Kumakura Minoru

In vivo characteristics of low molecular weight copoly(L-lactic acid/glycolic acid) formulations with controlled release of luteinizing hormone-releasing hormone agonist

A copolymer ofL-lactic acid (LA) and glycolic acid (GA), which has a relatively low number-average molecular weight (Mn=1600–3300) was synthesized by means of direct copolycondensation without catalysts. The luteinizing hormone-releasing hormone agonist, des-Gly10-[Leu6]-LH-RH ethylamide monoacetate (LH-RH agonist), was incorporated by the melt-pressing technique in copoly(LA/GA) to obtain a fine cylindrical formulation. This solid formulation was implanted subcutaneously in the back of male adult Wistar strain rats. The in vivo degradation of copoly(LA/GA) formulation without LH-RH agonist showed a marked acceleration with increasing GA component in the copolymer, and the resulting maximal value was obtained at 3070 mol% LA/GA composition; for example, the copolymer with Mn=2300 went up to 100% in the 6th week from the implantation. The period required for 100% in vivo degradation increased linearly with increasing Mnof the copolymer. From this linear relation it was found that the period required for 100% biodegradation per 1000 gmol increase ofMn corresponds to approximately 6 weeks. The serum LH-RH agonist level in rats in which the copoly(7030 mol% LA/GA, Mtn=2900) formulation was implanted, which was degraded up to 100% after 16 weeks implantation, was kept constant during the first 10 weeks and then decreased linearly until its level could no longer be detected in the 15th week from the implantation. This finding shows that LH-RH agonist is constantly released in vivo from the biodegradable formulation over a long period.

A new biodegradable pasty-type copolymer of L-lactic acid and δ-valerolactone with relatively low molecular weight for application in drug delivery systems

Copolymers of l-lactic acid (LA) and δ-valerolactone (VL) with a number-average molecular weight (Mn) of 1500–2600 were developed as biodegradable carriers for drug delivery. Copolymers were synthesized by direct copolycondensation in the absence of a catalyst. Depending on the mol% of l-lactic acid residues, three different morphologies are obtained: solid state (100-80 mol%), pasty state (70-30 mol%), and waxy state (15-0 mol%). The degradation of the copolymer was markedly influenced by Rhizopus delemer lipase. The rate of degradation of the pasty copolymer in the presence of the lipase is much faster than that for the solid or the waxy Copolymers. A nitrogen mustard derivative of estradiol-17β, Estramustine, was incorporated into a pasty-type copoly(LA/VL, 70/30 mol%) with Mn = 2500. The system was completely degraded in vivo (rat) 5 weeks after insertion. A pharmacological effect on the prostates of rats was observed during a period of 5 weeks.

A new biodegradable implant consisting of waxy-type poly(ε-caprolactone-co-δ-valerolactone) and estramustine

Abstract Biodegradable waxy-type copolyesters were prepared by direct copolycondensation of e-caprolactone (CL) and δ-valerolactone (VL) in the absence of catalysts, to apply as implantable matrices for drug delivery systems. The copolyesters are much more subject to erosion than their homopolyesters, in which the degradation is further accelerated by the action of lipase-type enzyme. Estramustine was incorporated into a small cylinder of waxy-type poly(CL-co-VL) with 92 mol% CL unit device by the so-called melt-pressing technique. The in vivo capability of this device was evaluated by implanting into the back of male rats. The drug release, although accompanying a burst phenomenon in the initial stage, was kept constant throughout an experimental period of 19 weeks from the 1st to 20th week. In this case, the release pattern was parallel to the degradation pattern, in support of the release being the rate-limiting step in the degradation of the polymer. The results showed about 75% of the initial drug content was still present in the device even after 20 weeks implantation. This finding means that the biodegradable poly(CL-co-VL) wax is very useful as an implantable matrix for a drug delivery system which controls the release over a relatively long period of time.

Behavior of enzyme activity in immobilized proteases.

Abstract 1. 1. Proteases such as trypsin, a-chymotrypsin, papain, and thermolysin were immobilized by radiation polymerization of various monomers at low temperatures, and behavior of enzyme activity in immobilized proteases was studied. 2. 2. The enzyme activity in immobilized proteases appeared to be different by the kind of proteases; the order of the magnitude of the enzyme activity was papain > trypsin > thermolysin > a-chymotrypsin. 3. 3. This difference of the enzyme activity was explained by the change of the molecular conformation in enzyme reaction.