Preparation and evaluation of once-a-day injectable microspheres of interferon alpha in rats.
Gelatin microspheres (ms) and gelatin/BSA (bovine serum albumin) or gelatin/alginate ms were prepared by encapsulating fluorescein isothiocyanate (FITC) labeled dextran or interferon alpha (IFN-alpha). Ms were obtained by an emulsion-solvent-extraction method. Gelatin and gelatin/BSA ms were obtained by treating water-in-oil (W/O) emulsions with iso-propyl alcohol. Gelatin/alginate ms having different composition (25/1, 20/1, 15/1, 10/1 and 5/1) were obtained by treating a W/O emulsion composed of gelatin and sodium alginate with 0.5 M calcium chloride solution. The average diameters of all the prepared ms were approximately 300 microns. The FITC-dextran loading efficiencies were 96.5 +/- 0.6% for gelatin ms (#1), 97.3 +/- 2.2% for gelatin/BSA ms (#2) and 68.7 +/- 2.2%, 55.0 +/- 3.9%, 47.5 +/- 3.3%, 44.4 +/- 1.2%, 27.1 +/- 2.2% for gelatin/alginate ms (#3-#7). The IFN-alpha loading efficiencies were 10.8 +/- 0.5% for gelatin/BSA ms (#8) and 22.5 +/- 1.8%, 17.6 +/- 0.9% and 14.5 +/- 0.5% for gelatin/alginate ms (#9, #10 and #11). In vitro release studies with ms containing FITC-dextran showed that the release rate of FITC-dextran from the ms decreased by the modification of gelatin ms with BSA or sodium alginate, although the effect of BSA addition to gelatin ms did not elucidate satisfactory sustained-release characteristics of FITC-dextran after subcutaneous (s.c.) injection to rats. By decreasing the formulated ratio of gelatin/alginate from 25/1 to 5/1, the mean T50%, the time when the half amount of FITC-dextran contained was released from the ms, increased from 1.7 +/- 0.1 to 13.8 +/- 3.6 h and three ms preparations (#4, #5 and #6) showed sustained-release characteristics on the serum FITC-dextran concentration-time profiles. Based on these results, three types of ms containing IFN-alpha were prepared and in vivo pharmacokinetic studies were performed in rats, where the dose of IFN-alpha was 2 x 10(4) IU/rat. By the addition of alginate to gelatin, the release rate of IFN-alpha was decreased and the serum IFN-alpha concentration-time profiles showed better sustained-release characteristics of IFN-alpha from #10 ms than the other IFN-alpha ms (#8, #9 and #11) after s.c. injection to rats.
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
Y
Y
Yoshikawa
Y
Y
Komuta
T
T
Nishihara
Y
Y
Itoh
H
H
Yoshikawa
K
K
Takada
D000464:Alginates; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019540:Area Under Curve; D003911:Dextrans; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005456:Fluorescent Dyes; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008863:Microspheres; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine; D013535:Suspensions
D000464:Alginates; D000970:Antineoplastic Agents; D003911:Dextrans; D005456:Fluorescent Dyes; D016898:Interferon-alpha; D013535:Suspensions; C015219:fluorescein isothiocyanate dextran; D012710:Serum Albumin, Bovine; D016650:Fluorescein-5-isothiocyanate