International Journal of Pharmaceutics: X最新文献

Tacrolimus, a potent immunosuppressant, is widely used in several formulations to treat organ rejection in transplant patients. However, its physicochemical stability poses significant challenges, including thermal instability, photostability issues, low solubility, and drug-excipient incompatibility. This review article focuses on the details of these challenges and discusses the analytical methods employed to study tacrolimus stability, such as thermal, spectroscopic, and chromatographic methods in different formulations. New formulations to enhance tacrolimus stability are explored, including lipid-based nanocarriers, polymers, and thin film freezing. Researchers and formulators can optimize tacrolimus formulations to improve efficacy and patient outcomes by understanding and addressing these stability challenges.

Pain produces several physiological, and degenerative complications. This study aimed to formulate meloxicam (MLX) in liposomes to increase solubility and deliver MLX in a controlled manner to overcome its poor aqueous solubility and relatively short t_1/2 problems. Liposomes were prepared by thin film hydration followed by ultrasonication. Tests for characterizing formulations included particle size, span, entrapment efficiency, drug loading, stability, differential scanning calorimetry (DSC), Fourier transformation infrared (FT-IR) spectroscopy, morphology, in vitro release, release kinetics mathematical modeling, and an in vivo pain model in dogs undergoing orthopedic surgeries, followed by in vivo pharmacokinetics, pharmacodynamics, and pain assessment studies in comparison to the reference standard, Mobitil®. Liposomal MLX had a particle size of around 100 nm, 82 % entrapment efficiency, and 4.62 % drug loading. Stability studies, DSC, and FT-IR spectroscopy indicated that liposomes were highly stable. The formulation showed an improved in vitro controlled release pattern and an enhanced in vivo pharmacokinetic behavior as manifested by higher t_1/2 and AUC_0–24 and lower Cl/F in comparison to Mobitil®. The pharmacodynamics study and pain scales demonstrated liposomal MLX managed postoperative pain better than Mobitil®. In conclusion, the incorporation of MLX in liposomes increased its solubility and stability, as well as its pain management properties.

Nucleic acid-based therapeutics are a common approach that is increasingly popular for a wide spectrum of diseases. Lipid nanoparticles (LNPs) are promising delivery carriers that provide RNA stability, with strong transfection efficiency, favorable and tailorable pharmacokinetics, limited toxicity, and established translatability. In this review article, we describe the lipid-based delivery systems, focusing on lipid nanoparticles, the need of their use, provide a comprehensive analysis of each component, and highlight the advantages and disadvantages of the existing manufacturing processes. We further summarize the ongoing and completed clinical trials utilizing LNPs, indicating important aspects/questions worth of investigation, and analyze the future perspectives of this significant and promising therapeutic approach.

Bone metastasis remains a clinical challenge and is still considered incurable. While nanoparticles-based drug delivery and photothermal therapy (PTT) show promise in treating subcutaneous solid tumor, their therapeutic outcome in treating bone metastasis is limited, due to the inaccessibility of bone metastatic site and the complexity of bone metastasis. Herein, we reported a simple nanoplatform composed of thermo-sensitive liposomes (TSL) and gold nanorods (GNR) to treat bone metastasis through improved chemotherapy combined with GNR-assisted PTT. Lipid combination of TSL was firstly tailored to regulate its stability under physiological condition as well as its sensitivity in responding to PTT-caused mild hyperthermia. The obtained TSL with loaded drug was then combined with GNR to form the nanoplatform through unsophisticated incubation. Cell experiments revealed that upon near-infrared (NIR) irradiation, the nanoplatform effectively inhibited the viability and migration ability of tumor cells through PTT, PTT-triggered thermo-sensitive drug release, and PTT-augmented sensitivity of tumor cells to drug. In a murine model of bone metastasis, the nanoplatform enabled effective delivery of loaded drug and GNR to bone metastatic site for rapid drug release upon local NIR irradiation. Through killing tumor cells and rebalancing the turnover of osteoclasts and osteoblasts, the nanoplatform largely preserved bone structure for pain relief and survival extension. Inspired by the simplicity of nanoplatform acquirement and treatment operation, the strategy of liposomes-based thermo-sensitive drug delivery in combination with GNR-assisted PTT is considered greatly promising in treating bone metastasis.

Cancer is the leading cause of death globally, and conventional treatments have limited efficacy with severe side effects. The use of nanotechnology has the potential to reduce the side effects of drugs by creating efficient and controlled anticancer drug delivery systems. Nanoparticles (NPs) used as drug carriers offer several advantages, including enhanced drug protection, biodistribution, selectivity and, pharmacokinetics. Therefore, this review is devoted to various organic (lipid, polymeric) as well as inorganic nanoparticles based on different building units and providing a wide range of potent anticancer drug delivery systems. Within these nanoparticulate systems, chitosan (CS)-based NPs are discussed with particular emphasis due to the unique properties of CS and its derivatives including non-toxicity, biodegradability, mucoadhesivity, and tunable physico-chemical as well as biological properties allowing their alteration to specifically target cancer cells. In the context of streamlining the nanoparticulate drug delivery systems (DDS), innovative nanoplatform-based cancer therapy pathways involving passive and active targeting as well as stimuli-responsive DDS enhancing overall orthogonality of developed NP-DDS towards the target are included. The most up-to-date information on delivering anti-cancer drugs using modern dosage forms based on various nanoparticulate systems and, specifically, CSNPs, are summarised and evaluated concerning their benefits, limitations, and advanced applications.

