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Two trials were carried out in order to compare the prophylactic effect of a subcutaneously implanted sustained release device (SRD) containing a mixture of a biodegradable copolymer, poly(caprolactone-co-L-lactide), and isometamidium (ISMM) with that obtained after intramuscular injection of the drug. In a first experiment under controlled conditions, two groups of cattle were treated with 0.5 mg/kg isometamidium either as a SRD or intramuscularly (i.m.), and exposed at monthly intervals to Glossina morsitans morsitans infected with Trypanosoma congolense. The average protection period was at least 24 months in the SRD treated against 5.7 months in the i.m. treated group. Using an ISMM enzyme-linked immunosorbent assay, the drug could be detected until 140 days post-treatment in the latter group, whereas in the former group, traces of the drug were detectable until 330 days after treatment. Furthermore, a field trial was carried out at the Madina Diassa ranch in Mali involving three groups of N'Dama cattle, each containing 23 or 24 animals. Two groups were treated with 1 mg/kg ISMM either as a SRD or i.m. and a third group served as untreated control. Twelve months after treatment, the cumulative infection rates were 56.5, 87.8 and 91.6% in the SRD implanted, the i.m. treated and the control groups, respectively. The ISMM concentrations were slightly lower than in the laboratory trial, but the overall pattern of drug disappearance from the sera of the SRD treated cattle was very similar in both trials. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower in the SRD treated than in the i.m. treated group.

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Copolymers of epsilon-caprolactone and L-lactide P(CL-LLA), epsilon-caprolactone and D,L-lactide P(CL-DLLA) and epsilon-caprolactone and trimethylene carbonate P(CL-TMC) were synthesized. The composition of comonomers and their sequence lengths were determined by means of 1H and 13C NMR measurements. The effect of the comonomer on the thermal properties was investigated by differential scanning calorimetry (DSC) analysis. The in vitro degradation of the rods obtained by melt extrusion of the synthesized copolymers and the commercial homopolymers poly(epsilon-caprolactone) P(CL) and poly(D,L-lactide) P(DLLA) was carried out in phosphate buffer (PB) pH 7.4 at 37 degrees C. The rate of degradation depends on comonomers and polymer composition. The in vitro release of the selected drugs, isometamidium chloride (IMM) and ethidium bromide (EtBr), from such devices was carried out under the same conditions as used for the in vitro degradation. The release experiments show that the release of IMM is faster than for EtBr. During the first stage, for IMM the release is governed by osmotic pressure whereas for EtBr the release is mainly diffusion-controlled. The in vitro release of these drugs is governed by polymer matrix degradation at the later stage of the release process. Comparative in vitro release study from the different polymers showed that the release depends mainly on the physical properties of the polymer. The in vivo experiments carried out in the field on cattle and in the laboratory on rabbits using the classical treatment (intramuscular injection) and the sustained release devices (SRD) subcutaneously implanted, showed that the prophylactic period is significantly enhanced in the case of SRD as compared to intramuscular injection. The comparative efficacy of SRD containing IMM and EtBr evaluated in the case of rabbits showed that, the SRD (IMM) prophylactic period is much longer than for SRD (EtBr).

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In this study, commercial available poly(epsilon-caprolactone)s and poly(d,l-lactide)s of different molecular masses were used. Slow release devices (SRD) were obtained as rods of suitable diameters by extrusion of polymer-drug mixtures (75:25, w/w) which were prepared by the solution casting method. The rods were coated by dipping them in a methylene chloride solution of the core polymer. The in vitro release of the selected drugs, isometamidium chloride (IMM) and ethidium bromide (EtBr) from such rods was carried out in phosphate buffer (PB) pH 7.4 at 37 degreesC. The release data show that the release of IMM is faster than for EtBr. During the first stage, the release of IMM is governed by osmotic pressure whereas the release of EtBr is mainly diffusion controlled. The in vitro release of these drugs is governed by polymer matrix degradation at the later stage of the release process. The in vitro release could be controlled by drug loading, polymer molecular mass, polymer mixtures, coating thickness and device geometry.

