Supercritical fluid extraction-liquid chromatography method development for a polymeric controlled-release drug formulation.

We have recently been involved in the development of a method for assaying the active component in a controlled-release drug formulation, which is composed of a drug substance covalently bonded to polymer matrix. The drug substance in the formulation is the active enantiomer of misoprostol, a synthetic analog of natural prostaglandins and the active ingredient in Cytotec. Our method development consisted of a systematic evaluation of dynamic, off-line supercritical fluid extraction (SFE) as sample preparation for the formulation assay. Extracts were analyzed with normal phase and reversed-phase HPLC methods. The reversed-phase system utilized postcolumn reaction to provide selective detection of the extracted prostaglandin sample components. Several SFE parameters were investigated to optimize the recovery of the drug substance from the formulation, including sample quantity, extraction cell volume, extraction duration, supercritical carbon dioxide modifier, temperature, pressure, and collection solvent. The SFE experiments were completed with a commercially available multicell extractor. Preliminary validation studies utilized a formulation made with radiolabeled drug to determine the recovery achieved under the optimized SFE conditions and assessed the precision of replicate determinations. Analysis was completed under the optimized conditions to quantitate levels of the active component and related compounds in lots of the experimental polymeric formulation and to determine the total weight per cent extracted.

Polymer delivery of the active isomer of misoprostol: a solution to the intestinal side effect problem.

SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

Catalytic functionalization of polymers: a novel approach to site specific delivery of misoprostol to the stomach.

The application of functionalized polymers to site-directed delivery of the antiulcer prostaglandin, misoprostol, is described. By use of homogeneous catalysis, the simple polymer, polybutadiene, was modified to incorporate the specialized requirements for controlled delivery of misoprostol to the stomach. An acid labile silyl ether bond to the C-11 hydroxyl of misoprostol was installed as the primary rate determining step for drug release, and a series of analogs, in which the steric hindrance about the silicon atom was varied, was prepared and evaluated for in vitro release rates, efficacy against indomethacin induced gastric damage and diarrheagenic activity. The diisopropylsilyl analog, the slowest releasing system studied, showed efficacy equal to misoprostol against indomethacin-induced gastric damage and no diarrhea at the highest dose tested.

Cisplatin-based chemotherapy in a renal transplant recipient.

Cisplatin-based chemotherapy is the treatment of choice for metastatic testicular cancer; however, the safety of conventional regimens in renal transplant recipients has been questioned. The authors report the course of a renal transplant recipient successfully treated with a cisplatin-based chemotherapy regimen for testicular seminoma and review three additional cases that have been reported in the English language literature to date. Emphasis is placed on review of the safety, optimal administration, and appropriate monitoring of cisplatin and controversy regarding the need for continued administration of immunosuppressive therapy.

Thrombotic thrombocytopenic purpura: combined treatment with plasmapheresis and antiplatelet agents.

Seven of eight patients with thrombotic thrombocytopenic purpura who were treated with both exchange plasmapheresis and antiplatelet agents (aspirin and dipyridamole) achieved complete remission. The eighth patient appeared to fail on this regimen but responded to corticosteroids and splenectomy. A ninth patient attained full remission after therapy with only aspirin and dipyridamole. The antiplatelet agents appeared to play an important role in the response of four patients. Eight patients received maintenance aspirin and dipyridamole. This maintenance therapy may have prevented relapses of thrombotic thrombocytopenic purpura in some patients as evidence of active, subclinical disease persisted for many weeks in most patients. Treatment with maintenance antiplatelet agents was discontinued in five patients after 7 to 18 months and no patient has relapsed. An effective therapeutic regimen for thrombotic throbocytopenic purpura would include initial therapy with exchange plasmapheresis, aspirin, and dipyridamole and maintenance therapy with antiplatelet agents.