The adhesion force of fine particles on the surfaces of tablets was measured using centrifugal and impact separation methods. Particle/substrate systems such as white alundum/slide glass and microcelac/microcelac tablet were used as model systems. Finededuster, which we developed, was employed for the removal of fine particles on tablet surfaces, changing the frequency of the brower and rotor power supply to measure adhesion force and examine the removal efficiency. The adhesive force of the fine particles and removal efficiency were obtained at every frequency of brower and rotor power supply. From these results, centrifugal and impact separation methods were two of the best ways to measure the adhesion force of fine particles on the surfaces of tablets. Removal efficiency increased with particle size under all operating conditions. A critical particle size, that is nearly 10 μm, existed, and larger particles were removed more efficiently.
We evaluated the validation of biphasic isophane insulin suspension (Humacart 3/7 and Penfill 30 R). The concentrations of total insulin, Zn, m-cresol and phenol in Humacart 3/7 and Penfill 30 R were consistent with the levels described in the interview form. To study the relationship between mixing (0, 5, 10 and 20 times) and the uniformity of the insulin suspension, Humacart 3/7 and Penfill 30 R were set into Penjector and Novopen, respectively. The total insulin concentrations of both insulin preparations varied between 50 and 170 U/ml without mixing, so mixing more than 10 times was necessary to equalize the insulin suspension. Total insulin concentrations through Penjector and Novopen decreased with increased leaving time after well mixing, thus these insulin preparations have to be injected as soon as possible after mixing. The differences in total insulin concentrations of Humacart 3/7 and Penfill 30 R after mixing were not significant, however the insulin concentrations of Humacart 3/7 filtered through a 0.45 μm membrane were higher than those of Penfill 30 R. The permeation rate of insulin in Humacart 3/7 using a permeation cell system was faster than that of Penfill 30 R. The differences in monomeric insulin concentration of the insulin preparations were not significant, however, the dimeric-hexameric insulin concentration in Humacart 3/7 was higher than that in Penfill 30 R. These results may indicate that the absorption of Humacart 3/7 is faster than that of Penfill 30 R in clinical use.
We have postulated a “satiated model” to explain the saturable hepatic uptake clearance of liposomes. This model assumes that the hepatic uptake clearance (CLh) decreases in proportion to the hepatic uptake amount. We have examined the competitive mechanisms in the hepatic uptake of liposomes using three kinds of liposomes composed of egg phosphatidylcholine (EPC) or hydrogenated EPC with cholesterol (Chol), and dicetylphosphate (DCP). Male Wistar rats were administered marker liposomes (2 μmol lipid/kg) consisting of multi-lamellar vesicles (MLV) composed of HEPC/Chol/DCP (HEPC-MLV*) alone (control) or with empty liposomes (200 μmol lipid/kg). The marker liposomes were also administered after 4 h of EPC-MLV injection. The CLh of HEPC-MLV* was remarkably decreased by 97% with empty, small unilamellar vesicles (SUV) composed of HEPC/Chol/DCP (HEPC-SUV). This result indicated that HEPC-SUV inhibited CLh of HEPC-MLV* by depleting serum opsonins. HEPC-SUV was suggested to inhibit the hepatic uptake of HEPC-MLV* according to the Michaelis-Menten model. On the other hand, competition by MLV composed of EPC/Chol/DCP (EPC-MLV) in the hepatic uptake of HEPC-MLV* was low, and there was no difference in the hepatic uptake amount of HEPC-MLV* with or without EPC-MLV. Pre-administration of empty EPC-MLV inhibited the CLh of HEPC-MLV* remarkably. These results indicate that empty EPC-MLV did not consume serum opsonins and were taken up via a different uptake pathway than that of HEPC-MLV*. EPC-MLV was suggested to inhibit the uptake of HEPC-MLV* after being taken up by the liver via some negative feedback mechanisms, which is explained by the satiated model.
We clarified that there were at least two kinds of competition mechanisms in the hepatic uptake of liposomes.
Recently, nonprescription switch OTC drugs have attracted a great deal of attention, and many such drugs are being developed. Among these drugs, ibuprofen is contained in many brands and various dosage forms on the market. Dissolution tests were performed for ibuprofen preparations both by the paddle (PD) method described in the Japanese Pharmacopoeia (JP) and by the rotating dialysis cell (RDC) method. Dissolution behavior tested by the RDC method more accurately represented pharmaceutical characteristics of these preparations than that when tested by the PD method.
We examined the possibility of a pharmacokinetic interaction between theophylline (THP) and propentofylline (PRF) by administering them simultaneously via an intravenous (i.v.) route to rats. The area under the plasma concentration-time curve (AUC) value for THP after single bolus i.v. administration of aminophylline (2.5 mg/kg, THP equivalent) in combination with 6.25 or 12.5 mg/rat PRF, and the total body clearance (CLt) value for that with PRF (12.5 mg/rat) were significantly greater and smaller than those for the aminophylline-alone group, respectively. The mean residence time (MRT) value for THP tended to increase with the dose of PRF, while the volume of distribution at steady-state did not change. On the other hand, aminophylline (6.25 or 12.5 mg/rat) coadministered with PRF (2.5 mg/rat) significantly decreased the elimination rate constant for PRF and increased the MRT value, but 2.5 mg/rat aminophylline did not. The AUC value for PRF tended to increase with increasing doses of aminophylline, while the CLt value was inclined to decrease. In conclusion, it was found that there was a mutual pharmacokinetic interaction between THP and PRF in rats, however, the magnitude was relatively small.
In order to achieve an increased compliance in infant patients, we have developed a dosage form which is masticable, has no bitter taste, and can be administered to infant patients without water. Gummi is defined as a gel confectionery made of sugars and gelatin, and Gummi Drug is defined as a gel preparation manufactured by adding a drug to Gummi. We have previously reported the method to prepare Gummi Drug of acetaminophen (AAP), characteristics in the release of AAP from Gummi Drug and the stability of Gummi Drug.1-3)
In this study, we administered an 8-fold divided, masticated model of Gummi Drug (8DG) and an AAP powder preparation to dogs orally. The plasma concentration changes of AAP were followed, and the pharmacokinetic parameters in the 8DG and AAP powder preparation were calculated.
The AUC0-6, AUC0-∞ and Cmax after the administration of 8DG were found to be lower than those after the administration of AAP powder preparation, and the Tmax after the administration of 8DG was longer than that after the administration of AAP powder preparation. However, there was no statistically significant difference in the pharmacokinetic parameters between 8DG and AAP powder preparation. Variations in the plasma concentration after the administration of 8DG were smaller than those after the administration of AAP powder preparation, suggesting that constant absorption of AAP in the digestive tract was achieved from 8DG.
Cyclomaltononaose (δ-cyclodextrin, δ-CD) is a member of the cyclomaltoses and is composed of nine α-(1→4)-linked d-glucopyranose units. Though it has already been purified from commercially available CD powder, DEXY PEARL K-50, the yield was very low. To improve the yield of δ-CD, we tried to isolate and purify it from a new CD source, CELDEX SG-30, and the final product was identified as δ-CD by HPLC and FAB-MS. Further, the yield from CELDEX SG-30 was superior to that from DEXY PEARL K-50.