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.

Nasal absorption kinetic behavior of azetirelin and its enhancement by acylcarnitines in rats.

PURPOSE: The long-term stability and nasal absorption characteristics of a basic nasal formulation of azetirelin, a thyrotropin-releasing hormone analog and its absorption enhancement by incorporation of acylcarnitines in the formulation were investigated. METHODS: The long-term stability of basic nasal azetirelin formulations at 25 degrees C was predicted by calculation from the Arrhenius plot of the data on 6 months' storage at 40, 50 and 60 degrees C. Nasal azetirelin absorption characteristics were kinetically examined by intranasal administration to rats, determination of plasma azetirelin level by radioimmunoassay, and fitting the data to a two-compartment model including absorption rate. RESULTS: Basic nasal azetirelin formulations of pH 4.0 and pH 5.1 were predicted to be highly stable. Residual azetirelin after 2 years storage at 25 degrees C was greater than 95%. Nasal absorption characteristics of this formulation in the pH 4.0-6.3 range showed pH-dependency, with pH 4.0 showing the highest absolute bioavailability (Bioav) of 17.1%. This nasal Bioav was 21 times greater than that of oral administration (0.8%). Acylcarnitines with 12 or more carbon atoms in the acyl chain greatly enhanced nasal absorption of azetirelin: Bioavs with lauroylcarnitine chloride (LCC) and palmitoylcarnitine chloride were 96.9% and 72.9%, respectively. This enhancement by LCC plateaued at the low concentration of 0.1%. CONCLUSIONS: The basic nasal azetirelin formulation at pH 4.0 is stable and shows adequate absorption, with nasal absorption having greater Bioav than oral absorption. The 12-carbon acylate LCC was the strongest enhancer among acylcarnitines and provided near-total delivery of the administered dose to the blood.

In vivo fate of folate-BSA in non-tumor- and tumor-bearing mice.

KB tumor cells exhibit an increased number of folate receptors on their membrane. This receptor has been proposed as a promising target for tumor drug targeting. Therefore, the disposition of folate-conjugated bovine serum albumin (folate-BSA) was examined as a model system for drug targeting. Nude mice which had received KB tumor cell transplants were given bolus intravenous administration of either 111In-labeled folate-BSA (111In-folate-BSA; 1 mg/kg) or unmodified 111In-BSA (111In-BSA; 1 mg/kg). The disposition characteristics and pharmacokinetics of 111In-folate-BSA were compared with those of the 111In-BSA as a control. The half-life of the beta-phase of 111ln-folate-BSA in plasma was 140 min. The tumor uptake rate index for 111In-folate-BSA was 0.46 microL/min/g, and that for 111In-BSA was 0.32 microL/min/g. This index of 111In-folate-BSA was slightly higher than that of 111In-BSA in vivo, by a factor of 1.4. In vivo experiments showed folate-BSA has a relatively long plasma duration. 111In-folate-BSA also showed selective distribution to tumors, but not as great as recent results from in vitro experiments. Therefore, the low vascular permeability of BSA into solid tumor tissue and inhibition of folate-mediated 111In-folate-BSA uptake by tumor cells from the blood may be the rate-limiting factor of distribution.

Electroresponsive pulsatile depot delivery of insulin from poly(dimethylaminopropylacrylamide) gel in rats.

We describe a model for pulsatile drug delivery with an electroresponsive polymer that is stimulated by an externally applied electrical field. Insulin loaded in an electroresponsive poly(dimethylaminopropylacrylamide) (PDMAPAA) gel was administered as a subcutaneous depot in rats. The gel induced a pulsatile plasma glucose decrease in correspondence to stimulation with a constant current of 1.0 mA (0.36 mA/cm2). The first drop occurred at 0.5 h after a 1-min application of current at 0 h and the second drop occurred at 3 h after a 10-min application of current at 2 h. Calculation of pharmacological bioavailability showed that the gel released 0.12% of the loaded insulin after these two stimuli. This in vivo study demonstrates the feasibility of this pulsatile delivery system. The mechanism of insulin release from the electroresponsive PDMAPAA gel is associated with electrokinetic flow of solvated insulin with water; that is, transportation process of counterions (electrophoresis) and water molecules (electroosmosis) in the crosslinked polyelectrolyte gel network.

Enhancement of nasal salmon calcitonin absorption by lauroylcarnitine chloride in rats.

PURPOSE: 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 percent. 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.

Intestinal absorption mechanism of amino-beta-lactam antibiotics. III. Kinetics of carrier-mediated transport across the rat small intestine in situ.

The transport kinetics of amino-beta-lactam antibiotics was studied by an in situ rat small intestinal recirculating perfusion technique. The disappearance rates of the antibiotics from the perfusing luminal solution followed mixed-type kinetics with saturable and nonsaturable processes. The kinetic parameters were determined. Pharmacokinetic analysis of the time courses of luminal disappearance, tissue accumulation, and blood concentration indicated that the transfer of the antibiotics from the in situ luminal solution to tissue is nearly irreversible. On the assumption that the saturable transport process involves a common carrier for these antibiotics, the predicted extents of mutual inhibition using the in situ kinetic parameters were in good agreement with the experimental values for cephalexin and cephradine. The effects of cephalexin and cefadroxil on the absorption of cyclacillin were also consistent with a common transport mechanism. The dipeptides, carnosine and L-phenylalanylglycine markedly inhibited cyclacillin absorption in a competitive fashion. Furthermore, cyclacillin inhibited the absorption of carnosine. The results indicate that the absorption of amino-beta-lactam antibiotics is closely related with that of dipeptides.