Electrostatically optimized adapalene-loaded emulsion for the treatment of acne vulgaris.

Adapalene (AD) is an FDA-approved drug that shows good therapeutic efficacy for the treatment of acne vulgaris. However, due to its negative charge, AD cannot efficiently penetrate across the also negatively-charged skin membrane. This study is the first to assess the treatment of acne vulgaris using electrostatically optimized AD emulsions prepared using anionic AD with methoxy polyethylene glycol-b-poly(ε-caprolactone) (MC) as an anionic emulsifier coupled with a newly synthesized MC with different contents of an amine pendant-group (MC-[NH2]x) as a cationic emulsifier. The AD emulsion prepared using MC-[NH2]x with high cationic charge potential was significantly stable in the short-term studies compared with anionic MC or no emulsifier. Furthermore, the AD emulsion prepared with the cationic MC-[NH2]x emulsifier provided a two or three times stronger therapeutic effect against acne vulgaris than the AD emulsion prepared with the anionic MC emulsifier or no emulsifier in an animal study. Additionally, the AD emulsion with high cationic charge potential exerted a remarkable inhibition of macrophage expression, as confirmed by histological analysis. Therefore, the electrostatic interaction between the negatively-charged skin membrane and the AD emulsion prepared with the cationic MC-[NH2]x emulsifier provides a promising therapeutic strategy for acne vulgaris.

An injectable, electrostatically interacting drug depot for the treatment of rheumatoid arthritis.

To the best of our knowledge, no studies have yet examined the electrostatic interaction of polyelectrolytes with electrolyte drugs for the treatment of rheumatoid arthritis (RA). Here, an injectable, electrostatically interacting drug depot is described. We prepared methoxy polyethylene glycol-b-poly(ε-caprolactone)-ran-poly(l-lactic acid) (MC) diblock copolymers with a carboxylic acid group (MC-C) at the pendant position. MC-C was polyelectrolytes that exhibited negative zeta potentials. Sulfasalazine [Sul(-)] and minocycline [Min(+)], electrolyte RA drugs, exhibited negative and positive zeta potentials, respectively. The electrolyte RA drugs were loaded into the polyelectrolyte MC-C solution to prepare injectable, electrostatically interacting depot formulations. The formulation with an attractive electrostatic interaction [Min(+)-MC-C] exhibited gradual release of Min(+) from the MC-C depot over an extended period and suppressed the growth of inflammatory RAW 264.7 cells without affecting synovial cells. Mature chondrocytes were observed after H&E and safranin O staining of the cartilage of Min(+)-MC-C intra-articularly injected RA-induced rats. In comparison with other formulations, Min(+)-MC-C induced the suppression of the expression of pro-inflammatory proteins TNF-α and IL-1ß in the articular knee joint, which resulted in the amelioration of RA. In conclusion, an injectable, electrostatically interacting depot formulation administered through intra-articular injection successfully provided almost complete amelioration of RA.

Preparation of Biodegradable and Elastic Poly(ε-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier.

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PCxLyA), which display specific rates of flexibility and elasticity. We synthesize the PCxLyA copolymers by ring-opening polymerization of ε-caprolactone and l-lactide. PCxLyA copolymers of various compositions were synthesized with 500,000 molecular weight. The PCxLyA copolymers mechanical properties were dependent on the mole ratio of the ε-caprolactone and l-lactide components. Cyclic tensile tests were carried out to investigate the resistance to creep of PCxLyA specimens after up to 20 deformation cycles to 50% elongation. After in vivo implantation, the PCxLyA implants exhibited biocompatibility, and gradually biodegraded over an eight-week experimental period. Immunohistochemical characterization showed that the PCxLyA implants provoked in vivo inflammation, which gradually decreased over time. The copolymer was used as a drug carrier for locally implantable drugs, the hydrophobic drug dexamethasone (Dex), and the water-soluble drug dexamethasone 21-phosphate disodium salt (Dex(p)). We monitored drug-loaded PCxLyA films for in vitro and in vivo drug release over 40 days and observed real-time sustained release of near-infrared (NIR) fluorescence over an extended period from hydrophobic IR-780- and hydrophilic IR-783-loaded PCxLyA implanted in live animals. Finally, we confirmed that PCxLyA films are usable as biodegradable, elastic drug carriers.

An Injectable, Click-Cross-Linked Small Intestinal Submucosa Drug Depot for the Treatment of Rheumatoid Arthritis.