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In order to compare the prophylactic effect provided by a poly(D,L-lactide) sustained-release device (SRD) containing isometamidium (ISMM) with that provided by the classical intramuscular injection of the drug, a field trial was carried out at the Madina Diassa Ranch in Mali. One- to 3-year-old N'Dama cattle were randomly divided into three groups. The first group (n = 42) was treated with ISMM at a dose of 1 mg/kg of body weight, the second group (n = 44) received the same dose of the drug via an SRD, which was subcutaneously implanted in the shoulder region, and the third group (n = 36) was kept as an untreated control group. All animals were treated with diminazene aceturate (7 mg/kg of body weight) 2 weeks before the start of the experiment and were tested monthly by the buffy coat technique for a period of 8 months. Glossina morsitans submorsitans was the most important tsetse species, with apparent densities (number of catches/trap/day) varying between 11.9 and 38.7 over the experimental period. Eight months after treatment the cumulative infection rates were 27.7, 58.5, and 77.4% in the group with the SRD implant, the group receiving the intramuscular injection, and the control group, respectively. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower (P = 0.006) in the group which received ISMM via the SRD than in the one which was treated with ISMM intramuscularly.

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Two successive experiments were carried out in which three cows were treated by intramuscular injection of either 0.5 mg/kg isometamidium or 1 mg/kg ethidium and compared with another group of three cows which received a subcutaneously implanted sustained release device (SRD) containing the same dose of drug. The prophylactic effect of both drug formulations was evaluated by exposing the animals at monthly intervals to Glossina morsitans morsitans infected with Trypanosoma congolense. The average protection period using the isometamidium- and the ethidium-SRD was extended by a factor of 3.2 and 2.8, respectively in comparison with the intramuscular injection of the drugs. In the analysis of isometamidium concentrations in the serum of the animals using a competitive drug-ELISA the drugs remained present for much longer periods in the sera of the implanted animals than in those of the intramuscularly treated cattle. The animals were still protected, however, a long time after the disappearance of detectable drug levels in the serum. No difference in drug sensitivity could be observed, when breakthrough isolates were compared from animals which received the ethidium-SRD and those treated intramuscularly, although a slight loss sensitivity occurred in the breakthrough isolates as compared to the parent trypanosome population.

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This article describes the synthesis of biodegradable polyphosphazenes. The rate of degradation can be varied in a controllable manner by the introduction of hydrolysis-sensitive amino acid ester side groups or by blending of polymers. Biodegradable polyphosphazenes can be used for the preparation of drug-containing implants and this is illustrated for devices containing the cytostatic agent mitomycin C. This article reviews data about the degradation characteristics of poly[(amino acid ester)phosphazene] derivatives that have been discussed previously. Some new data about MMC-containing poly[(organo)phosphazene] devices are discussed as well. (c) 1996 John Wiley & Sons, Inc.

RESUMEN

Two consecutive experiments were carried out to evaluate the prophylactic effect of biodegradable slow release devices (SRD), containing either isometamidium or homidium bromide. Rabbits subcutaneously implanted with SRD, were challenged with different Trypanosoma congolense stocks at regular intervals between 1 and 6.5 months after treatment. In a first experiment the efficacy of two types of isometamidium-SRD (poly(D,L-lactide) and poly(D,L-lactide-co-glycolide)) was compared with the classical intramuscular (i.m.) injection of the drug. Since the former polymer gave an average protection period, which was much longer than the other isometamidium formulation, a second experiment was carried out to evaluate the prophylactic effect of poly(D,L-lactide) SRD, containing either isometamidium or homidium bromide, with that of the i.m. injections of the same drugs at a dose of 1 mg kg-1. The average protection period of the homidium bromide SRD was significantly longer than that of the i.m. injected drug (112 vs. 49 days). No significant difference was obtained, however, when isometamidium was administered either as a SRD or as an i.m. injection. The average protection periods were, respectively, 106 +/- 37 days and 84 +/- 18 days. When breakthrough isolates derived from SRD-treated animals were compared with the original stocks of T. congolense, the former showed some loss of sensitivity to homidium bromide. No difference in sensitivity was observed, however, for isometamidium.

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