The pharmacokinetics of cisplatin in mice with s.c. RIF 1 tumours was studied after intratumoural (i.t.) administration of drug in solution and in different slow-release devices. The data were compared with those obtained after i.p. administration of cisplatin. The slow-release devices under test were manufactured from either starch (ST) or polymeric hydrogels with different water uptakes (named T1, T2 and T3). In vitro release from these devices was approximately 100% in 2 h for starch rods, 100% in 24 h for T3 hydrogels, 45% in 4 days for T2 hydrogels and less than 10% in 4 days for T1 hydrogels. In vivo release rates agreed well with the in vitro data for T1 and T2 rods and were slightly slower in vivo for the T3 rods. The ST rods released the drug 6 times slower in vivo than in vitro. Plasma concentrations after i.t. administration were lower than those measured after i.p. administration. Systemic exposure to both total and free platinum was reduced to 70% for i.t. as compared with i.p. administration. Tumour concentrations were 4 times higher after i.t. than after i.p. administration. Tumour and peak plasma levels of platinum increased with increasing release rates. With the faster-releasing formulations (ST and T3), tumour platinum concentrations were 100 times higher than after i.p. administration. With the slower releasing formulations (T1 and T2), total tumour platinum concentrations were 2 and 9 times higher, respectively, than after i.t. administration of cisplatin in solution. Platinum distribution within the tumour was homogeneous after i.p. administration. After i.t. administration of cisplatin in solution, platinum concentrations in the centre of the tumour were approximately 4 times higher than in peripheral tumour tissue. Implantation of cisplatin in T2 and T3 hydrogel rods resulted in large concentrations of platinum in the centre of the tumour (the site of implant), which decreased steeply towards the tumour periphery. In summary, i.t. administration of cisplatin solution produced better results than did systemic (i.p.) administration in terms of tumour versus plasma drug-concentration ratios. Administration of drug in slow-release rods proved even more advantageous, although this was offset by inhomogeneous drug distributions within the tumour.

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In this study we investigated the effect of the incorporation of cisplatin in slow-release systems on tumour response and animal toxicity after intratumoural (i.t.) administration. Solid slow-release rods with incorporated cisplatin were prepared either from starch or from three different polyether-hydrogel formulations. In vitro release rates from these rods were widely different. With the starch system, approximately 100% release was obtained in 2 h. For the hydrogel formulations, release was approximately 100% in 1 day for a formulation with 40% water uptake (T3), 45% within 4 days for a formulation with 14% water uptake (T2) and 8% within 4 days for a formulation with 4% water uptake (T1). The slow-release rods containing graded amounts of cisplatin were implanted i.t. in s.c. RIF1 murine tumours. The i.t. administration of cisplatin in starch rods did not reduce animal toxicity or increase tumour response relative to i.t. injections of cisplatin in solution. For the hydrogel rods, the tumour response and animal toxicity for a given dose of cisplatin decreased with decreasing release rate. Higher doses of cisplatin could therefore be delivered with the slower-releasing hydrogel formulations. The slowest-release hydrogel rods (T1) had very little effect on either tumour (growth delay) or host (animal weight loss), even at cisplatin doses 8 times that tolerated as an i.p. injection. The fast (T3)- and intermediate (T2)-release hydrogel rods resulted in dose dependent tumour growth delays that were longer than those obtained with i.p. or i.t. administration of cisplatin. The highest response, a tumour growth delay of 55 days, was obtained with the intermediate-release hydrogel rods (T2) at a cisplatin dose of 40 mg/kg. Analysis of tumour growth delay for a given level of toxicity indicated that the intermediate-release formulation (T2) was slightly better than the fast-release formulation (T3) and confirmed the therapeutic advantage of i.t. implants over systemic therapy.

A new formulation for nasal administration containing 17 beta-estradiol (E2) with dimethyl-beta-cyclodextrin (DM beta C) as a solubilizer and absorption enhancer is described. Nasal administration of this E2-DM beta C formulation gave a significantly higher E2 absorption than an E2 suspension in both rabbits and rats. Relative to an intravenous injection of the E2-DM beta C formulation, absolute bioavailabilities of 94.6 and 67.2% were calculated for the nasal E2-DM beta C formulation in rabbits and rats, respectively. Differences in bioavailability may have resulted from differences in experimental animal conditions. The effects on human nasal ciliary activity of the E2-DM beta C formulation were studied with an in vitro method. The formulation was found to exert only a minor effect on ciliary beat frequency. Thus, nasal delivery of E2, using a cyclodextrin inclusion formulation, may have potential for clinical application, e.g., in the therapy of postmenopausal disorders.

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