Ryoichi Wada

A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier

We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

Evaluation of a bilayer artificial skin capable of sustained release of an antibiotic

A bilayer artificial skin, composed of an upper silicone sheet and a lower collagen sponge, has been developed by modifying a technique proposed by Yannas and Burke. We have applied it clinically with success, but infection sometimes occurred in the area where the artificial skin was placed. To use it safely in an infected wound, we developed a new type of artificial skin capable of sustained release of antibiotic. Microspheres of poly-L-lactic acid containing an antibiotic, were installed in the upper silicone sheet. The usefulness of the new type of artificial skin was suggested by in vitro studies.

In vitro evaluation of sustained drug release from biodegradable elastomer

Poly(DL-lactic acid) (PLA), poly(ε-caprolactone) (PCL), and their copolymers (PLA-CL) with various monomer compositions were synthesized, and their properties as matrix for the sustained release of drugs were evaluated. The copolymerization technique produced very soft films which incorporated the drugs without deterioration of the elastic properties. Cisplatin and MD-805 were loaded in the films by casting the polymer solution containing the drugs. Fractions of the drugs released from the PLA-CL films were governed by the initial loading, the film thickness, and the polymer molecular weight. The drug release profiles obeyed the classical Fickian diffusion equation at least in the early stage, but significant hydrolytic degradation of the matrix polymers occurred in the later stage, influencing the kinetics of drug release. The monomer composition of copolymer affected the release profile more strongly than the initial molecular weight of the copolymer.

Controlled cisplatin delivery system using poly(D,L-lactic acid)

Cisplatin (CDDP)-containing poly(D,L-lactic acid) microspheres (CDDP-MS) and beads (CDDP-B) with an average molecular weight of the oligomer of 1.2 x 10(4) and 4% CDDP loading were prepared. In Tris buffer, 95% of CDDP disappeared from CDDP-MS within 3 d. In vitro and in vivo, CDDP-B released CDDP for 30-57 d, and for 21-42 d, respectively. The other CDDP-B with an average oligomer molecular weight of 9.6 x 10(3) with 5% lactic acid monomers, that contained 4% CDDP, showed a two-phase CDDP release pattern and CDDP disappeared within 41 d in vitro, and within 21 d in vivo. Histologically, tissue necrosis surrounding the CDDP-B was not severe.

Lactic acid oligomer microspheres containing an anticancer agent for selective lymphatic delivery. I. In vitro studies

Liberation controlee des medicaments inclus dans des matrices a base de polyether poly(urethane uree) en fonction de la structure moleculaire, des proprietes de solubilite, des proprietes thermiques

Kinetics of diffusion-mediated drug release enhanced by matrix degradation

Abstract Modified diffusion equations with a time-dependent diffusion coefficient were derived to formulate the kinetics of drug release from a quickly degradable matrix. To compare the theoretical equations with experimental observation, microspheres containing aclarubicin hydrochloride (ACR) were prepared by the solvent evaporation method using dl -lactic acid (LA) oligomers with different weight-average molecular weights ranging from 1,900 to 9,600. ACR release profiles from the LA oligomer microspheres were apparently of quasi-zero order, showing no burst effect during the whole duration of release, unless the molecular weight of LA oligomers was as low as a few thousand. The early stage of drug release from the LA oligomer microspheres was well explained in terms of Fickian diffusion and the apparent initial diffusion coefficient could be determined as a function of the molecular weight of LA oligomer. The diffusion coefficient decreased with time as a result of degradation of the matrix. It was concluded that the newly derived equations were applicable for the drug release from the biodegradable matrix such as DL-LA oligomers.

Biodegradation and antitumour effect of adriamycin-containing poly(l-lactic acid) microspheres

Adriamycin-containing poly (L-lactic acid) microspheres were prepared to develop a slow-releasing and long-acting adriamycin delivery system. An almost constant release of adriamycin from the adriamycin-containing poly(L-lactic acid) was achieved in Tris buffer and adriamycin disappeared within 20 d. Adriamycin was not detected in serum for up to 14 d, when the suspension of the adriamycin-containing poly(L-lactic acid) microspheres was injected into lung parenchyma, the femoral muscles of rabbits or the peritoneal cavity of mice. However, adriamycin remained in the rabbit muscles for up to 10 d under formation of scar tissue. When free adriamycin was added to P815 tumour cells in culture, the cell survival rate decreased with the exposure time. The treatment with the adriamycin-containing poly(L-lactic acid) microspheres showed a higher survival rate for mice bearing P815 tumour cells than with free adriamycin. In addition, the systemic side effects were insignificant when the adriamycin-containing poly(L-lactic acid) microspheres were given to mice instead of free adriamycin.

Salt Formation of Lactic Acid Oligomers as Matrix for Sustained Release of Drugs

Abstract— The calcium and sodium salts of l‐ and d, l‐lactic acid oligomers were obtained by immersion of the oligomer powders (weight average mol. wt 3000–10000) in aqueous solutions of CaCl2 and NaCl, respectively, at room temperature (22°C). The salt formation was analysed by atomic absorption measurement. The thermal properties, including glass transition temperature, melting temperature, and softening temperature, were altered by conversion of the terminal free acid of the oligomer to its salt. An in‐vitro release test of an anti‐cancer drug from the oligomer beads showed that the drug was released more rapidly from the beads prepared from the non‐converted oligomers than those prepared from the salts when the release test was carried out in media containing no calcium and no sodium ions.

New biodegradable oligoesters for pharmaceutical application.

Tartaric acid, malic acid, and glyceric acid were copolycondensed with glycolic acid at various molar ratios in feed to quickly synthesize biodegradable oligoesters. They were likely to have a moderately cross-linked structure with relatively low molecular weights and hydrophilic groups on the chains. In addition to macroscopic gels which were insoluble in any solvents, we could obtain the oligoesters which were insoluble in water but soluble in N,N-dimethylformamide. The degradation rate of the oligoesters was higher than that of lactic acid (LA) oligomers having molecular weights of a few thousands. On the contrary, their glass transition and flow temperatures were much higher than those of LA oligomers, indicating that their handling during the preparation of drug delivery dosage forms was much improved. The formulation of microspheres containing drugs from the oligoesters revealed that they were useful as biodegradable matrices having high degradation rates.