Search

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15 : S-55=3 : 1) as a lipophilic base and the other polyethylene glycol (PEG, 4000 : 1500=4 : 1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

The promoting effect of sodium guaiazulene-3-sulfonate (AZ) on nasal absorption of insulin and calcitonin was studied in rats. The promoting effect of AZ was compared with two established nasal absorption promoters i. e. sodium caprate(Na Cap) and glycyrrhetinic acid 3-O-monohemiphthalate disodium (GA-MHPh 2Na). The nasal absorption of insulin was estimated from plasma immunoreactive insulin and changes in glucose levels. Plasma glucose level was decreased by intranasal administration of 10 U/kg insulin with 1% AZ, The extent of total decrement of glucose level to control was 51% and comparable to that with 1% Na Cap. The addition of 1% AZ to the nasal formulations enhanced insulin bioavailability from 3.7% to 27.6%. The nasal absorption of salmon calcitonin was evaluated from serum calcitonin and changes in calcium levels. Serum calcium levels were de-creased by intranasal administration of 10 U/kg salmon calcitonin in the presence of two already known promoters as effectively as intramuscular administration of the same dose, The addition of 1% AZ also showed the same extent of decrease as these ; the extent of total decrement of serum calcium level to control was 26.6%. The optimum concentration of AZ was about 1%. Intranasal administration of 1% AZ alone hardly changed plasma glucose level and serum calcium level from control. Hence, promoting effect of AZ on nasal absorption of insulin and calcitonin was proved. These findings indicate that AZ can be safe and effective nasal absorption promoter of peptides.

The effects of some fibers on the in vitro and in situ rat small intestinal absorption of cadmium were studied. The fibers, such as cellulose, pectin, glucomannan, lignin, sodium alginate (Na alginate), and sodium carboxymethylcellulose (Na CMC), tended to depress the intestinal absorption of cadmium. The depressive effects of lignin, Na alginate, and Na CMC on the absorption of cadmium were much greater than those of cellulose, pectin, and glucomannan. In addition, the effects of these fibers on the in vitro intestinal transport of cadmium were examined in the presence of L-cysteine or L-histidine, a stimulator of transport of the metal. Lignin and Na CMC depressed the stimulation of transport of cadmium by L-histidine.

We studied the promoting effect of glycyrrhetinate and its derivatives on nasal absorption of insulin in rats. These derivatives can be divided into two groups based on mother structural skeleton. One group is 3-O-ester derivatives of glycyrrhetinate and the other group is 3-O-and 30-O-ester derivatives of a hydrogenated glycyrrhetinate analog. The former group consists of G2 2K, GA Na, GA-MHS 2Na and GA-HPh 2Ha and the latter group consists of DG-DHPh 2Na, HomAD-DHPh 2Na and HetAD-DHPh 2Na. These derivatives significantly promoted nasal absorption of insulin and decreased plasma glucose levels in rats. We found that the optimum concentration of these derivatives such as GA-MHS 2Na, GA-HPh 2Na and DG-DHPh 2Na was about 1%. The promoting effect of glycyrrhetinic ester groups on nasal absorption of insulin in rats is GZ 2K < GA Na < GA-MHS 2Na < GA-HPh 2Na. These results indicated that strength of the promoting effect differed by 3-O-ester groups. On the other hand, hydrogenated glycyrrhetinic ester analogs were more effective than the glycyrrhetinic ester group. Particularly, DG-DHPh 2Na and HomAD-DHPh 2Na were significantly promoted nasal absorption of insulin in rats, and bioavailability in the presence of these promoters was comparable to that following intravenous injection. It is indicated that glycyrrhetinate and its derivatives can be applicable to promotion of nasal absorption of insulin.

We investigated the promoting effect of medium chain fatty acid salts such as sodium caprylate, sodium caprate (Na C10) and sodium laurate on rat nasal absorption of insulin. Further, we studied the possible mechanism of the absorption promoting effect by fatty acid salts in terms of hemolytic activity, osmotic pressure, chelating effect and inhibition of leucine aminopeptidase activity. Na C10 exhibited the strongest absorption promoting effect on insulin among these fatty acid salts. The promoting effect of Na C10 was very rapid reaching the maximum immunoreactive insulin level within 5 min and its optimum concentration was about 1%. The amount of insulin absorbed after a nasal administration with Na C10 was about 98% of one half subcutaneous dose. The absorption promoting effect of fatty acid salts on insulin was at least in part associated with the chelating ability for calcium ions and the inhibitory action on leucine aminopeptidase activity.

Nasal absorption of insulin in rats was enhanced by addition of sodium glycyrrhetinate (GA Na), dipotassium glycyrrhizinate (GZ K2), and carbenoxolone (glycyrrhetinic acid hydrogen succinate) disodium salt (GAHS Na2). The latter agent was the most effective. On addition of 1% GAHS Na2, plasma immunoreactive insulin levels in rats showed a maximum level of 0.75 mU/ml at 15 min and plasma glucose levels were decreased to about 25 mg/dl after nasal administration of 10 U/kg insulin. In a comparison of the absorption rates of insulin by nasal and intravenous (i.v.) routes in rats, nasal absorptions of 10 U/kg insulin in the presence of 1% GAHS Na2, 0.5% GA Na and 1% GZ K2 were 26.5%, 13.2% and 14.5% of that in the case of a 5 U/kg i.v. dose, respectively. Hemolytic activies of GAHS Na2, GA Na and GZ K2 were milder than those of Na caprate and Na laurate, and nasal leucine aminopeptidase activity was more strongly inhibited by GAHS Na2 than by medium chain fatty acid salts, sodium glycocholate, GA Na or GZ K2. Therefore, it is suggested that GAHS Na2 is a very useful promoter which dose not irritate the nasal mucosal membrane or degrade insulin.

Bioequivalency of newly formulated digoxin powder containing mainly crystalline lactose, which is expected to improve the fluidity of powder, was compared with that of the previous formula containing non-crystalline lactose.The digoxin concentrations in serum of 8 healthy male volunteers were determined by Stratus Immunoassay System after oral administration of either new or old formulation of digoxin powders in a latin square crossover design.The extent and rate of bioavailability of the both digoxin powders were found to be bioequivalent.It was concluded that both formula had clinically equivalent bioavailability but the power of analysis in this bioequivalency test was lower than the guide-line valve given by the committee on bioequivalency test.

The enzymatic and chemical stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides has been studied. Chemical degradtion of the analogues was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chemical stability was greater under basic conditions. The chemical degradation of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymatic degradation of DDCN, DDUN and DDTN was not observed in human plasma, though cytarabine was degraded enzymatically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.

The effects of dietary fibers on the gastrointestinal absorption of cadmium were studied. The fibers, such as lignin, cellulose, and sodium carboxymethylcellulose (Na CMC), produced a slight decrease in the contents of cadmium in the tissues of rats following a single oral administration of cadmium. In addition, in rats fed continuously with the experimental diets containing cadmium together with fibers, lignin and Na CMC significantly decreased the contents of cadmium in the tissues. These results show that the fibers depressed the intestinal absorption of cadmium. It is suggested that the inhibitory effects of these fibers on the gastrointestinal absorption of cadmium were due to their intrinsic properties, such as ability to bind cadmium and effect on viscosity, and that the differences of inhibitory effects of the fibers on the intestinal absorption of cadmium were related to differences in such physical properties.