Proteus mirabilis is a major uropathogen implicated in catheter-associated urinary tract infections and infection-induced urolithiasis, often exhibiting multidrug resistance. Improving the solubility and bioactivity of existing drugs represents a promising pharmaceutical strategy to overcome these challenges. In this study, inclusion complexes of metronidazole with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared using physical mixing and kneading methods. Complexes were characterized using differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). In vitro release behaviour, minimum inhibitory concentration (MIC), and effects at sub-MIC levels on motility, urease-associated phenotype, and biofilm formation were evaluated. β-CD and HP-β-CD systems demonstrated improved release profiles compared to metronidazole alone. While MIC values remained within the mg/mL range, HP-β-CD complexes showed reduced MIC relative to aqueous metronidazole, achieving a four-fold reduction in MIC. At sub-MIC concentrations, β-CD and HP-β-CD formulations were associated with significant suppression of motility, reduced urease-associated phenotypes, and inhibition of biofilm formation. Molecular docking suggested spatial compatibility between metronidazole and cyclodextrins, though mechanistic conclusions remain predictive. These findings indicate that cyclodextrin-based complexation enhances physicochemical performance of metronidazole and may support adjunctive anti-virulence modulation in P. mirabilis. Further mechanistic and in-vivo studies are required to validate translational relevance.

ABSTRACT Ocular nonsteroidal anti‐inflammatory drugs (NSAIDs) are widely used as safer alternatives to corticosteroids for managing anterior segment inflammation and pain. By inhibiting cyclooxygenase (COX) enzymes and prostaglandin synthesis, NSAIDs effectively reduce post‐operative inflammation, allergic conjunctivitis, and intraoperative miosis during cataract surgery. Limited clinical evidence suggests benefits in preventing cystoid macular edema (CME), whereas experimental studies indicate potential therapeutic roles in retinal disorders such as diabetic retinopathy (DR), age‐related macular degeneration (AMD), and diabetic macular edema (DME) through anti‐angiogenic and neuroprotective mechanisms. Commonly used agents include diclofenac, indomethacin, ketorolac, bromfenac, flurbiprofen, and nepafenac, primarily formulated as topical ophthalmic solutions or suspensions. Compared to corticosteroids, NSAIDs do not raise intraocular pressure or induce cataracts, though mild adverse effects (such as burning, hyperemia, and keratitis) may occur; more severe complications like corneal melt are rare. This review provides a comprehensive analysis of NSAIDs in ophthalmology, covering their pharmacology, clinical applications, safety, delivery innovations, and future perspectives, including advanced formulations and emerging strategies to enhance their effectiveness in management of inflammatory ocular disorders.

Entecavir (Ent) is a first-line antiviral agent for chronic hepatitis B; however, its oral absorption is limited by poor intestinal permeability. In this study, bile salt-stabilized bilosomal vesicles were developed to enhance Ent oral delivery through improved gastrointestinal stability, intestinal permeation, and lymphatic transport. Ent-loaded bilosomes were prepared by thin-film hydration and optimized using a Box-Behnken design. A bile-salt-free vesicular formulation (niosomes, Nio(Ent)) was included as a comparative control to elucidate the role of membrane-incorporated bile salts. The optimized formulation (Bil(Ent-Opt)) exhibited nanoscale size (similar to 123 nm), narrow size distribution, high entrapment efficiency (>84%), and excellent stability under simulated gastrointestinal and bile-acid conditions, with minimal drug release in gastric media compared with Nio(Ent). Cellular studies in Caco-2/HT29-MTX co-cultures indicated enhanced uptake via clathrin-dominant and lipid raft-assisted endocytosis, while ex vivo studies demonstrated significantly increased permeability compared with Ent solution and Nio(Ent). In vivo pharmacokinetic evaluation revealed markedly improved systemic exposure, with approximately 7.4-fold higher plasma AUC and similar to 3.3-fold higher C-max compared with the solution, and similar to 2.2-fold higher AUC than Nio(Ent), along with prolonged residence time. In mesenteric lymph, Bil(Ent-Opt) showed substantially higher exposure (similar to 15-fold vs solution and >3-fold vs Nio(Ent)). The lymph-to-plasma concentration ratio indicated preferential lymphatic accumulation at later time points. Overall, bilosomal vesicles enhance gastrointestinal stability, intestinal permeation, and lymphatic exposure, resulting in significantly improved oral delivery of Ent and highlighting their potential for permeability-limited drugs.

