Tooru Mashimo

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.

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.

Studies of the slow releasing of testosterone from radiation-polymerized testicular prostheses implanted subcutaneously in the back of castrated rabbits.

A controlled release testicular prosthesis containing testosterone, which was previously dissolved in 2-hydroxyethyl methacrylate (HEMA) at a temperature of 80 degrees C, was prepared by radiation-induced polymerization in the supercooled state at a low temperature. The daily dose of testosterone released in vitro from the poly(HEMA) testicular prosthesis was kept constant at a rate of 5.5 +/- 1.5 mg/d throughout an experimental period of 900 d. In the in vivo experiments, the poly(HEMA) testicular prosthesis was implanted subcutaneously in the back of castrated rabbits over a maximum period of 11 mnth. The cumulative amounts of testosterone released in vitro and in vivo from the poly(HEMA) testicular prosthesis for a period of 11 mnth were found to be 2.1 g (30.0 wt% of initial drug) and 0.9 g (12.8 wt% of initial drug), respectively. The serum testosterone level in castrated rabbits with a poly(HEMA) testicular prosthesis rapidly decreased for periods up to 2 mnth (after increasing during the first 2 wk), then showed a moderate decrease for a few months, and finally held constant at a level of 10 ng/ml throughout the experimental period. It was concluded that a slight amount of testosterone is continuously released in vivo from the radiation-polymerized poly(HEMA) testicular prosthesis over a long period analogous with that in vitro.

Sequential polydepsipeptides containing tripeptide sequences and α-hydroxy acids as biodegradable carriers

Abstract Biodegradable polydepsipeptides having the sequences of l -alanyl- l -amino acyl-γ-ethyl l -glutamyl- l -hydroxy acyl [Ala-AA-Glu(OEt)-HA] were synthesized to evaluate the hydrolysis of the specimens by the action of enzymes. The enzymatic degradation and its degradation pattern were strongly dependent on the difference in size of side chain residues of l -aminoacyl and l -hydroxyacyl units in the sequence and, as a result, it was found that the introduction of l -leucic acid (Hmp) as HA unit in an Ala-Ala-Clu(OEt)-HA sequence leads to a typical S-type degradation pattern, in contrast to a parabolic-type for the introduction of glycolic acid (Hea). From the difference in action of enzymes, it was concluded that the sequential polydepsipeptides are much more subject to hydrolysis by esterase-type enzymes rather than by protease-type enzymes. For comparison, the in vivo degradation was examined; it depended strongly on the site of implantation, and degrading to the greatest extent when implanted in the kidney. Microscopic observation showed that the degradation occurs heterogeneously at the surface of the specimen with formation of micropores.

Effect of crystallinity on the in vivo degradation of poly(β-propiolactone) prepared by radiation-induced solid polymerization in organic solvent system at low temperature

Abstract Poly(β-propiolactone) [poly(PL)] samples with crystallinities of 32–67% were synthesized by radiation-induced solid polymerization at low temperature in the presence of various organic solvents. The crystallinity can be controlled by selection of solvent or by changing the content of solvent. This polymer which has an ester bond in the main chain degrades when implanted subcutaneously in the back of rats, e.g. a poly(PL) with crystallinity of 32% obtained by irradiating to 10 kGy at −78°C in a system containing of 12 ml of CCl 4 and 1 ml of PL monomer was perfectly degraded in vivo in the 50th week from the start of the test, in contrast to only 16% for pure poly(PL) with crystallinity of 67%. This finding means that the biodegradability of poly(PL) is strongly dependent upon the crystallinity. The relationship between the biodegradability ( y ) of poly(PL) after 20 weeks implantation and the crystallinity ( x ) gave a good straight line, in which the regression line was found to be y = −1.701 x + 120.6 and the correlation coefficient ( r ) was 0.985.