Physical-mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded films

The objective of this study was to investigate the moisture absorption, physical-mechanical and bioadhesive properties of hot-melt extruded hydroxypropylcellulose (HPC) films containing polymer additives. These additives included polyethylene glycol (PEG) 5%, polycarbophil 5%, carbomer 5%, Eudragit E-100 5%, and sodium starch glycolate (SSG) 5%. Relative humidity (RH) and temperature parameters of the films studied included 25 degree C at 0, 50, 80 and 100% RH, and 40 degrees C at 0 and 100% RH, stored for 2 weeks. Tensile strength and percent elongation were determined on an Instron according to the ASTM standards. The bioadhesive properties of the HPC/PEG 3350 5% film and the polycarbophil 5% containing films, with and without PEG, were investigated in vivo on the human epidermis. Although all films studied exhibited an increase in percent water content as the percent RH increased, the SSG containing film exhibited an almost three-fold increase in percent water content compared to that of the HPC/PEG film. The temperature storage condition of 40 degrees C/100% RH (versus 25 degrees C/100% RH) increased the percent water content of the SSG containing film. Percent elongation was highest for films containing polycarbophil 5% (without PEG). In addition, the HPC film containing polycarbophil 5% exhibited a greater force of adhesion and elongation at adhesive failure in vivo, and a lower modulus of adhesion when compared to the HPC/PEG film. A novel approach to determine bioadhesion of films to the human epidermis is presented.     

Matrix- and reservoir-based transmucosal delivery systems

Traditionally, per-oral delivery has been the primary route of administration for therapeutic agents targeting systemic delivery. However, oral administration subjects these compounds to extensive presystemic elimination, which may include gastrointestinal degradation, metabolism, or first-pass clearance via the liver, and may ultimately result in poor bioavailability. Parenteral routes, such as intravenous or intramuscular, permit therapeutic agents to gain direct entry into the systemic circulation and, therefore, reach the intended site of action more rapidly. Unfortunately, this mode of drug administration entails numerous disadvantages, including the requirement for close medical supervision and the need for specialized equipment. Transmucosal absorption of nitroglycerin from solutions through the oral cavity was demonstrated in the mid-nineteenth century, and since that time various conventional drug delivery systems for oral mucosal delivery have been proposed and have achieved clinical application. Technologic advances in biomaterials and techniques have resulted in the formulation of novel designs more pertinent to the oral cavity, meeting the challenges of the physicochemical properties of the drug entity itself and achieving the therapeutic aims of the drug delivery system. Issues of patient compliance and convenience have recently resulted in a trend toward once-a-day administration regimens, requiring drugs with high potency and sustained effect. Such drugs usually have a short biologic half-life, exhibit poor permeability and solubility, and are susceptible to enzymatic degradation. However, because of the advantages of delivering a drug through the oral mucosa, these drugs are viable candidates for delivery via this route. Many investigators have studied the potential of transmucosal delivery through the oral cavity, and the oral mucosa is increasingly being considered as a plausible route for many drug classes. Sublingual tablets, oral lozenges, chewing gum systems, and other dosage forms represent potential drug delivery systems for the oral mucosa, but most of the literature has not discussed information on specific drug delivery systems and their challenges. This article examines the anatomy, physiology, and absorption properties of the oral mucosal environment; explores the considerations for a transmucosal system; reviews these types of systems; and evaluates and proposes matrix and reservoir transmucosal applications.     

Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study.

PURPOSE: Trastuzumab as a single agent has activity in metastatic breast cancer; however, the mechanism of action for this clinical activity is uncertain. Whereas interruption of erbB family member signaling occurs, trastuzumab also mediates antibody-dependent cellular cytotoxicity in vitro and in vivo. Based on these data, a clinical trial was performed to test whether interleukin (IL)-2, by increasing FcRgammaIII(+) natural killer (NK) cell numbers and cytolytic function in vivo, when added to trastuzumab, can increase efficacy, be safely given, and avoid the use of chemotherapy. Experimental Design: In this Phase I trial, 10 patients with HER2-overexpressing metastatic breast cancer were treated with IL-2 (1.75 x 10(6) IU/m(2)/day, s.c.) for 7 weeks and trastuzumab (4 mg/kg load and then 2 mg/kg weekly) for 6 weeks. Safety, in vitro immune responses, and clinical responses were assessed. RESULTS: Ten women received a total of 12 cycles of therapy (each cycle lasted 7 weeks). No significant toxicities were seen, and one patient required an IL-2 dose reduction. Among the evaluable patients (10 cycles), the responses were one partial response, five cases of stable disease, and four cases of progressive disease. In vitro immune assays showed NK cell expansion and trastuzumab-mediated increased NK cell killing of breast cancer targets (antibody-dependent cellular cytotoxicity) in a HER2-specific manner but did not correlate with clinical responses. CONCLUSIONS: Trastuzumab + IL-2 is a well-tolerated outpatient regimen that results in NK cell expansion with enhanced in vitro targeted killing of HER2-expressing cells. These preliminary data suggest that this strategy may benefit heavily pretreated metastatic breast cancer patients.     