Background and Objectives: Ovarian cancer is a highly lethal gynecological malignancy and the fifth leading cause of cancer-related deaths. Diagnosis mainly involves gynecological examination and transvaginal ultrasonography. To evaluate the diagnostic performance of the Gynecology Imaging Reporting and Data System (GI-RADS) with regard to its ability to evaluate adnexal masses preoperatively, considering a definitive histopathological diagnosis. Materials and Methods: This study was approved by the ethics committee, and informed consent was obtained from all the patients. This research was conducted at Beni-suef University Hospital between June 2021 and January 2023 on 100 women who experienced pelvic pain due to an adnexal mass. Results: Our study results revealed that the combination of IV-V GI-RADS had high specificity (92.2%), sensitivity (87%), and a negative predictive value (95.9%), but moderate other diagnostic characteristics for predicting adnexal mass malignancy. Conclusions: The GI-RADS classification system is a reliable method for reporting ovarian masses, with high diagnostic accuracy for predicting malignancy. It aids in patient triage and clinical decision making. To optimize care, it is essential to inform referring clinicians about the objectives of the GI-RADS before its implementation in a treatment plan.

Zaleplon (ZLP) is a commonly used sedative-hypnotic drug that has low oral bioavailability because of its poor water solubility and extensive hepatic metabolism. This study aimed to encapsulate ZLP into spanlastic nanovesicles to enhance its bioavailability via transdermal delivery. Using Span 60 and Tween 80, ZLP-loaded spanlastics were fabricated using thin film hydration technique according to 32 full factorial design. In the applied design, the influence of formulation variables on vesicle size, entrapment efficiency, and cumulative drug amount released over 24 h was investigated, leading to the identification of the optimal formulation. The optimized spanlastics were nanosized, spherical vesicles measuring 297.2 ± 8.17 nm, with an encapsulation efficiency of 65.75 ± 3.28% and a 24-hour drug release rate of 76.44 ± 5.66%. FT-IR studies revealed no significant chemical interactions between ZLP and the excipients used. HPMC K100M transdermal patches loaded with the optimized ZLP-spanlastics were formulated utilizing solvent casting technique. The patches were smooth and elastic with uniform drug content, ranging from 92.65 ± 2.54 to 96.12 ± 1.57%. The steady-state flux (Jss) of the spanlastic transdermal patch (ZLP-SP1) across rabbit skin was over 3.62 times higher than that of the control transdermal patch, indicating a significant enhancement in drug permeation. The investigated transdermal patches were stable under accelerated conditions with non-irritating properties. The in-vivo studies have shown that the pharmacokinetic parameters of ZLP oral suspension and ZLP-SP1 are significantly different, with the relative bioavailability of ZLP-SP1 being 2.681%. Therefore, these fabricated transdermal patches could be effectively used to treat insomnia.

Background/Objectives: With advancements in biomaterial sciences, biofunctional excipients have emerged to focus on solving issues with the drugs’ inherent biopharmaceutical characteristics such as poor solubility, permeability, in vivo dissolution, and effective targeting. These advanced excipients significantly impact drug solubility, dissolution rates, absorption rates, permeation rates, penetration ability, targeting ability, and pharmacokinetic profiles. Methods: A literature review of recently published articles was prepared. Data were collected using scientific search engines. This review provided a detailed discussion of various biofunctional excipients including smart polymers, targeted polymers, bioadhesive polymers, lipids, amino acids, cyclodextrins, and biosurfactants. Each category was discussed in detail concerning its biofunctional applications, the mechanisms underlying these biofunctions, and examples of their effects on drug performance. Results: The data obtained indicated that the rapid advances in the manufacturing of pharmaceutical excipients have resulted in the development of a diverse array of smart or intelligent excipients that play a crucial role in enhancing inherent poor biopharmaceutical characteristics. Conclusions: These advancements have also facilitated the development of various drug delivery systems, including immediate, controlled, sustained, and targeted drug release systems. Also, numerous nano-based delivery systems have emerged utilizing the newly produced excipients.

