In vitro-in vivo relationship for amorphous solid dispersions using a double membrane dissolution-permeation setup.

The use of amorphous solid dispersions (ASDs) is one commonly applied formulation strategy to improve the oral bioavailability of poorly water-soluble drugs by overcoming dissolution rate and/or solubility limitations. While bioavailability enhancement of ASDs is well documented, it has often been a challenge to establish a predictive model describing in vitro-in vivo relationship (IVIVR). In this study, it is hypothesized that drug absorption might be overestimated by in vitro dissolution-permeation (D/P)-setups, when drug in suspension has the possibility of directly interacting with the permeation barrier. This is supported by the overprediction of drug absorption from neat crystalline efavirenz compared to four ASDs in a D/P-setup based on the parallel artificial membrane permeability assay (PAMPA). However, linear IVIVR (R2 = 0.97) is established in a modified D/P-setup in which the addition of a hydrophilic PVDF-filter acts as a physical boundary between the donor compartment and the PAMPA-membrane. Based on microscopic visualization, the improved predictability of the modified D/P-setup is due to the avoidance of direct dissolution of drug particles in the lipid components of the PAMPA-membrane. In general, this principle might aid in providing a more reliable evaluation of formulations of poorly water-soluble drugs before initiating animal models.

Stability and intrinsic dissolution of vacuum compression molded amorphous solid dispersions of efavirenz.

In this study, the stability and intrinsic dissolution of vacuum compression molded (VCM) amorphous solid dispersions (ASDs) of efavirenz (EFV) were investigated in relation to its solubility limits in seven polymers determined by the melting point depression (MPD) method. The extrapolated solubility limits of EFV at 22 °C ranged from 3 to 68% (w/w) with PVOH being the only polymer suggesting immiscibility with EFV according to both MPD and Hansen solubility parameters (HSPs). All ASDs with EFV loadings below or close to their calculated solubility limit did not show any signs of crystallization upon conditioning for 7 months at either 22 or 37 °C and 23 or 75% relative humidity. However, all ASDs with EFV loading above the solubility limit crystallized at high humidity, while the ASDs with cellulose derived carrier polymers proved kinetically stable at low humidity over 7 months. While the EFV intrinsic dissolution rates from the VCM ASDs were partly depending on the polymer dissolution rate, no correlation was observed between EFV matrix crystallization and its miscibility in the polymer. Altogether, the observations of the study underline the importance of combining preformulation miscibility determination and dissolution studies to rationally decide on both stability and viability of ASD formulations.

Prolonged exposure to bradykinin and prostaglandin E2 increases TRPV1 mRNA but does not alter TRPV1 and TRPV1b protein expression in cultured rat primary sensory neurons.

Sensitisation of the capsaicin receptor, transient receptor potential vanilloid type 1 (TRPV1) ion channel in nociceptive primary sensory neurons (PSN) underlies the development of inflammatory heat hyperalgesia. Removal of the negative-dominant splice variant of the TRPV1 molecule, TRPV1b from TRPV1/TRPV1b heterotetrameric channels, which should be associated with changes in the expression of TRPV1 and TRPV1b transcripts and proteins, has been suggested to contribute to that sensitisation. Respective reverse-transcriptase polymerase chain reaction (RT-PCR) and Western-blotting revealed that both TRPV1 and TRPV1b mRNA, and their encoded proteins are expressed in rat cultured PSN. Sequencing of the RT-PCR products showed that TRPV1b mRNA lacks the entire exon 7. Further, growing PSN for 2 days in the presence of 10µM bradykinin (BK) and 10µM prostaglandin E2 (PGE2) significantly increases TRPV1 responsiveness and TRPV1 mRNA expression, without producing any changes in TRPV1b mRNA, and TRPV1 and TRPV1b protein expression. These data challenge the hypothesis that alterations in the composition of the TRPV1 ion channel contributes to the sensitisation.

Sensory experience determines enrichment-induced plasticity in rat auditory cortex.

Our previous studies demonstrated that only a few days of housing in an enriched environment increases response strength and paired-pulse depression in the auditory cortex of awake and anesthetized rats [Engineer, N.D., Percaccio, C.R., Pandya, P.K., Moucha, R., Rathbun, D.L., Kilgard, M.P., 2004. Environmental enrichment improves response strength, threshold, selectivity, and latency of auditory cortex neurons. J Neurophysiol. 92, 73-82 and Percaccio, C.R., Engineer, N.D., Pruette, A.L., Pandya, P.K., Moucha, R., Rathbun, D.L., Kilgard, M.P., 2005. Environmental enrichment increases paired-pulse depression in rat auditory cortex. J Neurophysiol. 94, 3590-3600]. Multiple environmental and neurochemical factors likely contribute to the expression of this plasticity. In the current study, we examined the contribution of social stimulation, exercise, auditory exposure, and cholinergic modulation to enrichment-induced plasticity. We recorded epidural evoked potentials from awake rats in response to tone pairs and noise bursts. Auditory evoked responses were not altered by social stimulation or exercise. Rats that could hear the enriched environment, but not interact with it, exhibited enhanced responses to tones and increased paired-pulse depression. The degree to which enrichment increased response strength and forward masking was not reduced after a ventricular injection of 192 IgG-saporin. These results indicate that rich auditory experience stimulates physiological plasticity in the auditory cortex, despite persistent deficits in cholinergic activity. This conclusion may be beneficial to clinical populations with sensory gating and cholinergic abnormalities, including individuals with autism, schizophrenia, and Alzheimer's disease.