Preparation and evaluation of cyclodextrin polypseudorotaxane with PEGylated liposome as a sustained release drug carrier.

Cyclodextrins (CDs) can form polypseudorotaxanes (PPRXs) with drugs or drug carriers possessing linear polymers such as polyethylene glycol (PEG). On the other hand, PEGylated liposomes have been utilized as a representative anticancer drug carrier. However, little is known about the formation of CD PPRX with PEGylated liposome. In the present study, we first report the formation of CD PPRX with PEGylated liposome and evaluate it as a sustained release drug carrier. PEGylated liposome encapsulating doxorubicin was disrupted by the addition of α-CD. Meanwhile, γ-CD included two PEG chains and/or one bending PEG chain of PEGylated liposome and formed PPRX without the disruption of the membrane integrity of the PEGylated liposome. Moreover, the release of doxorubicin and/or PEGylated liposome encapsulating doxorubicin from the PPRX was prolonged in accordance with the matrix type release mechanism. These findings suggest the potential of γ-CD PPRX as sustained release carriers for PEGylated liposome products.

Polypseudorotaxanes of pegylated α-cyclodextrin/polyamidoamine dendrimer conjugate with cyclodextrins as a sustained release system for DNA.

Nonviral gene delivery suffers from a number of limitations including short transgene expression times and low transfection efficiency. In this study, we examined whether polypseudorotaxanes (PPRXs) of polyethylene glycol (PEG, molecular weight: 2,000)-grafted α-cyclodextrin (α-CyD)/polyamidoamine dendrimer conjugate (PEG-α-CDE) with CyDs have the potential for the novel sustained release systems for plasmid DNA (pDNA). The PEG-α-CDE/pDNA complex formed PPRXs with α-CyD and γ-CyD solutions, but not with ß-CyD solution. In the PEG-α-CDE/CyDs PPRX systems, 20.6mol of α-CyD and 11.8mol of γ-CyD were involved in the PPRXs formation with one PEG chain by α-CyD and γ-CyD, respectively, consistent with in the PEG-dendrimer/CyDs systems. PEG-α-CDE/pDNA/α-CyD PPRX and PEG-α-CDE/pDNA/γ-CyD PPRX formed hexagonal and tetragonal columnar channels in the crystalline phase, respectively. In addition, the CyDs PPRX provided the sustained release of pDNA from PEG-α-CDE complex with pDNA at least 72 h in vitro. The release of pDNA from CyDs PPRX retarded as the volume of dissolution medium decreased. Furthermore, the PEG-α-CDE/γ-CyD PPRX system showed sustained transfection efficiency after intramuscular injection to mice at least for 14days. These results suggest that the PEG-α-CDE/CyD PPRX systems are useful for novel sustained DNA release systems.

Potential use of polypseudorotaxanes of pegylated polyamidoamine dendrimer with cyclodextrins as novel sustained release systems for DNA.

In this study, we demonstrated the potential use of polypseudorotaxanes (PPRXs) of polyethylene glycol (PEG, molecular weight: 2000)-grafted polyamidoamine dendrimer (PEG-dendrimer) with cyclodextrins (CyDs) as novel sustained release systems for plasmid DNA (pDNA). PEG-dendrimer/pDNA complex formed PPRXs with α-CyD and γ-CyD solutions, but not with ß-CyD solution. In the PEG-dendrimer/CyDs PPRXs systems, 17.9 mol of α-CyD and 8.8 mol of γ-CyD were involved in the PPRXs formation with one PEG chain by α-CyD and γ-CyD, respectively. In addition, the CyDs PPRX formation provided the sustained release of pDNA from PEG-dendrimer complex with pDNA at least 72 h in vitro. In addition, the release of pDNA from CyDs PPRX retarded as the dissolution medium volume decreased. These results suggest that the PEG-dendrimer/CyD PPRX systems can work as a sustained DNA release system, and the PPRX formation with CyDs may be useful as a sustained drug delivery technique for other pegylated polymers.

Peak-less hypoglycemic effect of insulin glargine by complexation with maltosyl-ß-cyclodextrin.

Long-acting insulin products are desired that provide sustained blood glucose lowering without blood glucose level peaks. In the present study, to obtain the more desirable blood glucose lowering effect of long-acting insulin products, we investigated the effect of maltosyl-ß-cyclodextrin (G(2)-ß-CyD) on physicochemical properties and pharmacokinetics/pharmacodynamics of insulin glargine, which is the one of the most widely used insulin analog. G(2)-ß-CyD increased the solubility and suppressed the aggregation of insulin glargine in phosphate buffer at 9.5, probably due to the interaction of G(2)-ß-CyD with aromatic residues of the insulin glargine such as tyrosine. In addition, the dissolution rates of insulin glargine from its precipitates were increased by a complexation with G(2)-ß-CyD. Subcutaneous administration of an insulin glargine solution with G(2)-ß-CyD to rats gradually decreased blood glucose levels and provided a sustained blood glucose lowering effect without showing the glucose level peaks. These results suggest that G(2)-ß-CyD can be a useful excipient for sustained release and a truly peak-less formulation of insulin glargine.

Effect of sulfobutyl ether-ß-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-ß-cyclodextrin (SBE4-ß-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-ß-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-ß-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-ß-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-ß-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-ß-CyD can be a useful excipient for sustained release of insulin glargine.

Effects of Selected Anionic ß-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats.

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of ß-cyclodextrin sulfate (Sul-ß-CyD) and sulfobutylether ß-cyclodextrin (SBE7-ß-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-ß-CyD and SBE7-ß-CyD increased solubility of insulin glargine. SBE7-ß-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-ß-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-ß-CyD, but not Sul-ß-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-ß-CyD could be a useful excipient for sustained release of insulin glargine.