Seiya Kagatani

Enhancement of nasal salmon calcitonin absorption by lauroylcarnitine chloride in rats

AbstractPurpose. We investigated optimum formulation characteristics in the nasal absorption of salmon calcitonin (sCT) by incorporation of acylcarnitines. Methods. Nasal sCT formulations were administered to anesthetized rats. Plasma calcium level was measured and pharmacological bioavailability (P.bioav) was calculated. Results. Nasal sCT absorption was significantly enhanced by carnitines with acyl groups of 12 or more carbon atoms. Enhancement by lauroylcarnitine chloride (LCC) was observed at its critical micelle concentration and reached a plateau at the concentration of 0.1%. Optimal absorption was achieved at a molar ratio of LCC to sCT of 5:1. Enhancement was not influenced by osmolarity and maximum enhancement was obtained at pHs 3.1 and 4.0. Conclusions. The 12-carbon LCC was the strongest enhancer among acylcarnitines. Micelle formation played a key role in this enhancement effect.

Sugar-Branched-Cyclodextrins as Injectable Drug Carriers in Mice

The purpose of this study was to investigate stable complexation of drug in blood by sugar-branched-beta-cyclodextrins (beta-CDs) such as glucose (glu)- or galactose (gal)-branched-beta-CDs and the pharmacokinetic disposition of drug in sugar-branched-beta-CD complex. Complexation of steroidal drugs in sugar-branched-beta-CDs and their replacement by cholesterol were measured. The complexes of dexamethasone/glucosyl-beta-CDs (dexamethasone/glu-beta-CD or dexamethasone/glu-glu-beta-CD) were not replaced by cholesterol, which is a representative endogenous compound, whereas the complex of dexamethasone/beta-CD was replaced by cholesterol. The same results were obtained in steroidal drugs such as hydrocortisone, triamcinolone, and prednisolone. Thus, the use of glu-beta-CD and glu-glu-beta-CD permitted the stable complexation of the drug in water. Stability constants of dexamethasone/glu-glu-beta-CD and dexamethasone/gal-glu-beta-CD complexes are the same, which means that the sugar moiety of the side chain in beta-CD has little effect on stability constants. After the dexamethasone/gal-glu-beta-CD complex or the dexamethasone/glu-glu-beta-CD complex (dexamethasone: 1 mg/body) was administered intravenously to mice, dexamethasone concentrations in liver tissue and blood were measured. The dexamethasone/gal-glu-beta-CD complex (66.1 +/- 1.7 micrograms as dexamethasone/gram of liver tissue) was distributed to liver tissue significantly more than the dexamethasone/glu-glu-beta-CD (beta-CD) complex (59.9 +/- 1.0 micrograms as dexamethasone/gram of liver) at 30 min after administration (p < .05). Sugar-branched-beta-CD gave a water-soluble and stable complex for dexamethasone and changed the disposition of dexamethasone. Sugar-branched-beta-CDs are potentially excellent carriers for a steroidal injectable formulation.

Specific interaction between galactose branched-cyclodextrins and hepatocytes in vitro

Abstract The purpose of this experiment was to investigate specific interaction between galactose branched-cyclodextrins (gal-CyDs) and hepatocytes in vitro. Gal-CyDs were synthesized by an enzymatic method by using β -galactosidase. Gal-CyDs, galactose, glucose branched-CyDs (glu-CyDs) or glucose were incubated with hepatocytes on lactosyl polystyrene polymer (PVLA, high binding to hepatocytes) coated dish. It was found that adherence of hepatocytes to PVLA was inhibited by incorporation of gal-CyDs or galactose in the incubation medium at a concentration of 10 mM, but was not inhibited by incorporation of glu-CyDs or glucose at 20 mM. Further, after incubation of hepatocyte suspension with both fluorescein isothiocyanate-PVLA (FITC-PVLA) and gal-CyDs, gal-CyDs at 10 mM did inhibit the binding of FITC-PVLA to hepatocytes. In conclusion, it was suggested that enzymatically synthesized gal-CyDs have specific interaction with hepatocytes and may be useful as a drug targeting carrier to hepatocytes.

Nasal absorption kinetics of human growth hormone enhanced by acylcarnitines in rats

Abstract Pharmacokinetic analysis revealed that acylcarnitines enhanced overall nasal absorption of human growth hormone (HGH) in rats. Acylcarnitines dramatically shortened onset time, shortened absorption-duration time, and efficiently delivered HGH. HGH administered intranasally with acylcarnitines appeared in the blood within 0.28–2.7 min, far more rapidly than the 11.7 min after intranasal administration of HGH without acylcarnitines (CTL) or the 9.8 min after subcutaneous administration (SC). Absorption-duration times of HGH enhanced by acylcarnitines were in the range of 2.1–3.8 h, which are shorter than those of CTL (7.5 h) or SC (9.8 h). Among acylcarnitines at 1%, lauroylcarnitine chloride (LCC) showed the greatest absolute bioavailability (17.4%), which is 0.73 times the absolute bioavailability value for SC (22.1%). LCC enhancement reached a plateau at a concentration of 0.1%. This nasal absorption enhancement would be suitable for pulsatile administration. A single dose toxicity study also suggested that LCC had similar systemic safety to L -carnitine at a high dose of 100 mg/kg in mice. Further, the potential safety of LCC was ten times greater than palmitoylcarnitine chloride.

Nanosphere Coated with Lactosyl-Polystyrene Polymer as a Targeting Carrier to Hepatocytes

Polystyrene-latex nanosphere (PSL-NS, mean diameter: 85 nm) was coated with lactosyl-polystyrene polymer (PVLA, high affinity to hepatocytes) to evaluate its targeting characteristics to hepatocytes and PSL-NS surface hydrophilicity. Hepatocytes were adhered specifically with PVLA-coated dishes made of the same material as PSL-NS. Flow-cytometry investigation showed that PVLA-coated fluorescein-isothiocyanate (FITC)-PSL-NS was taken up by hepatocytes compared with noncoated FITC-PSL-NS as a control. These findings indicated PVLA-PSL-NS could target to hepatocytes. The surface of PVLA on PSL-NS had a higher hydrophilicity than polyethyleneglycol 6,000, Tween 80, poloxamer 407, and poloxamer 908, which indicated that PVLA-PSL-NS may avoid the reticuloendothelial system capture and have a long plasma duration after intravenous administration in vivo. Plasma coagulation can be prevented by the addition of polyvinylalcohol (0.1%) in PVLAPSL-NS solution when PVLA-PSL-NS was injected. We concluded that PVLA-PSL-...

Specific Interaction with Hepatocytes and Acute Toxicity of New Carrier Molecule Galactosyl-Polylysine

The new carrier molecules galactopyranosyl-glucuronyl-polylysines [Plys-Gal; molecular weights (MWs) of polylysine (Plys): 2,000, 10,000, and 25,000] were synthesized and their targeting characteristics to rats hepatocytes were evaluated. The maximum galactose substitution on Plys 2,000-Gal was found to be 8% of available sites. Adhesion of hepatocytes to Plys-Gal-coated dishes was inhibited by a lactosyl-polystyrene polymer (PVLA), which has been reported to be taken up via asialoglycoprotein receptors on hepatocytes. Plys 2,000-Gal had selective interaction with hepatocytes. After Plys-Gal was intravenously administered to mice (5, 10, and 20 mg/kg as Plys MW of 10,000 and 25,000), body weights were not different between mice administered Plys 10,000 or 25,000-Gal and saline as a control. It was suggested that the new carrier molecules Plys-Gals are very promising carriers for targeting drug to hepatocytes.