3D printed sex-specific medicines: Excipient-mediated modulation boosts systemic drug exposure by more than three-fold in male rats

Abstract

Excipients, historically regarded as inert, are now being recognised for their ability to actively modulate biological targets, including intestinal efflux transporters such as P-glycoprotein (P-gp). We have previously shown that polyethylene glycol (PEG) excipients can selectively enhance the oral bioavailability of P-gp substrate drugs, particularly in males. This study examined how 3D printed formulations containing PEG 2000 influence the pharmacokinetics of silodosin, a P-gp substrate drug used for the treatment of benign prostatic hyperplasia in ageing men, using male and female Wistar rats. Initial concentration screening studies with aqueous solutions revealed that a 1 % w/v PEG 2000 concentration (corresponding to 5 mg) maximally increased silodosin systemic exposure by 36 % compared to the control in males, with no significant effect in females, confirming sex-specific pharmacokinetic modulation. To exploit this unique phenomenon, 5 mg of PEG 2000 was incorporated as a functional excipient into silodosin-loaded printlets (3D printed tablets) fabricated via direct powder extrusion. The printlets achieved complete drug release within 70 min, exhibiting highly similar dissolution profiles between test and control formulations (f₂ = 88.6). In vivo pharmacokinetic studies revealed that printlets containing PEG 2000 resulted in a 213 % increase in plasma exposure in males relative to the control, while no significant enhancement was observed in females. By integrating biological variables such as sex into formulation design and leveraging the promising potential of 3D printing, this study demonstrates for the first time how excipient functionality can be harnessed to develop sex-specific oral therapies and advance personalised oral drug delivery. These findings pave the way for the future clinical translation of sex- and excipient-driven therapeutic approaches.

Introduction

Excipients, as defined by the US Food and Drug Administration (FDA) are “any component of a drug product other than an active ingredient” [1]. They constitute the majority of commonly prescribed oral formulations, accounting for approximately 71 % of their total mass [2]. Excipients were traditionally considered pharmacologically inert; however, growing evidence has revealed that they can actively modulate biological targets and alter drug pharmacokinetics (PK) [[3], [4], [5], [6]]. Clinical studies have demonstrated that certain solubilising excipients, particularly polyethylene glycol (PEG) 400, can markedly enhance the oral bioavailability of P-glycoprotein (P-gp) substrate drugs such as ranitidine and cimetidine [7,8]. Interestingly, this enhancement was observed only in male but not female human subjects.

To further elucidate this phenomenon, a Wistar rat model was established, which successfully reflected the sex-specific effects observed in humans [9]. PEG 400 increased the oral absorption of P-gp substrate drugs, such as ranitidine and ampicillin in male rats, but showed no effect in females or on non-P-gp substrates like metformin [10]. This sex-dependent modulation is not unique to PEG 400 but extends to other polyoxyethylated excipients, including PEG 2000, Cremophor RH 40, Poloxamer 188, and Tween 80, all of which have substantially enhanced drug absorption in male rats [11]. P-gp expression levels in male and female Wistar rats also strongly correlate with those in humans [12], confirming their suitability as a preclinical model for studying sex differences in drug absorption mediated by P-gp. Collectively, these findings highlight the role of excipient-transporter interactions in influencing drug bioavailability and underscore the importance of considering sex as a biological variable in the design and evaluation of oral drug formulations.

Silodosin is a Biopharmaceutics Classification System (BCS) Class III drug and an α1-adrenergic antagonist indicated for benign prostatic hyperplasia (BPH), a urological condition that is highly prevalent in ageing men [13,14]. It exhibits an oral bioavailability of only 32 %, primarily due to limited intestinal permeability and active efflux mediated by P-gp transporters [15,16]. Therefore, leveraging the sex-specific effects of excipients could be especially advantageous for drugs with P-gp-limited absorption and for male-specific indications. Among the aforementioned excipients that elicit sex differences, PEG 2000 is particularly attractive for solid oral dosage forms because its waxy solid state allows ready incorporation into solid matrices, further supporting its suitability for oral drug delivery.

Emerging pharmaceutical manufacturing technologies, particularly three-dimensional printing (3DP), offer a versatile platform for integrating tailored excipient-drug systems into solid dosage forms [[17], [18], [19]]. Among the commonly used material extrusion-based methods, direct powder extrusion (DPE) has gained attention as a single-step process that merges the principles of hot-melt extrusion (HME) and fused deposition modelling (FDM) [20]. DPE offers several advantages, including eliminating filament preparation, fabricating dosage forms in varying sizes and geometries, accommodating high drug loads directly from powder blends, and enabling precise control over drug release kinetics [[21], [22], [23], [24], [25], [26], [27], [28], [29]]. In addition, DPE has been reported to be suitable for point-of-care applications in clinical settings, offering improved quality control capabilities [30,31]. While DPE has shown promise in facilitating the development of personalised medicines for a range of patient populations, including paediatric patients and individuals with chronic and rare diseases, this capability may also extend to the formulation of sex-optimised oral therapies, an area that remains largely unexplored [[30], [31], [32], [33]].

We hypothesised that co-formulating silodosin with PEG 2000 would enhance its oral bioavailability. To study this, PK parameters of silodosin were evaluated following oral administration of both aqueous and solid formulations, with and without PEG 2000. Preliminary studies with aqueous solutions containing silodosin and varying concentrations of PEG 2000, along with a blank control, were conducted in Wistar rats. The PEG 2000 concentration that resulted in peak enhancement of silodosin absorption was selected for fabricating silodosin-loaded printlets (3D printed tablets), with (test) and without (control) PEG 2000, using DPE 3DP. Physicochemical characterisation was performed to determine printlet properties, including drug content and in vitro release profiles. This was followed by an in vivo PK study in male and female Wistar rats to investigate sex-related differences in silodosin absorption and systemic exposure.

Download the full article as PDF here 3D printed sex-specific medicines

or continue reading here

Materials

Eudragit® E PO (MW 150,000 g/mol) was obtained from Evonik Industries (Essen, Germany). PEG 2000 (MW 1800–2200 g/mol), talc (379.27 g/mol) and triethyl citrate (TEC, MW 276.28 g/mol, 99 %) were purchased from Sigma-Aldrich (Dorset, UK). Silodosin (MW 495.53 g/mol) was kindly gifted by Sun Pharmaceuticals Industries Limited (Gurugram, India). HPLC-grade water and acetonitrile (ACN, ≥99.9 % v/v, HPLC grade) were purchased from Fisher Scientific (Loughborough, UK). Potassium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid (5 M), and sodium hydroxide (1 N) were purchased from Thermo Fisher Scientific (Cheshire, UK).

Laxmi Prasanna Nandiraju, Patricija Januskaite, Siying Ruan, Yujia Qin, Iria Seoane-Viaño, Christine M. Madla, Keying Chen, Alvaro Goyanes, Yang Mai, Abdul W. Basit, 3D printed sex-specific medicines: Excipient-mediated modulation boosts systemic drug exposure by more than three-fold in male rats, Journal of Controlled Release, Volume 390, 2026, 114577, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2025.114577.

Read also our introduction article on 3D Printing here: