Okano Teruo

Block copolymer micelles as vehicles for drug delivery

Abstract There is a wide-spread consensus that characteristics of drug vehicles determine the applicability of the site-specific delivery of drugs. This article focused on the promising features of block copolymer micelles as drug vehicles mimicking the natural carrier-systems with supramolecular structures (i.e. viruses and lipoproteins). Considerable discussions are made on the physicochemical characteristics of polymeric micelles in aqueous milieu with shedding light on earlier works done in the field. Advantageous features of polymeric micelles as drug vehicles are summarized as: (1) formation of environmentally-separated microcontainer of drugs through supramolecular assemblage, (2) installation of anchoring moiety on the surface, (3) duration in the biological compartment and (4) programmable chronological stability. Then, our recent work concerning polymeric micelles with anti-tumor activity is presented to demonstrate these advantageous features of polymeric micelles. Worth noticing is that higher anti-tumor activity was achieved by adriamycin-conjugated micelles compared with parental adriamycin, indicating that a considerable improvement in cancer chemotherapy is feasible by the use of appropriate vehicle systems.

Polymer micelles as novel drug carrier: Adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer

Abstract A micelle-forming polymeric drug was synthesized using adriamycin (an anti-cancer drug) and poly(ethylene glycol)-poly(aspartic acid) block copolymers. The micelle had a narrow and unimodal size distribution, and its diameter was observed to be ca. 50 nm, the range corresponding to viruses. This micelle-forming polymeric drug exhibited good water solubility and good stability against precipitation irrespective of the large quantity of incorporated hydrophobie adriamycin. In vivo anti-cancer activity of this polymeric drug against P-388 mouse leukemia was studied by changing the length of the poly(aspartic acid) chain of the block copolymer. The polymeric drug showed excellent in vivo anti-cancer activity, judged from the ratio of the survival period of the treated mice to that of the control (T/C), with lower toxicity than that of adriamycin. These results point to a promising figure of polymeric micelles as novel drug carriers.

Inflammation responsive degradation of crosslinked hyaluronic acid gels

Abstract A biodegradable hydrogel of hyaluronic acid (HA) crosslinked with glycidylether was prepared and its degradation by hydroxyl radicals in vitro and by inflammation in vivo was investigated. In vitro, hydroxyl radicals produced by the reaction of H 2 O 2 and FeSO 4 induced a rapid but limited degradation of the crosslinked HA gels. The degradation profiles could be fit to a theoretical equation assuming that HA gels degrade preferentially from the gel surface. The in vitro degradation of crosslinked HA gels by hyaluronidase was negligible due to the prevention of access of hyaluronidase inside the gel. Drug microreservoirs (i.e., microspheres) were incorporated in a crosslinked HA matrix. These micro-spheres could be released during degradation of the matrix. In vivo implantation experiments revealed the degradability of the HA gel in response to inflammation. Therefore, crosslinked HA gels may be promising devices as inflammation (stimulus)-responsive degradable matrices for implantable drug delivery.

Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid

Abstract Heterogeneous structured devices consisting of lipid microspheres (LM) in degradable matrices of hyaluronic acid (HA) crosslinked with polyglycerol polyglycidylether were prepared and their inflammation responsive degradation was investigated in vivo. Hydroxyl radicals produced by the reaction of H2O2 and FeSO4 induced a rapid but limited degradation of the crosslinked HA gels. Zero ordered release of LM was achieved in proportion to the degradation of crosslinked HA gels according to surface-controlled mechanism. In vivo implantation experiments revealed the quantitative degradation of the HA gel in response to inflammation. Therefore, crosslinked HA gels may be promising devices as inflammation (stimulus)-responsive degradable matrices for implantable drug delivery.

Influencing factors on in vitro micelle stability of adriamycin-block copolymer conjugates

Stability of micellar structures in the presence of rabbit serum of adriamycin-conjugated poly (ethylene oxide)-poly(aspartic acid) block copolymers with several compositions was evaluated by gel-permeation chromatography. It was revealed that these adriamycin-block copolymer conjugates with the longer poly (ethylene oxide) chains and the shorter adriamycin-conjugated poly (aspartic acid) chains showed the more stable micelle formation. Physically trapped adriamycin in the inner core of the micelles was observed to influence on the stability. Furthermore, the stability of the micellar structures was found to well correlate with in vivo antitumor activity of the conjugates. These results present a strategy and a methodology in designing antitumor drug-block copolymer conjugates for highly selective delivery to tumors.

Preformulation of an Ara-A transdermal delivery system: Membrane fabrication and characterization

Abstract In order to develop a new transdermal delivery system providing variable drug delivery rates for antiviral Ara-A (9-β-arabino-furanosyladenine), it was first necessary to develop a method for designing rate-limiting polymeric membranes in transdermal devices having different permeability coefficients for Ara-A. Poly (2-hydroxyethyl methacrylate) (pHEMA) and copolymers of styrene (St) or N -vinylpyrrolidone (VP) with HEMA have been synthesized and the relationship between the hydration of membranes and the diffusion parameters has been investigated. The results of swelling measurements showed that swelling of polymer membranes was affected by the composition of copolymers, in which VP has a strong swelling effect and St has a deswelling effect. It is possible to control swelling properties in a range of approximately 46% to 195% at 37 °C in saline solution. The permeability coefficients of Ara-A in the copolymers showed a significant increase with increasing swelling of the copolymer membranes, and a good correlation between the permeability coefficient and swelling was observed. The observed linear relationship between the reciprocal of the hydration and the diffusion coefficients supports a diffusion mechanism based on the free-volume theory. The results show that the permeability coefficient of AraA through p(HEMA-VP) and p (HEMA-St) could be controlled in the range from 10 −5 to 10 −8 cm/s by changing the copolymer composition following the concept of a hydration-controlled transport process.

One-way membrane for transdermal drug delivery systems. II. System optimization

Effective flux of steroid solute through skin can be achieved by the use of ethanol as a co-solvent and penetration enhancer. To maintain constant drug release from a reservoir-type transdermal device and permeation through the skin, the composition of ethanol in the reservoir must remain constant. Ethanol permeability is much higher than that of either drug or water; any decrease in ethanol content may result in decreased drug flux. In an attempt to design a transdermal delivery device with constant ethanol enhancing activity, a model system was designed with separate ethanol reservoir, drug/solvent reservoir and receiver compartments. The ethanol and drug/solvent reservoir compartments were separated by a polydimethylsiloxane copolymer laminate membrane. This ‘one-way’ rate-controlling membrane (Yuk et al., Int. J. Pharm., 77 (1991) 221–229) optimized ethanol flux while preventing drug and water back flux. Permeation studies with model steroid solutes in this system demonstrated consistent ethanol enhancing activity with constant solute flux across the skin.