Current Pharmaceutical Design - Volume 32, Issue 14, 2026

Osteoporosis (OP) is a prevalent condition in postmenopausal women, marked by reduced bone density and an increased risk of fractures. Raloxifene (RLX), a selective estrogen receptor modulator (SERM), is the only drug approved for the management of OP in this patient population. RLX works by mimicking estrogen's effects on bone, reducing bone resorption and thereby increasing bone mineral density. However, despite its benefits, conventional oral RLX formulations have significant limitations. Its low bioavailability and poor aqueous solubility are compounded by extensive first-pass metabolism, which significantly reduces the drug's efficacy. Recent research has focused on nanocarriers for RLX to overcome these challenges, with lipid-based nanocarriers emerging as a promising approach to improve solubility, enhance absorption, and bypass first-pass metabolism via lymphatic uptake.

The authors gathered information about RLX from articles published up to 2025 and listed in PubMed, Web of Science, Elsevier, Google Scholar, and similar databases. The keywords used in our search included “Osteoporosis” “Raloxifene” “nanocarriers” etc.

The review of existing literature reveals substantial progress in developing innovative drug delivery systems for RLX, aimed at overcoming the limitations of conventional oral dosage forms in the treatment of OP and cancer. Several studies underscore the potential of novel formulations, including lipid-based nanocarriers, to improve raloxifene's pharmacokinetic profile, particularly through enhanced solubility, dissolution rate, and bioavailability.

The nanocarriers mediated raloxifene delivery represent promising strategies to enhance its bioavailability and therapeutic efficacy in osteoporosis treatment. By improving solubility and bypassing first-pass metabolism, these novel systems can potentially reduce dose-related side effects, offering safer and more effective long-term options for postmenopausal women with osteoporosis. This approach supports the continued exploration of both oral and non-oral delivery methods to overcome the limitations of conventional raloxifene formulations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most effective treatments for type 2 diabetes mellitus (T2DM). GLP-1 RAs stimulate pancreatic receptors, improving glycemia by boosting insulin secretion while decreasing glucagon secretion. GLP-1 receptors are present in pancreatic tissue. They are also found in extra-pancreatic tissue and have been shown to reduce body weight while also protecting the heart and endothelial cells. The most prevalent types of GLP-1 RAs can be injected twice daily (exenatide), once daily (lixisenatide and liraglutide), or once weekly (albiglutide, dulaglutide, exenatide once, semaglutide, tirzepatide). GLP-1 receptor agonists also reduce gastric emptying, preventing substantial post-meal glycaemic increases. Many publications have been written regarding GLP-1 RAs, covering various features of this family. However, the purpose of this study is to investigate the pharmacological design models and pharmacokinetic characteristics of the most regularly used members of this class, as well as to highlight contemporary developments in GLP-1 RAs. It also describes the physicochemical features, techniques of manufacture, the effects of molecular structure, and structural modifications on pharmacological activity.

The literature review was completed using a structured approach to identify and integrate relevant literature. It involved a broad search of reputable medical databases using inclusion and exclusion criteria.

They are classified as short-acting or long-acting based on the length of their action. Short-acting GLP-1 RAs and long-acting GLP-1 RAs have differing efficacy profiles. Furthermore, the methods of administration, mode of action, and side effects of these medications are relevant to their pharmacological design and pharmacokinetic properties.

The treatment of type 2 diabetes and obesity has evolved with the advent of GLP-1 RAs. These drugs have a multifaceted approach, emphasizing glycemic regulation, weight loss, and reduction of cardiovascular risk. Their unique mode of action, strong safety profile, and ability to be individualized according to each patient's needs make them a valuable therapeutic option in the management of metabolic disorders. Their pharmacological activities are also influenced by their different structural and pharmacokinetic properties.

GLP-1 RAs have a complex strategy due to their pharmacological nature. The variations in their design have led to various members with varying pharmacodynamic and pharmacokinetic features.

Canagliflozin hemihydrate (CANA), an antidiabetic drug that functions as a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is classified under the Biopharmaceutical Classification System (BCS) as a Class IV drug, characterized by low solubility and low permeability. This study aimed to enhance the solubility, dissolution, and permeability of CANA by preparing its inclusion complexes with α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD), followed by characterization of their crystalline and biopharmaceutical properties.