RCC is a malignant tumor arising from the urothelium of renal parenchyma that remains challenging to be treated. In this study, we assessed the anti-tumor effects of Resveratrol liposomes (RES-lips) combined with sorafenib on renal cell carcinoma (RCC) and explored the potential mechanisms underlying the improvement of sorafenib resistance models. Tumor growth and survival following treatment with sorafenib alone or in combination with RES-lips was evaluated in a RCC xenograft mouse model. Flow cytometry results demonstrated that the combination of RES-lips and sorafenib significantly enhanced the G1/S phase arrest of sorafenib-resistant cells. When compared with the PBS or monotherapy groups, treatment with RES-lips combined with sorafenib exhibited significant inhibition of tumor growth in the RCC xenograft mouse model with tumor growth inhibition (TGI) rates and complete remission (CR) rates of 90.1 % and 50 %, respectively. Concersely, the maximum TGI rate was 53.6 % in the RES-lips monoherapy group and 29.2 % and in the sorafenib monotherapy group, and no animals achieved CR. Additionally, the current combination therapy promoted the proliferation of unactivated splenic lymphocytes and the proliferation of soybean protein A- and lipopolysaccharide-stimulated lymphocytes compared with PBS or monotherapy treatments. Further western blotting analysis suggested that RES-lips may enhance the resistance of RCC to sorafenib by inhibiting PI3K-AKT-mTOR and VHL-HIF signaling pathways, ultimately augmenting the tumor growth inhibition effect of the combination therapy. RES-lips may improve the sorafenib resistance in RCC, and the underlying mechanism may be related to the regulation of PI3K-AKT-mTOR and VHL-HIF signaling pathways.

The study explored stearylamine containing cationic elastic liposomes to improve topical delivery and efficacy of ketoconazole (KETO) to treat deeply seated fungal infections. Stearylamine was used for dual functionalities (electrostatic interaction and flexibility in lipid bilayer). Hansen solubility program (HSPiP) estimated Hansen solubility parameters (HSP) based on the SMILE file and structural properties followed by experimental solubility study to validate the predicted values. Various formulations were developed by varying phosphatidylcholine and surfactants (tween 80 and span 80) concentration. To impart cationic properties, stearylamine (1.0 %) was added into the organic phase. Using quality by design (QbD) method, we optimized the formulations and evaluated for vesicle size, polydispersity index, zeta potential, morphology (scanning electron microscopy), in vitro drug release (%), and ex vivo permeation profiles. Result showed that there is a good correlation (0.65) between HSPiP predicted and actual experimental solubility of KETO in water, chloroform, S80, and tween 80. Spherical OKEL1 showed an established correlation between the predicted and the actual formulation parameters (size, zeta potential, and polydispersity index) (259 nm vs 270 nm, +2.4 vs 0.21 mV, and 0.24 vs 0.27). OKEL1 was associated with the highest value of %EE (83.1 %) as compared to liposomes. Finally, OKEL1 exhibited the highest % cumulative permeation (49.9 %) as compared to DS (13 %) and liposomes (25 %). Moreover, OKEL1 resulted in 4-fold increase in permeation flux as compared to DS which may be attributed to vesicular mediated improved permeation and gel based compensated trans epidermal water loss in the skin. The drug deposition elicited OKEL1 and OKEL1-gel as suitable carriers for maximum therapeutic benefit to treat deeply seated fungal infections.

Pharmacies are currently unable to stock proper oral dosage forms for pediatric populations. This leads to manipulation of medications or the need to compound specialized medications, which can be a time-consuming process. Using Semisolid Extrusion (SSE) additive manufacturing (AM), specialized medications can be produced in an expedited process from off-the shelf medication in a hospital or outpatient pharmacy setting. In this study, tablets with a desired dose of 5 mg of metoprolol tartrate derived from commercial Seloken™ 50 mg tablets were 3D printed in a hospital setting. Validation testing was done on five batches, highlighting tablets with a high uniformity in mass and dimension, drug content, acceptable microbial assays, and prolonged release during in-vitro analysis. The average drug content found for the tablets was within ±6% of 5 mg for all batches produced. Comparisons were done between the SSE tablets and capsules produced in an external compounding facility, highlighting several positive aspects of SSE-produced tablets beyond simply shortening the production timeline. The SSE tablets printed in this study are characterized by their smaller size, enhanced prolonged release properties, and more uniform drug content across the tested samples. Additionally, interviews with pharmaceutical professionals were conducted to determine the positive aspects of SSE and further improvements to bring this technique as seamlessly as possible into the pharmacy. This study underscores the feasibility of employing SSE in the production of specialized medications within a hospital environment. Furthermore, it highlights the methodological advantages SSE offers over existing production standards, demonstrating its potential to improve pharmaceutical manufacturing in healthcare settings.

Autologous vein grafts have attracted widespread attention for their high transplantation success rate and low risk of immune rejection. However, this technique is limited by the postoperative neointimal hyperplasia, recurrent stenosis and vein graft occlusion. Hence, we propose the platelet membrane-coated Poly(lactic-co-glycolic acid) (PLGA) containing sildenafil (PPS). Platelet membrane (PM) is characterised by actively targeting damaged blood vessels. The PPS can effectively target the vein grafts and then slowly release sildenafil to treat intimal hyperplasia in the vein grafts, thereby preventing the progression of vein graft restenosis. PPS effectively inhibits the proliferation and migration of vascular smooth muscle cell (VSMCs) and promotes the migration and vascularisation of human umbilical vein endothelial cells (HUVECs). In a New Zealand rabbit model of intimal hyperplasia in vein grafts, the PPS significantly suppressed vascular stenosis and intimal hyperplasia at 14 and 28 days after surgery. Thus, PPS represents a nanomedicine with therapeutic potential for treating intimal hyperplasia of vein grafts.

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. β-elemene (β-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/β-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/β-ELE) for co-delivery of PTX&β-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/β-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/β-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.