Osteoarthritis (OA) is a prevalent joint disease characterizedby chronic, progressive inflammation and cartilage degeneration, for which current treatments remain limited. In this study, we propose a dual-drug delivery strategy that simultaneously suppresses inflammation and rejuvenates impaired cartilage by incorporating kartogenin (KGN) and methylprednisolone hemisuccinate (MPHS) into a single microsphere system with sequential release in the local microenvironment. To achieve coordinated dual-drug release, KGN and MPHS were loaded into the inner core and outer layer of the microspheres, respectively. Both KGN and MPHS exhibited sustained release profiles; however, MPHS showed a shorter burst-release phase than KGN due to the protective effect of the outer layer. The release of MPHS effectively suppressed interleukin-1β (IL-1β)-induced inflammation in bone marrow stromal cells (BMSCs) pellets, thereby enhancing KGN-mediated chondrogenic differentiation of BMSCs in vitro. In parallel, sustained delivery of KGN also led to the recruitment of BMSCs and subsequent chondrogenesis, ultimately leading to cartilage rejuvenation. Importantly, the sequential release of KGN and MPHS from the dual-drug microspheres synergistically enhanced in vitro chondrogenic differentiation of BMSCs, resulting in concomitant inflammation alleviation and cartilage repair. Collectively, these findings demonstrate that the KGN/MPHS-incorporated microspheres possess dual chondrogenic and anti-inflammatory functions and represent a promising therapeutic strategy for OA treatment.

Amounts of methylprednisolone in breastmilk are very low and no adverse reactions in breastfed infants have been reported, even with intravenous doses of 1 gram. With maternal intravenous doses of 1 gram, fully breastfed infants would receive doses less than their daily cortisol output, and much less than the therapeutic dose used in neonates.[1,2] Accumulation of the drug does not occur in breastmilk with consecutive daily doses of 1 gram. Avoiding breastfeeding during the infusion and for as little as 2 hours after a 1 gram intravenous dose markedly reduces infant exposure. Smaller oral doses and local injections, such as for tendinitis, require no special precautions. Local injections might occasionally cause temporary loss of milk supply.

Spinal cord injury (SCI) is a neurological disease with a high rate of disability. Inflammation plays a key role in all stages of pathological of SCI and interacts with ferroptosis to induce deterioration. Methylprednisolone sodium succinate (MPSS) is currently the only drug in clinical to treat SCI through anti-inflammation, but due to the lack of efficacy and systemic adverse reactions, the drug therapy of SCI is still limited. Therefore, a locally administered injectable thermosensitive hydrogel MPSS/Fer-1@HA-MC was designed to treat SCI synergistically by anti-inflammation and anti-ferroptosis. Considering the insolubility of Fer-1 in water, Fer-1@β-CD inclusion complex was used to co-contained with MPSS in HA-MC hydrogel. Faster release of dissolved MPSS inhibits inflammation in acute and subacute stages of SCI. With a smaller solubility of Fer-1@β-CD, Fer-1 released slowly and persistently to anti-ferroptosis and anti-inflammation in whole stages. Therefore, motricity function of SCI mouse was repaired after treat with MPSS/Fer-1@HA-MC, better than single-drug hydrogels. Furthermore, MPSS/Fer-1@HA-MC inhibit inflammatory damage by decreased the expression of IL-1β, CD68, ROS and iNOS, and inhibit ferroptosis by reduced the overexpression of TfR1 and lipid peroxidation, and increased GPX4 level in whole stages. In summary, MPSS/Fer-1@HA-MC successfully achieved a more sustained and comprehensive therapeutic of SCI.