Bone metastasis is commonly observed in cancer patients, necessitating high-dose chemotherapy for effective treatment. Repurposing mebendazole (Meb) has shown promise in inhibiting cancer progression. To overcome its poor solubility and enhance tumor targeting, nanocrystals were employed as a delivery platform. The current work aimed to develop optimized Meb nanocrystals with improved bone metastasis therapeutic potential via passive targeting. Optimization was achieved through high shear homogenization and stabilizer selection (HPMC E15) to produce nanocrystals with enhanced colloidal stability and size uniformity. In vitro characterization and in-vivo assessment were conducted to compare the selected optimized formulation with the Meb solution. Two Meb nanocrystal formulations, homogenized (NC4) and unhomogenized (NC*), were compared to determine the importance of particle size reduction. The results revealed that NC4, prepared using anti-solvent precipitation combined with high shear homogenization, exhibited a promising particle size (121.20 ± 6.20 nm) and higher drug release in the acidic pH, favorable for passive targeting. The in vivo results confirmed the superior effects on tumor growth inhibition (90.01%), pain remission, and bone tumor markers of NC4 over NC*. NC4 showed an absence of kidney and liver toxicity. In conclusion, these comprehensive findings strongly support the clinical relevance of NC4 in treating bone metastasis. Its ability to passively target the drug, inhibit tumor growth, alleviate pain, and exhibit favorable biomarker profiles and safety make it a promising candidate for improving the management and outcomes of patients with bone metastasis.

With advancements in drug repurposing, the search for effective and less harmful anticancer agents remains a critical endeavor. Raloxifene, although not a typical anticancer drug, holds promise in this context. However, its poor solubility poses a significant challenge to its therapeutic potential and formulation efficiency. Functional excipients such as cyclodextrins (e.g., β-cyclodextrin, hydroxy propyl β-cyclodextrin, and Captisol) and pH-modifying excipients (e.g., tartaric acid, azelaic acid, and arginine) were investigated to enhance solubility, dissolution, cytotoxicity and cellular uptakes employing Caco-2 cell lines through binary solid dispersions. In silico studies suggested the potential for salt formation with raloxifene-azelaic acid and raloxifene-tartaric acid, as well as inclusion complexes with cyclodextrins. Experimental results showed that pH-modifying excipients, particularly tartaric and azelaic acids, significantly improved solubility (up to an 800-fold increase), outperforming cyclodextrins (8-fold increase) compared to the untreated drug. Cytotoxicity studies on the human breast cancer (Michigan cancer foundation, MCF-7) cells revealed that raloxifene-tartaric acid significantly enhanced cell killing, achieving efficacy comparable to the standard anticancer drug Taxol. Additionally, both fluorescence-labeled raloxifene: hydroxy propyl β-cyclodextrin coprecipitated mixtures (Coppt) and raloxifene: tartaric acid Coppt exhibited concentration- and time-dependent cellular uptake, with mean fluorescence intensity increasing significantly at 24 h, indicating rapid internalization and sustained intracellular retention, especially at higher concentrations. More interestingly, the superior cellular uptake was in favor of the latter, indicating the pH-modifying excipient tartaric acid, and these findings correlated well with solubility and dissolution studies.

For many decades, conventional pharmaceutical excipients have been used to optimize the palatability, processing ability, flowability, and compressibility of various types of medication throughout the production process [...]

With increasing longevity globally, the search for effective and patient-friendly anti-aging solutions has been growing. Retinoic acid (Ret) is an FDA-approved anti-aging and anti-wrinkling formula, however, its poor solubility and poor tolerability hamper its use in cosmetically accepted formulations. In this study, cyclodextrins and arginine were investigated for improving the solubility and tolerability of retinoic acid through the formation of inclusion complexes and salt formation, respectively. Two different methods were employed: physical mixing and kneading. The prepared dispersions were investigated for molecular docking (MD), solubility, thermal and spectral analyses, cytotoxicity, and scratch assays. The optimized disperse systems were formulated in a gel formulation and characterized for rheological, in vitro release, and kinetics. The MD, DSC, and FTIR results indicated that both β- and hydroxy propyl (HP) β-cyclodextrins could host RA in their cavities and form inclusion complexes. Ret can form a salt with the basic amino acid arginine. Solubility studies of RA significantly (p < 0.01) enhanced by 14- to 81-fold increases with the investigated cyclodextrins and arginine. The cell viability recorded for Ret:HP β-CD K and Ret:arginine K was significantly increased compared to that for Ret alone. The IC50% recorded for azelaic acid (mild to non-irritant control), Ret, Ret:HP β-CD K, and Ret:arginine K were 1000, 485, 1100, and 895 µg/mL, respectively. The two carriers (HP β-CD and the amino acid arginine) were able to significantly (p < 0.05) reduce the irritation potential of Ret. Furthermore, comparable gap closure rates were recorded for Ret alone, Ret:HP β-CD K, and Ret:arginine K, indicating that inclusion complexation and ion pair formation reduced the irritation potentials without undermining the efficacy.

