Medication adherence is an important factor in the success or failure of drug treatment. No matter how good a drug is, if a patient cannot or does not want to take it, the therapeutic effect of the drug will not be sufficient and as expected. Therefore, we have been developing formulations with "clinical functionality", namely, formulation characteristics that enhance the likelihood of obtaining the expected therapeutic effect. We researched formulations that are easy to take and deliver expected results; these formulations include gummy drugs as confectionery-like formulations and orally disintegrating (OD) tablets that can be easily swallowed. In particular, OD tablets have been jointly developed with pharmaceutical companies and have been commercialized. Clinical trials with gummy drugs and OD tablets have been conducted to verify the impact of these formulations with clinical functionality on improving medication adherence.
A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82–1.09, and 2 combinations ranged between 0.74–1.32.The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.
A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.
A "cocktail" approach, which involves simultaneous administration of multiple CYP-specific probes, concurrently detects the activity of multiple CYP enzymes. We developed and validated a rapid and selective LC-MS/MS method for determining the plasma concentrations of 5 CYP probe drugs and metabolites (caffeine/paraxanthine, CYP1A2 substrate; losartan/losartan carboxylic acid (E3174), CYP2C9 substrate; omeprazole/5-hydroxyomeprazole, CYP2C19 substrate; dextromethorphan/dextrorphan, CYP2D6 substrate; and midazolam/1'-hydroxymidazolam, CYP3A4 substrate) by single-step extraction, followed by a single LC-MS/MS run. An Ostro™ 96-well plate was used for extraction of CYP substrates and metabolites from human plasma and urine. Following optimization of the chromatographic conditions, all the peaks were well separated, and retention times ranged between 4.4 and 11.7 min. The total run time for a single injection was within 13 min. The accuracy and precision values suggested that the assay had high accuracy and reliability in plasma and urine samples. No significant matrix interference was observed. To demonstrate the efficacy of this method, plasma and urine concentrations of 5 CYP probe substrates and their metabolites were determined after simultaneous oral administration of 5 drugs to 4 healthy volunteers. All the substrates and metabolites were detected over an 8 h period, and the plasma concentrations of each substrate at 8 h after administration were above the lower limit of quantification. Urine concentrations of drugs and their metabolic ratio were evaluated after the administration. In conclusion, the advantage of our cocktail approach is that it enables in vivo assessment of the activity of various drug-metabolizing enzymes in a single assay.
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.
The purpose of the present study was to develop orally disintegrating tablets (ODTs) containing fat-soluble drugs that disintegrate rapidly while having appropriate tablet strength. We chose vitamin E (VE) as a model drug; d-α-tocopheryl acetate, as the oily VE (VE-OI), and d-α-tocopheryl acid succinate, as the powder VE (VE-PO), were used. The oily VE was added directly to ODTs (VE-OI ODTs) and also used for the preparation of two types of VE granule, i.e., granules prepared using adsorption to calcium silicate (VE-FL granules) and granules prepared using spray-drying with gelatin (VE-SD granules); each type of granule was added to ODTs (VE-FL ODTs and VE-SD ODTs). Powder VE was added directly to ODTs (VE-PO ODTs). Various VE ODTs were prepared using these four additional methods with varying amounts of VE per tablet and were evaluated with respect to their manufacturability, physicochemical characteristics, and stability. It was demonstrated that a tablet porosity of 30% to 35% and tensile strength of 7 kg/cm2 or greater are required to provide VE ODTs with rapid disintegration and appropriate tablet strength, and that VE-SD granules and powder VE are suitable forms of VE to be added. When stability tests of VE-SD ODTs and VE-PO ODTs were performed, VE-PO ODTs exhibited prolongation of disintegration time and increased tensile strength, whereas VE-SD ODTs showed none of these changes. These changes were thought to be attributable to a decrease in the pore size of VE-PO ODTs resulting from the softening and migration of powder VE under hot storage conditions.
Gummy drugs are dried jelly formulations prepared by adding a gelling agent to saccharides, which are then cooled and solidified. Epinastine hydrochloride (Epi) is commonly used to treat allergic diseases as a prescription and over-the-counter drug. However, the extremely bitter taste of Epi would affect its acceptability among patients. In this study, we aimed to improve the palatability of a gummy drug containing Epi (Epi-G) via organoleptic masking. Epi-G (10 mg of Epi/3.5 g of gummy drug) with two different organoleptic masking formulations, namely aspartame, cocoa powder, and chocolate flavoring (C-Epi-G) or aspartame, L-menthol, and lemon flavoring (L-Epi-G). The gustatory sensation test included six healthy adult volunteers (23.3 ± 1.8 years). We used a visual analogue scale (VAS) to evaluate bitterness, sweetness, and the overall palatability of each Epi-G formulation during chewing and after spitting out the drugs. In the gustatory sensation test, the VAS scores for bitterness and sweetness were decreased and increased for C-Epi-G and L-Epi-G, respectively, compared with the values for Epi-G without organoleptic masking. The VAS scores for overall palatability during chewing for C-Epi-G and L-Epi-G were significantly increased by 2.3- and 2.0-fold, respectively, versus the value for Epi-G. The score after spitting out C-Epi-G remained higher than that of Epi-G. These data illustrated that Epi-G with organoleptic masking had good palatability, which could improve patient adherence to treatment. The gummy drugs could represent an alternative dosing formulation for pediatric and geriatric patients by allowing them to take the drugs more easily than other oral formulations.
