Evaluation of in Vitro and in Vivo Transdermal Absorption of Solifenacin Succinate.

Solifenacin (Sol), an antimuscarinic agent has been widely used for the treatment of overactive bladder. Transdermal formulations can be administered without water as well as absorbed slowly into the blood over a long period of time. The aim of this study was to develop cream and tape formulations of Sol, and evaluate the transdermal permeation and absorption of the drug from the two formulations in vitro and in vivo, respectively. In the preparation of cream formulation, Sol succinate was dissolved in purified water, and the mixture was added to the hydrophilic cream. Then, aqueous sodium hydroxide was added to the cream. In the tape formulation, Sol succinate was dissolved in a solvent with propylene glycol, diisopropanolamine, triethyl citrate, and EUDRAGIT E100. The dissolved solvent was poured onto a polyethylene film. Cream (5%) and tape (15%) formulations demonstrated high skin permeability. Addition of an adsorption enhancer (N-methyl-2-pyrrolidone) did not further increase the level of skin permeability. In subsequent in vivo experiments in rats, both the cream and tape formulations led to slow absorption of Sol into plasma, with increased t1/2 compared with oral administration. Plasma Sol concentrations peaked 24 h after transdermal application and the drug was still detectable in plasma 72 h after application. Additionally, the cream (5%) and tape (15%) formulations resulted in a higher area under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72) compared with oral formulation (30 mg/kg). In conclusion, significant in vitro permeability and in vivo absorption of Sol from the transdermal formulations were observed.

Dynamics of D-serine reflected the recovery course of a patient with rapidly progressive glomerulonephritis.

We experienced a case of a 36-year-old female with rapidly progressive glomerulonephritis (RPGN) due to anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and systemic lupus erythematosus (SLE) nephritis. Chiral amino acid metabolomics revealed a prominent profile of D-serine in this patient. At the fulminant period of RPGN, the level of plasma D-serine, a potential biomarker in CKD that reflects actual glomerular filtration ratio (GFR), was extremely high. On the other hand, urinary fractional excretion (FE) of D-serine, which was usually much higher than that of L-isoform, was 0% in this patient. These abnormal D-serine profiles normalized in response to the intensive treatment. Normalizations of blood D-serine levels were in parallel with those of blood creatinine levels and potentially reflect the recovery of GFR. FE of D-serine increased transiently before the normalization of D-serine profile, suggesting that kidney promotes urinary excretion of D-serine for the normalization of plasma D-serine level. These unexplored clinical features of D-serine well reflected the clinical course of this patient. Blood D-serine level can also serve as a biomarker in acute kidney injury (AKI) or RPGN, and, in combination with FE of D-serine, may render the clinical practitioners to judge the efficacy of intensive treatments.

D-Serine reflects kidney function and diseases.

D-Amino acids, long-term undetected enantiomers of L-amino acids, are now emerging as potential biomarkers, especially for kidney diseases. Management of chronic kidney disease (CKD), a global problem with its high prevalence and poor prognosis, is currently unsatisfactory due to the difficulty in estimating kidney function and in early detection of diseases. We now show that intra-body dynamics of D-serine reflect kidney function and diseases. The blood level of D-serine correlated well with the actual glomerular filtration ratio, a key kidney function. This correlation was compatible with those of conventional kidney markers, and blood level of D-serine was relatively unaffected by such clinical factors as body size. The balance between excretion and reabsorption of amino acids by the kidney was controlled with chiral selectivity, and the reabsorption of D-serine was sensitive to the presence of CKD. The combination of blood level and urinary dynamics of D-serine effectively distinguished CKD from non-CKD. These lines of evidence provide new insights into the enantioselective amino acid dynamics in the human body that reflect disease pathophysiology. D-Serine may serve as a vital biomarker that suppress CKD onset through the precise assessment of kidney function and the diagnosis of CKD.

Combination effect of physical and gustatory taste masking for propiverine hydrochloride orally disintegrating tablets on palatability.