A simple and rapid immunological technique for visualising chromosome-mediated gene transfer (CMGT)

A method is described for visualising chromosome-mediated gene transfer (CMGT) by detecting chromosomes labelled with bromodeoxyuridine (BrdU) using a monoclonal antibody to BrdU. In this experiment, the CCRF-CEM T cell line was grown in the presence of BrdU and the labelled chromosomes were isolated and transfected into human embryonic fibroblasts. Uptake and retention of chromosomes were compared for transfection with either PEG or DMSO treatments. Following transfection the labelled chromosomes could be visualised in recipient cells using a monoclonal antibody to BrdU, followed by immunoperoxidase staining. Chromosome uptake into cells was similar for both DMSO and PEG treatments and was a relatively frequent event; about 1 in 5 recipient cells had labelled material present. This technique can be used to assess the technical aspects of the earliest stages of chromosome-mediated gene transfer.     

Characterization of hot-melt extruded drug delivery systems for onychomycosis.

The objectives of this investigation were to study the physico-chemical properties of hot-melt extruded (HME) films for onychomycosis and to determine the stability of the model antifungal drug incorporated within these films. The influence of etching and instrument variables on the bioadhesion of these drug delivery systems for the human nail was also studied. Six 250 g batches (F1-F6) of hydroxypropyl cellulose (HPC) and/or poly(ethylene oxide) films containing ketoconazole (20%) were extruded using a Killion extruder (Model KLB-100). The thermal properties of HME films were investigated using differential scanning calorimetry (DSC). Scanning electron microscopy (SEM) was used to examine the surface morphology of the films and X-ray diffraction (XRD) was used to investigate the crystalline properties of the drugs, physical mixtures as well as the HME films. Stability studies were performed on the films stored at 25 degrees C/60%RH. The bioadhesive properties of these films were investigated on the human nail (ex vivo) using a Texture Analyzer. The nail samples tested were either non-treated (control) or treated with an etching gel. The parameters measured were peak adhesion force (PAF) and area under the curve (AUC). The Hansen solubility parameter was calculated using a combination of Hoy and Hoftyzer/Van Krevelen methods to estimate the likelihood of drug-polymer miscibility. SEM provided direct physical evidence of the physical state of the drug within the films. The theoretical post-extrusion content of ketoconazole remaining in the six film batches ranged from 90.3% (+/-2.2) to 102.4% (+/-9.0) for up to 6 months and from 83.9% (+/-3.6) to 91.6% (+/-3.0) for up to 12 months. Bioadhesion studies of HPC film tested on 'etched' nails recorded significantly higher PAF and AUC than that of the non-treated 'control' nails. Ketoconazole was found to be relatively stable during the extrusion process. Melting points corresponding to the crystalline drugs were not observed in the processed films. The Hansen solubility parameters predicted miscibility between the polymers and the drug. The predictions of the solubility parameters were in agreement with DSC, XRD and SEM results. Bioadhesion measurements of the film on the human nail substrate were generally higher for the etched nails than that of the control nails.     

Aprepitant for the control of chemotherapy induced nausea and vomiting in adolescents

Nausea and vomiting are common side effects of chemotherapy in adult and pediatric patients. Even with standard antiemetic therapy, a significant number of patients continue to experience acute and delayed symptoms. When used in combination with standard antiemetic therapy, a new class of antiemetics, the neurokinin-1 (NK-1) receptor antagonists, have been shown to improve both acute and delayed nausea and vomiting in adults. In this report, we describe the NK-1 receptor antagonist aprepitant in two adolescent patients receiving highly emetogenic chemotherapy who had experienced refractory nausea and vomiting with previous chemotherapy courses. The addition of aprepitant to the antiemetic regimen in the patients resulted in significant subjective improvement in nausea and vomiting as well as quality of life. These results in our adolescent patients are promising, but there is a need for well-designed studies to determine the efficacy, dosing, and safety of aprepitant in children of all ages.     

Papilledema and dural sinus obstruction

We present two cases of meningioma obstructing the posterior sagittal sinus, producing elevated intracranial pressure and papilledema by impairing cerebral venous drainage. In both patients, this mechanism was not recognized preoperatively and resulted in optic atrophy and significant visual loss.     

The use of passive haemolysis in the quantitative estimation of anti-protein antibodies

The conditions for the establishment of a method for the quantitative assay of antiprotein antibodies by the use of passive haemolysis were studied by using an anti-BSA—BSA system as a model.

When haemolytic assaying of antibody was carried out under standard conditions with a fixed concentration of optimally sensitized red cells, in the presence of excess complement (10 C′H₅₀) reproducible titrations could be performed to detect 0.12 μg. N Ab with an error of ±10 per cent.

Factors affecting the specific lysis of optimally sensitized cells were studied and some parameters fixed. The amounts of coated erythrocytes and complement and the length of time of reaction were seen to influence the final degree of lysis given by a fixed amount of antibody.

The conditions of optimal sensitization of erythrocytes with protein antigen by the use of bis-diazotized benzidine (BDB) are indicated. It was found that, when conjugation was carried out at 0° with proper amounts of a standardized cell suspension, BDB and antigen, the resulting coated cells were highly sensitive to immune haemolysis and highly resistant to `spontaneous' lysis.