethasone solid dispersions (DEX-SDs) in vitro to reduce systemic exposure and minimize DEX side effects. The DEX-SDs formulations were designed to resist degradation in the stomach and small intestine and release the drug in the colon only using a pH-sensitive polymer such as Eudragit S100 [25]. The addition of Eudragit® S 100 in the formulation offers many advantages due to its excellent biocompatibility and suitability for colon-targeted drug delivery applications. This approach aimed to increase the local concentration of DEX in the colon while reducing its systemic exposure, improving its therapeutic efficacy, and minimizing DEX adverse effects such as hormonal disturbances, weight gain, mood changes, and, in chronic cases, Cushing’s Syndrome [26,27]. However, there are also some challenges associated with the use of colon-targeted SDs. For instance, the stability of SDs over time and under different storage conditions is a cause of concern. It should be investigated thoroughly, particularly in situations where the SD formulation is only kinetically stabilized (via immobilization of the drug), as opposed to thermodynamically stabilized solid dispersions (systems in which the drug is molecularly dispersed and intimately bonded with the polymeric carrier) [28,29].

DEX-SDs were characterized for drug loading efficiency and yield, Fourier-transform infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Powder X-ray diffraction (PXRD), polarized light microscope (PLM), solubility, dissolution, and mechanism of drug release. The results of this study may have the potential to provide a new and effective treatment approach for IBD and enhance our understanding of the use of solid dispersions for targeted drug delivery.

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Materials

Dexamethasone (DEX) was kindly supplied by Angene Chemical (Nanjing, China). Eudragit S100 was obtained from Corel Pharma Chem. (Gujarat, India). HPMC was purchased from Sigma-Aldrich (Dorset, UK). Acetonitrile, methanol, and ethanol (HPLC grade) were obtained from Tedia (Fairfield, OH, USA). All other reagents and chemicals used in this research were of analytical grade.

Ahlam Zaid Alkilani, Sara Omar, Jehad Nasereddin, Rania Hamed, Rana Obeidat, Design of colon-targeted drug delivery of dexamethasone: Formulation and in vitro characterization of solid dispersions, Heliyon, Volume 10, Issue 14, 2024, e34212, ISSN 2405-8440, https://doi.org/10.1016/j.heliyon.2024.e34212.

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