The solubility of CANA in aqueous medium and phase solubility with α and β-cyclodextrin were conducted. The inclusion complexes in different CANA: α-CD ratios (1:0.25 to 1:6 mM) and CANA: β-CD ratios (1:0.50 to 1:8 mM) were prepared using the freeze-drying method. The complexes were subjected to drug content analysis, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD), angle-dispersive X-ray diffraction (ADXRD), in vitro dissolution, and permeation studies.

Phase solubility study indicated significant improvements in aqueous solubility of CANA with α-CD and β-CD. The solubility of CANA increased significantly (more than 100-fold in BCD8 with 0.577 mg/mL) upon complexation. BCD8 (1:7) with 97.366% and ACD6 (1:4) with 94.6% showed the highest % drug content. FTIR confirmed interactions between CANA and CDs due to the disappearance or shifting of some characteristic peaks (e.g., 3390.68 to 3268.91 cm^-1 and 1078.07 to 1024.06 cm^-1 in ACD6, while 3265.05 to 3268.91 cm⁻¹ and 1025.99 to 1024.06 cm⁻¹ in ACD7).

XRPD and ADXRD showed the crystalline nature of CANA and CDs, while the complexes exhibited amorphization with diffused peaks. The lowest crystallite size was observed in ACD6 (449.688) and the highest in ACD3 (966.936 Å). D-spacing was found to be smallest in ACD8 (0.722 Å) and BCD6 (4.080 Å), and the highest in ACD1 (7.276 Å), BCD7, and BCD8 (7.063 Å). The drug release ranged from 64.265% (ACD3) to 94.306% (BCD7) and increased with lower crystallinity. ACD8 (87.33%) and BCD7 (93.41%) exhibited the highest % of drug permeability.

Inclusion complexation with α-CD and β-CD significantly improved the solubility and dissolution of CANA in aqueous medium. These findings suggest that cyclodextrin-based inclusion complexes offer a promising approach to enhancing the biopharmaceutical performance of poorly soluble drugs, such as CANA.

Cholesterol is considered a major factor contributing to cardiovascular diseases. Statins, the most commonly prescribed cholesterol-lowering drugs, are known to have various limitations. Inhibition of Adenosine Triphosphate-Citrate Lyase (ACLY) has been proposed as an alternative therapeutic strategy for managing hypercholesterolemia by lowering cholesterol levels. This has led to the discovery of a cell-permeable small molecule ACLY inhibitor.

ACLY enzyme activity was assessed using an ACLY Assay Kit with the ADP-Glo Kinase Assay Kit. HepG2 cells were treated with test compounds to demonstrate cholesterol and fatty acid synthesis. Pharmacokinetic studies were performed on CD-1 mice following a single oral dose of the compounds. Hypercholesterolemia was induced in mice through a High-Fat and High Cholesterol Diet (HFHCD), and drugs were administered orally for six weeks. Serum and hepatic lipid profiles were subsequently analyzed.

To increase the pharmacochemical properties, four analogues of BMS-303141, ID0018, ID0023, ID0085, and ID0106, were designed and synthesized. These compounds showed superior ACLY inhibitory activity and dose-dependent suppression of cholesterol and fatty acid synthesis in HepG2 cells. Among the analogues, ID0085 exhibited the most potent ACLY inhibition (IC50: 45 nM, 10-fold lower than BMS-303141) and achieved near-complete suppression in cholesterol and fatty acid synthesis at the highest concentration. Pharmacokinetic studies revealed improved half-lives and systemic exposures for all analogues. In hypercholesterolemic mouse models, test compounds significantly reduced serum total cholesterol (32.0-57.3%) and low-density lipoprotein cholesterol (67.5-80.2%) levels compared to the vehicle group. Notably, ID0085 also increased high-density lipoprotein cholesterol levels.

Among the synthesized analogues, ID0085 exhibited the most potent ACLY inhibition, superior pharmacokinetic properties, and significant improvements in both serum and hepatic cholesterol profiles compared to BMS-303141.

Based on the results, ID0085 appears to be the most promising therapeutic candidate for the treatment of hypercholesterolemia.