Hisako Yuasa

Synthesis of low-molecular-weight copoly(l-lactic acid/ɛ-caprolactone) by direct copolycondensation in the absence of catalysts, and enzymatic degradation of the polymers

Low-molecular weight copolymers of l -lactic acid (LA) and ɛ-caprolactone (CL) were synthesized by direct copolycondensation without catalysts at 200°C under a nitrogen atmosphere. The reaction proceeds by direct condensation between linear LA and linear 6-hydroxycaproic acid produced by hydrolysis of the cyclic CL. These copolymers were characterized with respect to molecular weight by gel permeation chromatography, composition by 1 H nuclear magnetic resonance (n.m.r.) spectroscopy, sequence by 13 C n.m.r. spectroscopy, and crystallinities by both differential scanning calorimetry and X-ray measurement. The morphology of copoly (LA/CL) can be subdivided into three states as a function of monomer composition according to the differences in T g and crystallinity, e.g. solid (0–15 mol% CL composition ranges), paste (30–70 mol% CL composition ranges) and wax (85–100 mol% CL composition ranges). The in vitro degradation of the copolymer was examined by treatment in buffer solutions with and without enzymes and, as a result, Rhizopus delemer lipase showed the strongest degradation activity. In this case, the degree of enzymatic degradation is strongly dependent on the morphology of copoly(LA/CL), in which the pasty copolymer is much more subject to hydrolysis than the solid and waxy copolymers. For comparison the in vivo degradation of the copolymer was investigated by implanting it subcutaneously in the back of rats.

Biodegradable implant composites for local therapy

Abstract Implantable polymer-drug composites prepared by radiation polymerization have been applied to cancer therapy. Local chemotherapeutic treatment can be achieved by te use of implantable needles and buttons consisting of polymer and various anticancer agents. For example, the luteinizing hormone releasing hormone (LHRH) agonist-polymer needles have been successfully used for the hormone therapy of prostatic organ cancers. The effects of chemical structure on the in vivo degradation and controlled release were studied for biodegradable polymers of polypeptides, poly(α-hydroxy acids) and polydepsipeptides.

In vivo characteristics of low molecular weight copoly (D,L-lactic acid) formulations with controlled release of LH-RH agonist.

Amorphous and crystalline copolymers with a relatively low molecular weight of 1800 were synthesized by direct copolycondensation of D-lactic acid and L-lactic acid in the absence of a catalyst, to evaluate their in vivo capabilities as biodegradable carriers for drug delivery systems. A luteinizing hormone-releasing hormone agonist, des-Gly10-(D-Leu6)-LH-RH ethylamide, was incorporated in a fine cylindrical copolymer formulation, under melt-pressing technique, a mild heat-pressure condition. This formulation was implanted subcutaneously in the back of male rats. The rate of in vivo degradation of amorphous copolymer was much faster than that of crystalline copolymer. Contrary to this tendency, the in vivo release of the drug from this amorphous formulation was held constant over a longer period, compared with the crystalline formulation. This can be closely related to the difference in dispersion of the drug in the formulation.

In vivo controlled release of a luteinizing hormone-releasing hormone agonist from poly(dl-lactic acid) formulations of varying degradation pattern

Abstract Biodegradable formulations with a desired lag time were prepared from blends of low molecular weight poly( dl -lactic acid) (low MW-PLA, number-average molecular weight: M n = 1400 , parabolic-type degradation pattern, 100% in vivo degradation at 5th week of implantation) and high molecular weight poly( dl -lactide) (high MW-PLA, M n = 11 500 , S-type degradation pattern with a lag time of 10 weeks). A luteinizing hormone-releasing hormone agonist (LH-RH agonist), des-Gly10-[Leu6]LH-RH ethylamide monoacetate, was incorporated into the small cylinders of PLA blends. The initial burst of drug release from cylindrical formulation, which was implanted subcutaneously in the back of male rats, could be controlled by adjusting the amount of high MW-PLA in the blend and, as a result, it was found by measuring the pharmacological influence on rat prostate and serum drug levels that the best efficacy and the most constant release over a long period are obtained with a 25/75% low MW-PLA/high MW-PLA blend.

In vivo characteristics of high, molecular weight copoly(l-lactide/glycolide) with S-type degradation pattern for application in drug delivery systems

Amorphous copoly(L-lactide)/glycolide, 70/30 mol%) with weight average molecular weights of 16,900-41,300 were synthesized by ring-opening polymerization in the presence of catalysts using a molecular weight moderator lauryl alcohol. The in vivo degradation profiles of the copolyesters, which were evaluated by implanting them subcutaneously in the back of rats, showed a typical S-type degradation pattern. A luteinizing hormone-releasing hormone agonist (LH-RH agonist), des-Gly10-[Leu6]-LH-RH ethylamide monoacetate, was incorporated into the small cylinders of copoly (L-lactide/glycolide) with a weight average molecular weight of 24,000. The cumulative amount of drug released in vivo from the cylinders showed an S-type profile in analogy with the in vivo degradation pattern. This was demonstrated from data such as serum drug level and pharmacological influence on rat prostates.