Simvastatin (SVA) is a well-prescribed drug for treating cardiovascular and hypercholesterolemia. Due to the extensive hepatic first-pass metabolism and poor solubility, its oral bioavailability is 5%. Solid lipid nanoparticles (SLNs) and hydrogel-coated SLNs were investigated to overcome the limited bioavailability of SVA. Four different lipids used alone or in combination with two stabilizers were employed to generate 13 SLNs. Two concentrations of chitosan (CS) and alginate (AL) were coating materials. SLNs were studied for particle size, zeta potential, in vitro release, rheology, and bioavailability. The viscosities of both the bare and coated SLNs exhibited shear-thinning behavior. The viscosity of F11 (Chitosan 1%) at 20 and 40 rpm were 424 and 168 cp, respectively. F11 had a particle size of 260.1 ± 3.72 nm with a higher release; the particle size of F11-CS at 1% was 524.3 ± 80.31 nm. In vivo studies illustrated that F11 had the highest plasma concentration when compared with the SVA suspension and coated chitosan (F11 (Chitosan 1%)). Greater bioavailability is measured as (AUC0→24), as compared to uncoated ones. The AUC for F11, F11-CS 1%, and the SVA suspension were 1880.4, 3562.18, and 272 ng·h/mL, respectively. Both bare and coated SLNs exhibited a significantly higher relative bioavailability when compared to that from the control SVA.

Caffeine (CAF) is a non-selective adenosine A1 receptor antagonist which predominates in fat cells. When CAF binds to adenosine receptors, it increases cyclic adenosine monophosphate; inhibiting adipogenesis and inducing fat lipolysis. Resveratrol (RSV) is an antioxidant polyphenol possessing different anti-obesity mechanisms. Topical application of both hydrophilic CAF and lipophilic RSV is limited. This study aimed to develop novel caffeinated-resveratrol bilosomes (CRB) and caffeine-bilosomes (CB) that could non-invasively target and deposit in fat cells. RSV bilosomes (RB) were prepared as a non-targeted system for comparison. CRB showed nanosize (364.1 nm +/- 6.5 nm) and high entrapment for both active compounds. Rats treated topically with CRB revealed a significant decrease (P = 0.039) in body weight. Histological analysis of the excised skin demonstrated a reduction in the subcutaneous fatty layer thickness and a decrease in the size of connective tissue-imbedded fat cells. Kidney histological examination of RB-treated rats showed subcapsular tubular epithelial cells with cytoplasmic vacuolation. This reflects a systemic effect of RSV from the non-targeted RB compared to CRB, which had a targeting effect on the adipose tissue. In conclusion, CAF in CRB significantly enhanced RSV deposition in adipose tissue and assisted its local-acting effect for managing obesity and cellulite.

Simvastatin (SMV) is a well-known antihyperlipidemic drug that has demonstrated wound healing effects. However, its clinical application is hindered by poor solubility. Therefore, the objective of this study was to enhance the solubility of simvastatin by utilizing various concentrations of solvents and co-solvents for formulation in selected topical dosage forms. Mixed-solvent systems, namely Buffer-methanol, Buffer-ethanol, and Buffer-dmso, were employed. Additionally, the impact of different polymer concentrations, including carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), and chitosan (CHT), on drug solubility was investigated.The solubility profile of SMV in 2% w/v polymeric solutions (CMC, HPMC, and CHT) was found to be 73.5, 62.1, and 59.6 µg/ml, respectively. Notably, the use of a 2% w/v chitosan solution resulted in a remarkable 50-fold increase (73.5 µg/ml) in SMV dissolution compared to its aqueous solubility (1.45 µg/ml). This significant enhancement allows for the incorporation of large amounts of the drug in formulations.Our findings indicate that the Chitosan system with ethanol exhibited the highest solubilization effect and demonstrated the necessary characteristics for the preparation and handling of wound dressing films. This suggests a promising approach for the development of topical formulations with improved solubility and potential therapeutic benefits of simvastatin.

