Büchi's model based analysis of local anesthetic action in procaine hydrochloride: Vibrational spectroscopic approach.

The drug action of ester type local anesthetic (LA) procaine hydrochloride (PRC HCl) is activated by blocking Na+ ion flow when it binds to the ion channel in the ligand gated sodium ion channel protein. Büchi's model, explains binding action of ester type LA drug with receptor in terms of charge transfer, dipole-dipole, hydrogen bonding and van der Waals interactions through lipophilic, ester and hydrophilic moieties. The present work investigates molecular structural and vibrational spectral features of para amino benzoate group, ester part and tertiary amino group respectively belonging to lipophilic, ester and hydrophilic moieties, accountable for the binding of drug to sodium channel. The electron transport mechanism through the ring responsible for structural deviation from benzenoid to quinonoid form and consequent dipolar nature of carbonyl group have been investigated, based on the analysis of XRD, DFT computed molecular structure, 8a ring mode and NBO charges. The characteristic UV absorption peaks and vibrational marker bands of LA drugs have been identified and the charge transfer interaction responsible for lipophilic binding has been investigated. The blocking of Na+ in the ion channel has been probed using attractive and repulsive energy profile. The molecular polarizability has been computed to substantiate the correlation between the structure activity relationship of LA drug molecule and molecular polarizability. The low toxicity of PRC HCl was evaluated using in vitro cytotoxicity study, confirming it as a potential short acting local anesthetic.

Low prevalence of anaemia among the wives of serving personnel in a military station: A community-based study.

BACKGROUND: Various studies in India have reported the prevalence of anaemia to be more than 50% among women of the reproductive age group. A community-based study was done to find out the prevalence of anaemia in non-pregnant, non-lactating wives of serving soldiers in a military station. METHODS: It was a cross-sectional study. The sample size was 600. Venous blood was collected for haemoglobin and ferritin levels. Analysis was done by SPSS 20. RESULTS: The mean age at marriage was 19.8 years (SD + 2.76). The average age at first childbirth was 20.88 years. Major symptoms reported were weakness (24.34%), giddiness (23.47%), fatigue (20.17%) and heavy bleeding (3.13%). Prevalence of anaemia in our study was 13.9%, which is much below the national prevalence. Prevalence of iron-deficient status was reported in 153 (26%) individuals. Out of these, 81 subjects were non-anaemic (Hb > 12d/dL) but were iron deficient (ferritin <15 µg/L). Sixty out of these 81 subjects reported presence of fatigue and 36 had weakness. Statistically significant associated observations of anaemia were low Body Mass Index, irregular menstrual pattern, shortened menstrual cycle and increased duration of bleeding (p < 0.05). Low ferritin levels were significantly associated with low BMI, not using Oral Contraceptive Pills and bleeding for more than 3 days during menstrual cycle (p < 0.05). CONCLUSION: The scenario of low prevalence of anaemia in women under the cover of the Armed Forces Medical Services represents an 'island of excellence'.

Association of p53 codon72 Arg>Pro polymorphism with susceptibility to nasopharyngeal carcinoma: evidence from a case-control study and meta-analysis.

Tumor suppressor p53 is a critical player in the fight against cancer as it controls the cell cycle check point, apoptotic pathways and genomic stability. It is known to be the most frequently mutated gene in a wide variety of human cancers. Single-nucleotide polymorphism of p53 at codon72 leading to substitution of proline (Pro) in place of arginine (Arg) has been identified as a risk factor for development of many cancers, including nasopharyngeal carcinoma (NPC). However, the association of this polymorphism with NPC across the published literature has shown conflicting results. We aimed to conduct a case-control study for a possible relation of p53 codon72 Arg>Pro polymorphism with NPC risk in underdeveloped states of India, combine the result with previously available records from different databases and perform a meta-analysis to draw a more definitive conclusion. A total of 70 NPC patients and 70 healthy controls were enrolled from different hospitals of north-eastern India. The p53 codon72 Arg>Pro polymorphism was typed by polymerase chain reaction, which showed an association with NPC risk. In the meta-analysis consisting of 1842 cases and 2330 controls, it was found that individuals carrying the Pro allele and the ProPro genotype were at a significantly higher risk for NPC as compared with those with the Arg allele and the ArgArg genotype, respectively. Individuals with a ProPro genotype and a combined Pro genotype (ProPro+ArgPro) also showed a significantly higher risk for NPC over a wild homozygote ArgArg genotype. Additionally, the strength of each study was tested by power analysis and genotype distribution by Hardy-Weinberg equilibrium. The outcome of the study indicated that both allele frequency and genotype distribution of p53 codon72 Arg>Pro polymorphism were significantly associated with NPC risk. Stratified analyses based on ethnicity and source of samples supported the above result.