Synthesis of biodegradable copoly(l-lactic acid/aromatic hydroxy acids) with relatively low molecular weight

Abstract Biodegradable copolyesters having aromatic rings (C6H5, CH2 · C6H5) as side-chain residues, e.g. l -lactic acid (LA)/ dl -mandelic acid (MA) and LA/ l -3-phenyllactic acid (PheLA), were synthesized by direct copolycondensation without catalyst at 200°. These copolyesters were characterized with respect to composition (1H-NMR spectroscopy), molecular weight (gel permeation chromatography), crystallinity (differential scanning calorimetry) and in vivo degradation (animal experiments). The in vivo degradation pattern changed from a typical parabolic-type to an S-type with increasing aromatic hydroxyacid content in the copolyester and molecular weight of the copolyester. In this case, the degree of in vivo degradation of copoly(LA/PheLA) exceeded that of copoly(LA/MA), because of differences related to the side-chains of aromatic hydroxyacyl units in the copolyesters.

Biodegradable poly(dl-lactic acid) formulations in a calcitonin delivery system

A synthetic analogue of eel calcitonin, [Asu1, 7]-ECT, was incorporated into biodegradable poly(DL-lactic acids) with number-average molecular weights (Mn) of 1400-4400 by the melt-pressing technique. The in vitro release of drug from a parabolically degradable poly(DL-lactic acid) with Mn = 1400 showed an initial burst release and completed the release in 3 d from the start of the test. The drug release from a Mn = 4400 polymer with an S-type degradation pattern was kept at 14 +/- 5 units/d for an experimental period of 24 d.

Fusibility of Poly(N-carboxy α-Amino Acid Anhydride) Materials Treated under Pressure-Heat Conditions and in Vitro-in Vivo Degradation of Hot-Pressed Materials

Abstract Powdered poly(N-carboxy α-amino acid anhydride) materials were treated at temperatures of 50, 100, 150, and 200°C under a pressure of 150 kg/cm2. A number of hot-pressed materials showed simultaneous fusion and contraction in volume. The fusion temperature of the hot-pressed materials was generally lower than the true melting point of the powdered materials at atmospheric pressure (determined with a Differential Scanning Calorimeter). The hot-pressed materials had high rigidity and transparency. The in vitro-in vivo degradation of hot-pressed materials was also investigated. The homo- and copoly(α-amino acid) materials used in this study were scarcely degraded, though debenzylated t e rpolymers such as β-benzyl-L-aspartate/aspartic acid/L-leucine and γ -benzyl-L- glutamate/glutamic acid/L - leucine we re significantly degraded in both the in vitro and in vivo experiments. It was found that the in vivo degradation profile of hot-pressed terpolymer materials corresponds relatively well to degradati...

In vivo characteristics of low molecular weight copolymers composed of L-lactic acid and various dl-hydroxy acids as biodegradable carriers for drug delivery systems

Low molecular weight and amorphous copolyesters composed of 70 mol% L-lactic acid and 30 mol% DL-hydroxy acids such as DL-lactic acid, DL-alpha-hydroxy-n-butyric acid, DL-alpha-hydroxyisovaleric acid and DL-alpha-hydroxyisocaproic acid were synthesized by direct copolycondensation in the absence of catalysts, to evaluate their in vivo capabilities as biodegradable carriers for drug delivery systems. For this purpose, the copolyester was moulded into a small cylindrical specimen under melt-pressing technique and implanted subcutaneously in the back of male adult rats. The in vivo degradation pattern can be subdivided into three types: the formations of parabolic type (L-LA/DL-HBA copolymer), linear type (L-LA/DL-LA copolymer) and S type (L-LA/DL-HIVA and L-LA/DL-HICA copolymers). A luteinizing hormone-releasing hormone agonist, des-Gly10-(D-Leu6)-LH-RH ethylamide monoacetate (LH-RH agonist), was incorporated into the small cylinders of copolyester formulations, of which the strongest pharmacological influence was observed in a copoly(L-LA/DL-HICA) formulation system, resulting in the maintenance of effective pharmacological influence throughout an experimental period of 15 wk, at which the in vivo release rate of LH-RH agonist was held constant at approximately 45 micrograms/d.

In vivo release of cisplatin from a needle-type copolymer formulation implanted in rat kidney

Cisplatin, cis-dichlorodiamine platinum (II), was incorporated in a needle-type copolymer formulation (0.8 mm diameter, 6 mm long) by radiation-induced polymerization. The copolymer used was copoly(diethylene glycol dimethacrylate/polyethylene glycol #600 dimethacrylate, 80/20 vol%). This copolymer, containing 6 mg of cisplatin, was implanted into the kidney of adult male Wistar rats (420 +/- 20 g). A total of 70 d was required for 100% release of cisplatin in vivo. The kidney tissue surrounding the formulation was strongly necrotized by the action of cisplatin. Two layers of necrosis could be distinguished: necrotic tissue surrounding the formulation and necrobiotic tissue surrounding the necrotic tissue. The amount of necrotic tissue changed markedly over time, but no change was apparent in the amount of necrobiotic tissue. The maximal amounts of necrotized tissue were observed 14 d after implantation: 3100 microns and 600 microns thick for the necrotic and necrobiotic tissues, respectively.