Background: Poor solubility and dissolution rate of drugs are largely responsible for erratic drug absorption and limited oral bioavailability. Etodolac (ETO) is a non-steroidal anti-inflammatory drug (NSAID) that is classified as BCS class II (dissolution rate-dependent absorption). ETO has high safety and efficacy in pain relief and control of inflammation. ETO is commercially available as (400- 600 mg) tablets; poor solubility and dissolution rate of ETO could result in variable oral absorption and inconsistent analgesic responses. The aim of this study was to improve solubility and dissolution rates of ETO by complexation with cyclodextrins (CDs). Methods: Four different CDs namely β-, γ-, HP β-CDs, and HP γ-CDs were prepared using three different methods; solvent evaporation (CO), freeze-drying (FD), and physical mixing (PM). The prepared drug: excipient mixtures were investigated for aqueous solubility, as well as via DSC, XRD, FTIR, SEM, dissolution, and docking. Results: The results revealed a solubility phase diagram of the AL type, indicating a 1:1 complexation of ETO: CD. These results agreed with our molecular docking calculations. DSC, FTIR, XRD, and SEM results confirmed the formation of an inclusion complex. The complexation efficiency, solubility, and dissolution enhancement were in the order of HPγ-CD > γ-CD > HPβ-CD > β-CD. FD method was superior to both CO and PM. Conclusion: Superior dissolution enhancements of ETO were recorded for the FD mixture (up to 90% dissolved in less than 10 min). In conclusion, γ- and hydroxypropyl γ-derivative of cyclodextrins can be considered a promising excipient for enhancement of dissolution rates concerned for ETO.

Amino acids have attracted attention as a potential functional excipient for optimizing biopharmaceutics characteristics of poorly soluble drugs. The amino acids are a diverse class with many functional groups, natural compounds, biocompatible, and low-molecular-weight substances. Two amino acids serine and arginine were investigated with meloxicam. Meloxicam has extremely low solubility; being NSAIDs, gastric upset, and ulcer are common side effects. Solid dispersions were produced by precipitation and physical mixing techniques. The produced combinations underwent in vitro dissolution, docking, DSC, FTIR, XRD, solubility, and gastric ulcer formation studies. Docking indicated ion pair/salt formation between the basic amino acid arginine and meloxicam. Both solubility and dissolution rates were increased by up to 3000-fold and 12-fold, respectively. DSC, FTIR an XRD supported these findings. Rats treated with meloxicam showed loss of surface gastric epithelium integrity and ulceration. The animal group received meloxicam: arginine showed intact gastric mucosa with the surface epithelium and gastric glands well organized and nearly similar to the untreated control. Arginine with the guanidine group that was capable of preserving gastric mucosa after repeated administration for 10 days. This study highlighted the role of arginine as a functional excipient that did not only improve solubility and dissolution rates but ameliorated the long-standing gastric side effects attributed to meloxicam.

INTRODUCTION:Breast cancer is one of the main causes of mortality in women globally. Early and accurate diagnosis represents a milestone in cancer management. Several breast cancer diagnostic agents are available. Many chemotherapeutic agents in conventional dosage forms are approved; nevertheless, they lack cancer cell specificity, resulting in improper treatment and undesirable side effects. Recently, nanotheranostics has emerged as a new paradigm to achieve safe and effective cancer diagnosis and management. AREA COVERED:This review provides insight into breast cancer epidemiology, barriers hindering the early diagnosis, and effective delivery of chemotherapeutics. Also, conventional diagnostic agents and recent nanotheranostic platforms have been used in breast cancer. In addition, mechanisms of cancer cell targeting and nano-carrier surface functionalization as an effective approach for chemotherapeutic targeting were reviewed along with future perspectives. EXPERT OPINION:We proposed that modified nano-carriers may provide an efficacious approach for breast cancer drug targeting. These nanotheranostics need more clinical evaluations to confirm their efficacy in cancer management. In addition, we recommend the use of artificial intelligence (AI) as a promising approach for early and efficient assessment of breast lesions. AI allows better interpretation and analysis of nanotheranostic data, which minimizes misdiagnosis and avoids the belated intervention of health care providers.