Orally disintegrating tablets (ODTs) containing propiverine hydrochloride (which is extremely bitter and leaves a feeling of numbness in the mouth) were prepared with a combined use of physical and organoleptic taste masking. Propiverine-loaded masking particles (PLMPs) were prepared with different amounts of gastric-soluble coatings as physical masking. ODTs without organoleptic masking were prepared by mixing each group of PLMPs with Ludiflash®, crospovidone, and magnesium stearate. ODTs with organoleptic masking were also prepared by addition of L-menthol, aspartame, thaumatin, and cinnamon. Fifteen-minute dissolution of propiverine in solutions with pH 1.2 was ≥ 85% for all ODTs, whereas that in pH 6.8 solutions was ≤ 85% and increased with physical masking. A single blind randomized crossover trial was conducted. Ten healthy volunteers were asked to quantify the bitterness, numbness, and overall palatability using a 100-mm visual analog scale (VAS) at the period of disintegration as well as 1 and 5 min later. VAS scores of bitterness, numbness, and overall palatability improved along with increasing amounts of physical masking, and the effects persisted for 5 min. VAS scores for numbness increased over time regardless of the amount of physical masking. Bitterness, numbness, and overall palatability were significantly improved by organoleptic masking if the amount of physical masking was small. Combined use of physical and organoleptic masking is useful for improving palatability of ODTs containing propiverine.

Transdermal absorption of natural progesterone from alcoholic gel formulations with hydrophilic surfactant.

OBJECTIVES: The aim of this study was to evaluate the in vitro skin permeation and in vivo transdermal absorption of natural progesterone (Prog) from alcoholic gel-based transdermal formulations containing Prog dissolved stably at a concentration of 3%. METHODS: 3% Prog dissolved gel formulations were prepared containing with water, ethanol, 1,3-butylene glycol, carboxyvinylpolymer, diisopropanolamine, polyoxyethylene (2) oleylether and benzyl alcohol. The gel formulations added different hydrophilic surfactants and isopropyl myristate or propylene glycol dicaprylate (PGDC) as oily solvents were applied in vitro permeation study through excised rat skin on unocclusive condition. The gel formulations added polyoxyethylene (20) oleylether (Oleth-20) as hydrophilic surfactant and PGDC were applied in vivo single- and repeated-dose transdermal absorption study of rat on unocclusive condition. RESULTS: The results of evaluation of the gel formulations by an in vitro skin permeation study revealed a high flux of Prog from the formulation containing Oleth-20 and Oleth-20 with PGDC. The results of single and repeated in vivo transdermal absorption studies confirmed that good plasma levels of Prog were achieved and maintained by Oleth-20 and PGDC containing gel formulation. CONCLUSIONS: The Oleth-20 and PGDC containing ethanolic gel formulation seemed to have the ability to maintain a high activity of Prog and high diffusivity or solubility of Prog in the epidermis on the practical formulation application.

In vitro and in vivo evaluation under finite conditions of a transdermal oil-in-water type emulsified formulation of propiverine hydrochloride.

A transdermal oil-in-water type emulsified formulation containing propiverine hydrochloride, used for treatment of an overactive bladder (OAB), was evaluated for in vitro skin permeation under finite conditions and in vivo transdermal absorption. Propiverine hydrochloride solubility was determined using 1,3-butyleneglycol, polyoxyethylene (2) oleylether, isostearyl alcohol, and lauryl alcohol. The solubility increased as the solubility parameter value increased. In vitro skin permeation in hairless mouse skin and in vivo transdermal absorption in rats were measured using propiverine hydrochloride dissolved in a simple solution containing these solvents. Dependent on the increase in in vitro flux, the in vivo area under the curve up to 72 h (AUC0-72) was increased. Therefore, the emulsified formulation was prepared containing these ingredients using polyoxyethylene (20) stearylether for optimization. The emulsified formulation was used to conduct in vivo single- and repeated-dose absorption studies in rats. After single-dose transdermal administration of the emulsified formulation, the AUC0-72 was equivalent to that of the simple solution. Furthermore, results using the emulsified formulation indicated an increase in AUC0-72 and significant extension of the elimination half-life, in comparison with oral administration. After repeated-dose administration, a significant minimum plasma concentration was observed compared with oral administration. These results demonstrate that the emulsified formulation is a good option for transdermal delivery of propiverine hydrochloride.

Skin permeation of lidocaine from crystal suspended oily formulations.

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, Japp, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2=IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0-20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest Japp among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.