Here, a click-cross-linked small intestine submucosa (SIS) drug depot is described for the treatment of rheumatoid arthritis (RA). To the best of the knowledge, there have been no studies related to the intra-articular injection of methotrexate (Met)-loaded click-cross-linkable SIS (Met-loaded Cx-SIS) for RA treatment. As the key objective of this work, injectable formulations of tetrazine-modified SIS (TE-SIS) and transcyclooctene-modified SIS (TC-SIS) are employed as drug depots. Within a few seconds, the simple mixing of equal amounts of TE-SIS and TC-SIS suspensions forms a gelatinous click-cross-linked SIS (Cx-SIS) drug depot in vitro and in vivo. The formed Cx-SIS depot is maintained in the articular joint over an extended period, while SIS alone rapidly disappears. Injectable formulations of Met-loaded Cx-SIS and Met-loaded SIS are prepared and then injected into articular joints to form drug depots. Compared to animals treated with Met-loaded SIS, RA animals treated with Met-loaded Cx-SIS show effective RA repair, as well as extensive regeneration of chondrocytes and glycosaminoglycan deposits. Collectively, these results indicate that the Met-loaded Cx-SIS depot is successfully formed after intra-articular injection of click-cross-linkable SIS, and that this formulation induces long-lasting Met release and allows Met to act effectively in the articular joint, resulting in RA repair.

Effects of elastic band exercise on subjects with rounded shoulder posture and forward head posture.

[Purpose] This study performed to investigate the effect of elastic band exercise program on the posture of subjects with rounded shoulder and forward head posture. [Subjects and Methods] The body length, forward shoulder angle, craniovertebral angle, and cranial rotation angle of participants (n=12) were measured before and after the exercise program. Furthermore, the thicknesses of the pectoralis major, rhomboid major, and upper trapezius were measured using an ultrasonographic imaging device. The exercises program was conducted with elastic bands, with 15 repetitions per set and 3 sets in total. [Results] The length of the pectoralis major, forward shoulder angle, and craniovertebral angle showed significant changes between before and after the exercise program, whereas the changes in the other measurements were not significant. The thickness of the upper trapezius showed a significant increase between before and after the elastic band exercise. [Conclusion] These findings suggest that the elastic band exercise program used in the study is effective for lengthening the pectoralis major and correcting rounded shoulder and forward head posture.

Treadmill exercise facilitates synaptic plasticity on dopaminergic neurons and fibers in the mouse model with Parkinson's disease.

Exercise for patients with Parkinson's disease (PD) helps to alleviate clinical symptoms such as tremor, balance instability, gait dysfunction, and rigidity. However, molecular mechanism about effect of exercise is poorly unknown. In this study, we investigated effect of exercise in synapse and dendritic spine of nigrostriatal dopaminergic neurons on mice with PD. The C57BL/6J male mice (n=40) were divided by sham group, sham-exercise treated group, 1-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) treated group, and MPTP-exercise treated group. For exercise treatment, the mice were put on the treadmill to run for 8m/min, 30min/day, and 5 times/week for 2 weeks. Coordination ability was checked by rota rod test. Expression of tyrosine hydroxylase (TH), synaptophysin, and post-synaptic density protein 95 (PSD-95) was confirmed at substantia nigra pars compacta (SNpc) or striatum using western blotting, or immunohistochemistry. To check dendritic spine in striatum, we used Golgi staining. The results revealed that MPTP treated group displayed poor coordination ability compared with sham group. However, MPTP-exercise treated group showed good coordination ability compared with MPTP treated group. As well as, we also found that MPTP-exercise group increases expression of synaptophysin, PSD-95, TH, and dendritic spine in nigrostriatal dopaminergic neurons and fibers than MPTP treated group (p<0.05). Our findings suggest that exercise may give beneficial effects to patients with PD by facilitating synaptic plasticity and increasing dendritic spines.

Preparation and Evaluation of Dexamethasone-Loaded Electrospun Nanofiber Sheets as a Sustained Drug Delivery System.

Recently, electrospinning technology has been widely used as a processing method to make nanofiber sheets (NS) for biomedical applications because of its unique features, such as ease of fabrication and high surface area. To develop a sustained dexamethasone (Dex) delivery system, in this work, poly(ε-caprolactone-co-l-lactide) (PCLA) copolymer with controllable biodegradability was synthesized and further utilized to prepare electrospun Dex-loaded NS using water-insoluble Dex (Dex(b)) or water-soluble Dex (Dex(s)). The Dex-NS obtained by electrospinning exhibited randomly oriented and interconnected fibrillar structures. The in vitro and in vivo degradation of Dex-NS was confirmed over a period of a few weeks by gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR). The evaluation of in vitro and in vivo Dex(b) and Dex(s) release from Dex-NS showed an initial burst of Dex(b) at day 1 and, thereafter, almost the same amount of release as Dex(b) for up to 28 days. In contrast, Dex(s)-NS exhibited a small initial burst of Dex(s) and a first-order releasing profile from Dex-NS. In conclusion, Dex-NS exhibited sustained in vitro and in vivo Dex(s) release for a prolonged period, as well as controlled biodegradation of the NS over a defined treatment period.