Identification of TUL01101: A Novel Potent and Selective JAK1 Inhibitor for the Treatment of Rheumatoid Arthritis.

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound 36) based on a triazolo[1,5-a]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC50 value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated the high activity and selectivity (37-fold for JAK2). At the same time, TUL01101 also demonstrated excellent metabolic stability and pharmacokinetics (PK) profiles were assayed in three species (mouse, rat, and dog). Moreover, it has been validated for effective activity in the treatment of RA both in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models, with low dose and low toxicity. Now, TUL01101 has progressed into phase I clinical trials.

[Genetic polymorphisms of 16 STR loci in Tibetan Mastiff].

OBJECTIVE: To explore the genetic polymorphisms of 16 STR loci from 449 Tibetan Mastiffs in order to set up gene polymorphism database of Tibetan Mastiff. METHODS: The PCR amplification was performed using the 16 STR loci fluorescent multiple amplification kit for dog. The amplified products were detected and statistically analyzed. RESULTS: In the 16 STR loci from 449 Tibetan Mastiffs, CDP was 0.999 999 999 999 999 and CEP was 0.999 997 795. Except FH2010 (10 alleles), PEZ21 (12 alleles), and PEZ05 (13 alleles), the other STR loci had more than 15 alleles. In the 16 STR loci, H was > 0.5 and PIC was > 0.7. CONCLUSION: The 16 STR loci have high polymorphism to be suitable for individual identification and paternity testing of Tibetan Mastiff. The data obtained through this study can be used to establish DNA polymorphism database of Tibetan Mastiff.

Formulation and in vitro/in vivo correlation of a drug-in-adhesive transdermal patch containing azasetron.

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two-chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO-TAK 87-9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy-induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches.

Effect of the stability of hydrogen-bonded ion pairs with organic amines on transdermal penetration of teriflunomide.

The aim of this work was to investigate the effect of the stability of hydrogen-bonded ion pairs with organic amines on transdermal penetration of teriflunomide (TEF). Five organic amines, diethylamine (DEtA), triethylamine (TEtA), diethanolamine (DEA), triethanolamine (TEA), and N-(2'-hydroxyethanol)-piperdine (NP), were chosen to form ion pairs with TEF separately, and the passage of each TEF ion pair through the rabbit skin was evaluated in vitro. FTIR and (1)H NMR spectroscopy were performed to confirm the formation of ion pairs between TEF and organic amines in solution. The stability parameter of ion pairs in terms of ion-pair lifetimes (T(life)) was calculated from the NMR data. TEF could form ion pairs with these amines via hydrogen bond. The formation of ion pairs enhanced the percutaneous absorption of TEF except TEF-DEA. It was found that, for most studied organic amines, the longer the ion-pair lifetime, the higher the flux of skin permeation. The stability of TEF ion pairs was a pivotal factor influencing the skin permeation of TEF.

Silicone adhesive, a better matrix for tolterodine patches-a research based on in vitro/in vivo studies.

OBJECTIVE: To design and optimize a drug-in-adhesive (DIA) type transdermal patch for tolterodine (TOL) based on acrylic and silicone matrixes. METHODS: Initial in vitro studies were conducted to optimize the formulations. Two types of adhesive matrixes, drug loading, and enhancers were evaluated on the TOL transport across rabbit skin. For in vivo studies, patches were administered to rabbit abdominal skin. Pharmacokinetic assessments were performed based on plasma level of TOL up to 28 h for acrylic patch and 52 h for silicone patch after topical application. RESULTS: The final formulation of acrylic adhesive type patch consisted of 10% TOL (w/w) and 5.8 × 10(-4) mol isopropyl myristate (IPM) and 2.9 × 10(-4) mol Span 80 in per unit gram (mol/g) of adhesive, while 2.5% TOL (w/w) and 2.9 × 10(-4) mol/g IPM for silicone adhesive type patch. Comparison of the pharmacokinetic parameters between two types of patches showed that the steady-state concentration of silicone type patch was 2-fold higher than that of acrylic type patch being 0.97 mg/L versus 0.49 mg/L, and the absolute bioavailability was 27.5% for silicone type patch and 6.3% for acrylic type patch, respectively. In addition, the prediction of in vivo drug level from the in vitro permeation data of silicone adhesive formulation was in good agreement with actual observed concentration data in rabbits. CONCLUSION: These results indicate that the silicone type of TOL patch is an appropriate delivery system for the treatment of overactive bladder (OAB).

Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension.

Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation, compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats.

Transdermal patches for site-specific delivery of anastrozole: In vitro and local tissue disposition evaluation.

Anastrozole is a potent aromatase inhibitor and there is a need for an alternative to the oral method of administration to target cancer tissues. The purpose of the current study was to prepare a drug-in-adhesive transdermal patch for anastrozole and evaluate this for the site-specific delivery of anastrozole. Different adhesive matrixes, permeation enhancers and amounts of anastrozole were investigated for promoting the passage of anastrozole through the skin of rats in vitro. The best in vitro skin permeation profile was obtained with the formulation containing DURO-TAK 87-4098, IPM 8% and anastrozole 8%. For local tissue disposition studies, the anastrozole patch was applied to mouse abdominal skin, and blood, skin, and muscle samples were taken at different times after removing the residual adhesive from the skin. High accumulation of the drug in the skin and muscle tissue beneath the patch application site was observed in mice compared with that after oral administration. These findings show that anastrozole transdermal patches are an appropriate delivery system for application to the breast tumor region for site-specific drug delivery to obtain a high local drug concentration.