Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

PURPOSE: Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation. METHODS: Excipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product. RESULTS: The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 µm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties. CONCLUSION: The spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond.

Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease.

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.

Thermally-prepared polymorphic forms of cilostazol.

Prior to this study, cilostazol, an antithrombotic drug, was thought to exist as a single crystalline phase with a melting point of approximately 159 degrees C (Form A). On cooling, melts often form a glass that, when heated, may crystallize as additional crystalline polymorphic forms. Cilostazol, when reheated, subsequently forms polymorphs that melt at approximately 136 degrees C (Form B) and 146 degrees C (Form C). Free-energy temperature diagrams estimated from calorimetry data reveal that each pair of the cilostazol polymorphs (A-B, B-C, and A-C) is monotropic. Essentially pure samples of suitable crystalline shape and size permitted single crystal structural analysis of Forms A and C. Theoretical solubility ratios calculated using calorimetry data indicate that at 37 degrees C, Form B should be more than four times more soluble and Form C should be more than two times more soluble than Form A. Forms B and C could not be crystallized from solvents. Metastable forms from super cooled melts analyzed by intrinsic dissolution and Fourier transform-Raman experiments demonstrated that Forms B and C undergo a rapid, solvent-mediated recrystallization to Form A, making dissolution rate measurements difficult.

Polymorphic forms of cilostazol.

Two unique conformational polymorphic forms of the compound 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one (cilostazol), C(20)H(27)N(5)O(2), have been discovered and characterized using single-crystal X-ray structural analysis. A third polymorph also exists, but acceptable crystals could not be obtained. Features of both reported polymorphic structures include a chair conformation of the cyclohexyl ring and puckering in the quinolinone ring. The major feature distinguishing the two polymorphic forms is a rotational twisting of the butoxy chain between the tetrazole and quinolinone rings. This difference in conformation influences the intermolecular forces, and hence the packing of the two molecules during crystallization.