Chronic ocular diseases can seriously impact the eyes and could potentially result in blindness or serious vision loss. According to the most recent data from the WHO, there are more than 2 billion visually impaired people in the world. Therefore, it is pivotal to develop more sophisticated, long-acting drug delivery systems/devices to treat chronic eye conditions. This review covers several drug delivery nanocarriers that can control chronic eye disorders non-invasively. However, most of the developed nanocarriers are still in preclinical or clinical stages. Long-acting drug delivery systems, such as inserts and implants, constitute the majority of the clinically used methods for the treatment of chronic eye diseases due to their steady state release, persistent therapeutic activity, and ability to bypass most ocular barriers. However, implants are considered invasive drug delivery technologies, especially those that are nonbiodegradable. Furthermore, in vitro characterization approaches, although useful, are limited in mimicking or truly representing the in vivo environment. This review focuses on long-acting drug delivery systems (LADDS), particularly implantable drug delivery systems (IDDS), their formulation, methods of characterization, and clinical application for the treatment of eye diseases.

Innovative hybrid chitosan-sodium alginate (Ch-Ag) microparticles (MPs) were fabricated using both the ionic gelation method as well as the pre-gelation technique. The hybrid Ch-Ag MPs were studied for size, zeta potential, morphology, mucoadhesion, in-vitro release, corneal permeation, and ocular irritation using lens and corneal epithelial cell lines. The average particle size ranged from 1322 nm to 396 nm. The zeta potential for the prepared formulations showed an increase with increasing Ch concentrations up to a value of >35 mV; the polydispersity index (PDI) of some optimized MPs was around 0.1. Compared to drug-free MPs, ketorolac-loaded Ch-Ag MPs demonstrated a drug proportion-dependent increase in their size. SEM, as well as TEM of KT-loaded MPs, confirmed that the formed particles were quasi-spherical to elliptical in shape. The KT release from the MPs demonstrated a prolonged release profile in comparison to the control KT solution. Further, mucoadhesion studies with porcine mucin revealed that the KT-loaded MPs had effective mucoadhesive properties, and polymeric particles were stable in the presence of mucin. Corneal permeation was studied on bovine eyes, and the results revealed that Ch-based MPs were capable of showing more sustained KT release across the cornea compared with that for the control drug solution. Conclusively, the cytotoxicity assay confirmed that the investigated MPs were non-irritant and could confer protection from direct drug irritation of KT on the ocular surface. The MTT cytotoxicity assay confirmed that KT-loaded MPs showed acceptable and reasonable tolerability with both human lens and corneal epithelial cell lines compared to the control samples.

Oral phosphodiesterase inhibitors have emerged as a game changer for the treatment of erectile dysfunction (ED) since attaining FDA approval for its first member, sildenafil, in 1998. Topical penile therapy could be a viable replacement for oral medication that would transform the treatment of ED for many decades to come. This innovative idea could offer a safer topical alternative with less vision and cardiovascular side effects than the oral route. This work aims at developing proniosomal gels for three selected members (sildenafil, vardenafil, and tadalafil) and investigating the proniosomal gels on a rodent model. Niosomes derived from the parent proniosomal gels were characterized for entrapment efficiency (EE%), size, polydispersity index (PDI), zeta potential, and morphology. Proniosomal gels were evaluated for skin permeation, in vivo mating behaviors, and biochemical assays of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) post penile topical administrations. The optimized proniosomes loaded with tadalafil (F1-T) were compared with oral tablets (Cialis®). Proniosomal gels demonstrated significant enhancement of skin penetration by up to 5.5-fold, compared to control topical suspension. Tadalafil-loaded proniosomes showed superior skin permeability over sildenafil- and vardenafil-loaded proniosomes. In addition, significant improvement was noticed regarding intromission number, intromission ratio, NO, and cGMP for the proniosomal gel F1-T, compared to the untreated control. No statistically significant (p > 0.05) differences in sexual performance or biochemical parameters (NO and cGMP levels) were recorded among orally and topically (tadalafil proniosomal gel) administered groups. These findings support tadalafil topical penile therapy as a promising alternative to the oral route.