Degradation of polydispersed poly(L-lactic acid) to modulate lactic acid release.

Polydispersed poly(L-lactic acid) (PLLA) membranes comprised of blends of monodispersed PLLA of weight average molecular weight of 82,500 and 7600 were fabricated to investigate the effect of polydispersity on degradation characteristics. The PLLA blends exhibited large spherulites of high molecular weight chains embedded in a low molecular weight matrix. During degradation in phosphate buffer at pH 7.4 and 37 degrees C for 28 d, the release rate of lactic acid increased as the percentage of the low molecular weight component in the blend was increased. For low molecular weight compositions larger than 50%, voids were created in the degrading blends due to the degradation of low molecular weight chains and the concurrent dissolution of lactic acid, and also the release of undegraded particles of high molecular weight. These studies demonstrate the feasibility of modulating lactic acid release during in vivo degradation of PLLA implants by adjusting the polymer polydispersity.

Chemical release from topical formulations across synthetic membranes: infinite dose.

Drug release rates from topical preparations are sometimes measured by monitoring the cumulative mass of drug appearing in a receptor solution (MR). If the topical formulation and receptor solution are in direct contact, then MR increases linearly with square root of t. When a synthetic membrane is placed between the topical formulation and receptor solution, drug appearance in the receptor solution is delayed and MR is not immediately linear in square root of t. As a result, linear regressions of MR with square root of t produce positive values for the square root of t-intercept. Here, we mathematically model chemical release from an infinite-dose, topical formulation across synthetic membrane to quanitiatively determine the physical meaning of the square root of t-intercept. To correctly determine drug diffusivity in the topical formulation, the experiment must be conducted long enough that MR is linear in square root of t. Theoretically based procedures are presented for testing which data should not be used in linear regression of MR with square root of t. Theoretical predictions are compared with previously published experimental results for ethyl salicylate across a poly(dimethylsiloxane) (Silastic) membrane and for hydrocortisone across several different synthetic membranes.

A new method for estimating dermal absorption from chemical exposure. 1. General approach.

To evaluate systemic chemical exposure from dermal absorption, one must know the mass of chemical absorbed including the portion that has entered the skin but not yet entered the body's interior system. Algebraic equations are presented for estimating dermal absorption including the effects of exposure time and chemical nature of the compound, in particular lipophilicity and molecular weight. The proposed equations account for larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. These algebraic expressions are shown to represent adequately the exact solution of the unsteady-state diffusion equations for a two-membrane composite. Finally, procedures are proposed for estimating a priori the required physicochemical data when experimental values are not available. Specifically, the Potts and Guy permeability correlation is split into parts separately representing stratum corneum partitioning and diffusivity.

A new method for estimating dermal absorption from chemical exposure: 2. Effect of molecular weight and octanol-water partitioning.

A new method for estimating dermal absorption including the effects of exposure time and chemistry is described generally in Part 1 of this series. This method accounts for the larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. A key parameter in this procedure, the ratio of the stratum corneum and epidermis permeabilities (B) depends on molecular weight and octanol-water partitioning. Several approaches for approximating B and its affect on the dermal absorption prediction are discussed here. Generally, the parameter B is only important for highly lipophilic chemicals which also have relatively small molecular weights. When B is important, the recommended prediction for B is based on the Potts and Guy correlation for human stratum corneum permeability.

A new method for estimating dermal absorption from chemical exposure. 3. Compared with steady-state methods for prediction and data analysis.

PURPOSE: This paper compares unsteady-state and steady-state methods for estimating dermal absorption or analyzing dermal absorption data. The unsteady-state method accounts for the larger absorption rates during short exposure times as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. METHODS: Example calculations for dermal absorption from aqueous solutions are presented for five environmentally relevant chemicals with molecular weights between 50 and 410 and log10Kow between 0.91 and 6.8: chloromethane, chloroform, chlordane, 2,3,7,8-TCDD, and dibenz(a,h)anthracene. Also, the new method is used to evaluate experimental procedures and data analyses of in vivo and in vitro permeation measurements. RESULTS: In the five example cases, we show that the steady-state approach significantly underestimated the dermal absorption. Also, calculating permeability values from cumulative absorption data measured for exposure periods less than 18 times the stratum corneum lag time will overestimate the actual permeability. CONCLUSIONS: In general, steady-state predictions of dermal absorption will underestimate dermal absorption predictions which consider unsteady-state conditions. Permeability values calculated from data sets which include unsteady-state data will be incorrect. Strategies for analyzing in vitro diffusion cell experiments and confirming steady state are described.

Inhibition of smooth muscle cell growth in vitro by an antisense oligodeoxynucleotide released from poly(DL-lactic-co-glycolic acid) microparticles.

We fabricated poly(DL-lactic-co-glycolic acid) (PLGA) 50:50 microparticles loaded with an antisense (AS) oligodeoxy-nucleotide (ODN) against the rat tenascin mRNA and determined the effect in vitro of the AS-ODN released on smooth muscle cell (SMC) proliferation and migration. AS-ODN was entrapped using a double-emulsion-solvent-extraction technique with high efficiency. Release of AS-ODN was characterized by a small initial-burst effect followed by a period of controlled AS-ODN release for up to 20 days. SMC proliferation studies exhibited dose-dependent growth inhibition with AS-ODN-loaded microparticles. Microparticles loaded with scrambled (SC) ODN showed less growth inhibition than AS-ODN. Moreover, only the AS-ODN-loaded microparticles inhibited migration. These results demonstrate the feasibility of entrapping an AS-ODN to rat tenascin in PLGA microparticles for controlled delivery to inhibit SMC proliferation and migration.