Tacey X. Viegas

Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules

Danazol was dissolved in non-aqueous mixtures containing either polyethylene glycol 400 or polysorbate 80, and filled into hard gelatin capsules at 50 mg concentrations. The bioavailability of these formulations was compared with commercial danazol capsules in a two-way crossover study using young female beagle dogs. Both formulations showed greater oral bioavailability when compared with either the 100 or 200 mg commercial brand of danazol. The bioavailability of the polyethylene glycol 400 and polysorbate 80 formulations was enhanced 3.7 and 15.8 times, respectively, when compared at the 100 mg dose level.

Osmotic behavior of poloxamer 407 and other non-ionic surfactants in aqueous solutions

Solutions of non-ionic surfactants were prepared in water and buffer. The osmotic behavior of these solutions were studied by measuring their osmolality, using the freezing point depression method. Graphical representation of osmolality versus concentration depicted non-linear parabolic curves that were applied to logarithmic and polynomial mathematical models. One such surfactant, poloxamer 407, was selected and studied in solutions of water and buffer. We observed curves of similar profile, which were attributed to its interaction and association in aqueous solution. In the liquid state the osmotic influence is due to the surfactant-water interaction. When the solution is warmed and converted to the gel state, the polymer is taken out of play and the osmotic influence is due to the aqueous solution only. This phenomenon was supported by in vitro red blood cell tonicity observations.

Evaluation of creams and ointments as suitable formulations for peldesine

In-vitro studies were conducted to study the efficacy of mixed and self-emulsifying creams and hydrophobic ointment formulations in delivering peldesine (BCX-34) into and across cryopreserved human cadaver skin (HCS). Oil-in-water cream formulations, containing 1% w/w of radiolabeled C(14) BCX-34 and propylene glycol (PG), glycerin (GLY), isopropyl myristate (IPM), oleic acid (OA) and capric-caprylic esters (CE) were prepared. Petrolatum and lanolin based ointments were also prepared with PG. Sections of the HCS, 250 microm thick, were fitted to vertical Franz diffusion chambers containing a receptor medium of pH 7.4 phosphate buffer solution maintained at 37 degrees C. Using the finite dose technique, 4-6 mg of a formulation sample was applied to the epidermal surface of each section and drug diffusion was permitted for 12 and 24 h periods. The distribution of drug into the HCS epidermis, dermis and into the receptor medium was measured by scintillation spectroscopy. The results show good correlation of the calculated in-vitro values for flux and skin-vehicle partition coefficients against the observed amounts of drug detected in the HCS. The mixed emulsion cream formulation containing PG delivered higher amounts of drug into the skin when compared to the same formulation containing GLY cream. The self-emulsifying cream formulation containing IPM had a higher skin-vehicle partition coefficient and delivered more drug into the dermis when compared to those formulations that contained OA and CE. The petrolatum ointment delivered six times more drug into the epidermis than the lanolin ointment, and had higher skin-vehicle partition values. In conclusion, creams containing PG and petrolatum-base formulations would be suitable for BCX-34 dermal delivery.

Percutaneous absorption of bendroflumethiazide from gel and membrane-controlled gel systems: an in vitro and in vivo study

A number of gel formulations were developed for bendroflumethiazide (BFTZ). The gels were composed of BFTZ dissolved in an alcohol–polyol–water medium and mixed with polyacrylic acid. Based on preformulation studies it was determined that a transdermal therapeutic system (TTS) could be constructed with 5% BFTZ, 40% ethanol (EtOH), 20% of a 1:1 mixture of 2-pyrrolidone and N-methyl-2-pyrrolidone (pyrol), 2% polyacrylic acid (PA) and 33% purified water, sandwiched between an aluminum foil backing and a porous polypropylene rate-control membrane. The device was tested, with and without the rate-control membrane, by in vitro diffusion across whole thickness SKH-1 hairless mouse skin and by in vivo percutaneous absorption in New Zealand White rabbits. In vitro results indicate that this device will deliver BFTZ at penetration rates of 0.66 and 0.98 μg/cm2 per h across hairless mouse skin, with and without the rate-control membrane, respectively. In vivo results show that blood levels of 50–300 ng/ml could be reached over a 12-h dosing period. Stability studies on the gel formulation and the TTS indicate that elevated storage temperatures will change the viscosity of the gel matrix and the release of BFTZ from the device.

Formulation of Penetration Enhancers in Polymers

AbstractTwo commercial polymer matrices were prepared : the hydrophilic macromolecular polyvinyl alcohol-povidone type and the hydrophobic microseal silastic silicone type. Different blends of the penetration enhancers Azone, 2-Pyrol and M-Pyrol in glycerine were incorporated with the drug, levodopa. The in-vitro dissolution of drug from these matrices and its diffusion through a semi-permeable membrane were measured. Results show that povidone polymers released 10 times more levodopa than did silicone polymers. The penetration enhancers significantly increased the rate of release of drug.

An In Vitro Method of Evaluating Tolnaftate Release from Topical Powder

A dissolution apparatus was constructed to evaluate tolnaftate release from topical powders. It consisted of a mesh unit to support the powder, a receptor phase, and a sink. This report describes three parameters that were used to evaluate this technique. First, three different areas of contact were examined using 52-, 41-, or 30-µm mesh supports. Second, the effect of the pH on the dissolution rate was studied, using aqueous buffers of pH 3, 5, 7, or 8 as the receptor phase. Finally, different topical powder formulations containing different amounts of tolnaftate were tested. The results obtained showed that the percentage of tolnaftate released from topical powders increased at low pH levels and with the larger mesh support. The percentage released was greater in a starch–talc preparation than in a talc-only preparation. The mesh was replaced by a semipermeable membrane (2.5- to 4 nm pore size) to function as an in vitro model for intradermal diffusion. The results showed that a cream initially released more drug than powder formulations.

REMOVED: Physicochemical properties of the potent influenza neuraminidase inhibitor, peramivir (BCX-1812)

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