Rationale: Slow-releasing formulation of local anesthetics (LAs) has been a promising strategy for pursuing long-acting opioid-free analgesia. Although many formulations based on carrier materials have been successfully developed, challenges still remain in addressing not only the biocompatibility and biodegradability issues of carrier materials, but also potential local inflammation caused by LAs. Methods: In this study, we developed a slow-releasing ropivacaine formulation based on methylprednisolone sodium succinate (MP), a small-molecule drug used in clinic. Firstly, we studied the self-assembling behavior of MP and its interaction with ropivacaine hydrochloride (RH). Then we studied how MP could manipulate the crystallization of RH and how the release profile of obtained ropivacaine crystals could be controlled. Lastly, we investigated the long-acting analgesic effect and safety of different formulations in animal models. Meanwhile we also monitored the anti-inflammatory effect of MP on cell and animal levels. Results: MP could self-assemble into nanoparticles, which could adsorb RH and induce the formation of homogeneous ropivacaine microcrystals. Higher MP ratio in the system led to the formation of smaller ropivacaine microcrystals with a moderate release rate, which generated much longer and reliable analgesic effect in animal models with considerable safety. On the other hand, MP in the formulation showed substantial anti-inflammatory effect, which was also helpful to further relieve pain and alleviate local toxicity. Conclusion: Using MP as a dual-functional adjuvant, long-acting LA formulations with considerable safety could be prepared, providing a facile solution for long-term pain management in clinic.

Since the FDA approval of the first nanodrug Doxil® in 1995, twenty subsequent liposome and lipid nanoparticle (LNP) based drugs (of which 10 are nanodrugs), were approved by the FDA. The application of such drug-products was considerably boosted by the mRNA-LNP based vaccines used to stop the COVID-19 pandemic. Research on lipid-based vesicles and nanoparticles for drug delivery dates to the 1970s and has culminated in both continuous flow and extrusion-based fabrication processes for current state-of-the-art GMP industrial production of nanoliposomes and lipid nanoparticles. In this study, we compare these two approaches for the preparation of two PEGylated nanoliposome-based drug-products, keeping all other production steps leading to the final drug-product identical. One of these products, generic Doxil®, is remotely and actively loaded with the anthracycline doxorubicin (an amphipathic weak base) driven by a transmembrane ammonium gradient, while the other is methylprednisolone hemisuccinate (an amphipathic weak acid) remotely and actively loaded via a transmembrane acetate gradient. We demonstrate that a microfluidics-based micromixer approach yields equivalent or even better drug-products, especially since the downsizing by microfluidics is not performed above the temperature range of lipid phase transition. The main difference in the physico-chemical features is that size distribution of the microfluidics prepared PEGylated nano liposomes was significantly narrower and morphological analysis by cryo-TEM confirmed higher homogeneity. An additional advantage of the microfluidic approach is that it is a continuous production. Therefore, it enables the direct production of large volumes of high-quality nano-liposomal based drug-products.

The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336 mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800 mg, the distribution volume (Vd) averaged 1.17 L/kg, and the model predicted elimination half-life (t1/2) was 2.6 h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t1/2 of 1.7 min, and followed by MPL phosphate (MPPS) 3.8 min, MPL hemisuccinate (MPHS) 16 min, and MPL suleptanate (MPSP) 2.9 h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (ka) of 1.5 h[-1] for MPSS and 96 h[-1] for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and ka of 2.1 h[-1], while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans.

Hypertrophic scar (HS) is characterized by an abnormal fibroblast-myofibroblast transformation; non-apoptosis of fibroblasts; and redundant expression of TGF-β1, VEGF, α-SMA, and collagen I/III. An HS affects patients' physical and psychological quality of life, leading to joint dysfunction and skin cancer. However, there is currently no satisfactory drug to treat this disorder. In this study, we constructed methylprednisolone sodium succinate (MPSS) encapsulated ZIF-90 (MPSS@ZIF-90) for the effective treatment of an HS. The encapsulation of MPSS in ZIF-90 can achieve the controllable drug release of MPSS and prolong its effective treatment time. MPSS@ZIF-90 enhanced the apoptosis of human hypertrophic scar fibroblasts and downregulated the overexpression of TGF-β1, VEGF, α-SMA, and collagen I/III both in vitro and in vivo. The instant injection of MPSS@ZIF-90 effectively intervened with the formation of the HS after 28 days. On the contrary, MPSS@ZIF-90 greatly reduced the HS with two injections and 14 days of treatment after the HS was formed. This work provides evidence of effective intervention in the formation of an HS and the therapeutic effectiveness of MPSS@ZIF-90 with short treatment periods in vivo. It suggests that MPSS@ZIF-90 can be used as a biomedical option in the treatment of skin wounds and may reveal the potential molecular basis for promising future antifibrotic agents against scarring.