Spectroscopic analysis and charge transfer interaction studies of 4-benzyloxy-2-nitroaniline insecticide: a density functional theoretical approach.

A widespread exploration on the intra-molecular charge transfer interaction through an efficient π-conjugated path from a strong electron-donor group (amino) to a strong electron-acceptor group (nitro) has been carried out using FTIR, FT-Raman, UV-Vis, fluorescence and NMR spectra on insecticide compound 4-benzyloxy-2-nitroaniline. Density functional theory method is used to determine optimized molecular geometry, harmonic vibrational wavenumbers and intensities using 6-311G(d,p) basis set by means of Gaussian 09W program suit. A comprehensive investigation on the sp(2) to sp(3) hybridization and non-planarity property has been performed. Natural bond orbital analysis is used to study the existence of C-H⋯O, N-H⋯O and C-H⋯π proper and improper hydrogen bonds. The HOMO and LUMO analysis reveals the possibility of charge transfer within the molecule. A complete assignment of the experimental absorption peaks in the ultraviolet region has also been performed. Isotropic chemical shifts of (13)C, (1)H, (15)N and (18)O NMR and nuclear spin-spin coupling constants have been computed using the gauge-invariant atomic orbital method. The biological activity of substituent amino and nitro groups are evident from the hydrogen bonds through which the target amino acids are linked to the drug as evidenced from molecular docking.

DFT computation and experimental analysis of vibrational and electronic spectra of phenoxy acetic acid herbicides.

An absolute vibrational analysis has been attempted on the basis of experimental FTIR and NIR-FT Raman spectra with calculated vibrational wavenumbers and intensities of phenoxy acetic acids. The equilibrium geometry, bonding features and harmonic vibrational wavenumbers have been calculated with the help of B3LYP method with Dunning correlation consistent basis set aug-cc-pVTZ. The electronic structures of molecular fragments were described in terms of natural bond orbital analysis, which shows intermolecular O-H···O and intramolecular C-H···O hydrogen bonds. The electronic absorption spectra with different solvents have been investigated in combination with time-dependent density functional theory calculation. The pKa values of phenoxy acetic acids were compared.

Alteration in haematological and biochemical parameters of Catla catla exposed to sub-lethal concentration of cypermethrin.

A 60-day experiment was carried out to study the effect of sub-lethal concentration of cypermethrin (1/10th of LC(50)) exposure on haematological and biochemical parameters of the Indian major carp, Catla catla fingerlings. Under exposure, the total erythrocyte count, total leucocyte count, haemoglobin content and haematocrit were decreased. All the studied serum parameters viz. total serum protein, albumin, globulin contents and albumin-globulin ratio were significantly decreased in cypermethrin-exposed fishes. A marked increase was recorded in alanine aminotransferase and aspartate aminotransferase activities in liver, whereas lactate dehydrogenase activity of muscle and acetylcholine esterase activity in brain were inhibited in cypermethrin-exposed fish. The membrane transport enzymes (total adenosine triphosphatase, sodium-potassium adenosine triphosphatase and magnesium adenosine triphosphatase) activities were decreased significantly in the gills of C. catla exposed to sub-lethal concentration of cypermethrin. The present study indicates that sub-lethal exposure of C. catla fingerlings to cypermethrin alters the haematological and biochemical parameters.

Nonplanar property study of antifungal agent tolnaftate-spectroscopic approach.

Vibrational analysis of the thionocarbamate fungicide tolnaftate which is antidermatophytic, antitrichophytic and antimycotic agent, primarily inhibits the ergosterol biosynthesis in the fungus, was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features, harmonic vibrational wavenumbers and torsional potential energy surface (PES) scan studies have been computed using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bonding orbital (NBO) analysis and optimized molecular structure show the clear evidence for electronic interaction of thionocarbamate group with aromatic ring. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Vibrational analysis reveals that the simultaneous IR and Raman activation of the C-C stretching mode in the phenyl and naphthalene ring provide evidence for the charge transfer interaction between the donor and acceptor groups and is responsible for its bioactivity as a fungicide.

DFT computations and spectroscopic analysis of a pesticide: chlorothalonil.

NIR FT-Raman and IR spectra of the biologically active molecule, chlorothalonil have been recorded and analyzed. The molecular geometry and vibrational wavenumbers of the title compound in the ground state have been calculated by density functional theory (DFT) with 6-31G(d) basis set. In order to obtain the information about the influence of intramolecular interaction on the molecule, the calculated geometries of chlorothalonil molecule was compared with the experimental data. The results of the optimized molecular structure gave clear evidence for the intramolecular charge transfer (ICT). Time-dependent density functional theory (TD-DFT) calculation of the electronic spectra has been performed and compared with the experimental UV-visible spectrum. Mulliken's net charges have been calculated and compared with the atomic natural charges. The effects of chlorine and cyanide group substituent in benzene ring in the vibrational wavenumbers have been analyzed. NBO analysis is useful to understand the intramolecular hyperconjugative interaction between lone pair Cl and sigma*(C-C) bond orbital.

