System model driven selection of robust tablet manufacturing processes based on drug loading and formulation physical attributes.

Mechanistic process modeling presents an opportunity to reduce experimental burden, enabling relationships between process parameters and product attributes to be mapped out using in-silico experiments. A system model of a pharmaceutical tablet manufacturing process comparing dry granulation with direct compression is developed to answer key material and process design questions. The system model links API physical properties and formulation to process parameters to map out the robust operating space. To demonstrate the application of the model, several drug product formulation design questions were considered:A computational framework was developed using the system models to generate process classification and design space maps to aid robust pharmaceutical formulation and process decision making. Process classification maps were produced to assess the feasibility of roller compaction and direct compression for different material properties and formulations. Constraints on the critical quality attributes of the intermediate and final products were defined using the Manufacturing Classification System. Design space maps presented here demonstrate how system models can be used to support formulation and process design. The design space maps illustrate how the process operating space can be increased or decreased as the API mass fraction is varied. The process design and selection system model demonstrate how an understanding of the API physical properties can be used to model the impact of formulation and process design. Furthermore, these models can be instrumental in the dialogue with colleagues developing the API in order to set the requirements of the API physical properties to ensure successful and robust formulation and process designs.

Gray-scale and color Doppler sonographic features of the vaginal cuff and cervical remnant after hysterectomy.

OBJECTIVE: The purpose of this study was to define the sonographic characteristics of the vaginal cuff and cervical remnant after hysterectomy and to establish normal measurements of each after each type of surgery. MATERIALS AND METHODS: One hundred twenty-one women who had undergone hysterectomy (mean age, 51 years; range, 31-80 years) were studied using transabdominal or transvaginal sonography. Seventy-six patients were acquired retrospectively and 45 prospectively. Hysterectomy types included abdominal, 52% (63/121); supracervical, 17% (20/121); vaginal, 17% (20/121); and unknown, 15% (18/121). Two reviewers, who were blinded to clinical information, evaluated each cuff or remnant in consensus. Transabdominal anteroposterior, transvaginal anteroposterior, and transvaginal length measurements before and after transducer compression, and amount of color Doppler flow as shown by percentage of color pixels (n = 36 patients) were correlated with hysterectomy type and patient age. RESULTS: Supracervical cuffs were larger (p < 0.01) than abdominal and vaginal hysterectomy cuffs (transabdominal sonography anteroposterior, 2.8 vs 1.5 and 1.6 cm; transvaginal sonography anteroposterior, 3.3 vs 1.8 and 1.7 cm; and transvaginal length, 3.0 vs 2.1 and 1.9 cm). Anteroposterior measurements, but not length, decreased significantly with advancing age. Transvaginal length decreased with compression (mean, 0.84 cm; p < 0.0001). Color Doppler flow scores (minimum, 56% [20/36]; mild, 28% [10/36]; moderate, 14% [5/36]; and absent, 3% [1/36]) did not vary with age, time since surgery, or type of surgery. CONCLUSION: The remnant is larger in every dimension after supracervical hysterectomy compared with both abdominal and vaginal hysterectomy and commonly shows some color Doppler flow.

Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma.

RATIONALE: Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB to enter the nucleus. OBJECTIVES: To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation. METHODS: The effect of inhibiting IKK-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation. MEASUREMENTS: The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined. MAIN RESULTS: Two structurally distinct molecules and dominant negative technology demonstrated that inhibition of IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony-stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-2 inhibitor blocked NF-kappaB nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia, and late asthmatic reaction, similar in magnitude to that obtained with budesonide. CONCLUSION: This study demonstrates that inhibiting IKK-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared with that of a steroid.