Aspect graph construction with noisy feature detectors.

Many three-dimensional (3D) object recognition strategies use aspect graphs to represent objects in the model base. A crucial factor in the success of these object recognition strategies is the accurate construction of the aspect graph, its ease of creation, and the extent to which it can represent all views of the object for a given setup. Factors such as noise and nonadaptive thresholds may introduce errors in the feature detection process. This paper presents a characterization of errors in aspect graphs, as well as an algorithm for estimating aspect graphs, given noisy sensor data. We present extensive results of our strategies applied on a reasonably complex experimental set, and demonstrate applications to a robust 3D object recognition problem.

A proposed model to include a residual NAPL saturation in a hysteretic capillary pressure-saturation relationship.

A residual non-aqueous phase liquid (NAPL) present in the vadose zone can act as a contaminant source for many years as the compounds of concern partition to infiltrating groundwater and air contained in the soil voids. Current pressure-saturation-relative permeability relationships do not include a residual NAPL saturation term in their formulation. This paper presents the results of series of two- and three-phase pressure cell experiments conducted to evaluate the residual NAPL saturation and its impact on the pressure-saturation relationship. A model was proposed to incorporate a residual NAPL saturation term into an existing hysteretic three-phase parametric model developed by Parker and Lenhard [Water Resour. Res. 23(12) (1987) 2187], Lenhard and Parker [Water Resour. Res. 23(12) (1987) 2197] and Lenhard [J. Contam. Hydrol. 9 (1992) 243]. The experimental results indicated that the magnitude of the residual NAPL saturation was a function of the maximum total liquid saturation reached and the water saturation. The proposed model to incorporate a residual NAPL saturation term is similar in form to the entrapment model proposed by Parker and Lenhard, which was based on an expression presented by Land [Soc. Pet. Eng. J. (June 1968) 149].

Preformulation studies for the development of a parenteral liquid formulation of an antitumor agent, AG337.

AG337 is a potential anticancer agent designed by using protein structure-based techniques. The objective of this work was to evaluate the feasibility of a high concentration liquid formulation of AG337 intended for intravenous administration. The solubility of AG337 in pure water was above 100 mg/mL at pH < 3. The drug's solubility decreased precipitously as the solution pH increased above 3 upon titration with 0.1 N NaOH. The solubility of AG337 in water as a function of temperature (ranged from 2-40 degrees C) was determined. As anticipated, the drug's solubility increased somewhat linearly as the solution temperature increased. Degradation kinetics of 15% and 10% AG337 solutions at elevated temperatures was determined to assess the feasibility of a liquid formulation as opposed to previously developed lyophilized powder for injection. Only one major degradation product was detected in the HPLC as a result of chemical hydrolysis of AG337 to AG408. Arrhenius plot (i.e., kobs versus 1/T) revealed an activation energy of 25 kcal/mol. The shelf life (t95%) of 10% AG337 solution of pH 2 at 25 degrees C was predicted to be roughly 8 years. Various terminal sterilization methods, which include moist/dry autoclaving (121 degrees C), e-beam, and gamma-irradiation, were evaluated for the 10% AG337 solution. Autoclaving cycles, ranged from 20 to 90 minutes, caused instantaneous degradation of AG337 solution and induced further degradation upon long-term storage. Again, AG408 was the major degradation product following autoclaving. On the other hand, irradiation techniques induced very little degradation, but turned clear glass vials to brown upon irradiation.

Controlled transdermal delivery of fentanyl: characterizations of pressure-sensitive adhesives for matrix patch design.

Transdermal delivery of fentanyl from various adhesive matrix formulations to achieve a steady-state skin flux was investigated. For this purpose, various pressure-sensitive adhesives selected from the three chemical classes of polymers (polyisobutylene (PIB), acrylate, and silicone adhesives) were characterized with respect to fentanyl's solubility, diffusion coefficient, and permeability coefficient. The solubility of fentanyl in various pressure-sensitive adhesives at 32 degrees C was determined by the drug absorption-desorption method. The solubilities of fentanyl in these adhesives were in the following order: acrylate > silicones > PIB. The permeability coefficient and diffusion coefficient of fentanyl in these adhesives were determined by the membrane diffusion method. The diffusion coefficient rank order was silicone-2920 > silicone-2675 > or = acrylate > PIB. The release profiles of fentanyl in the aqueous buffer from these adhesives with 2-4% drug loading was evaluated. The release rate of fentanyl from the acrylate polymer was significantly higher than those of silicone and PIB adhesives. The in vitro flux of fentanyl through cadaver skin from various adhesives with 2% drug loading was determined at 32 degrees C using modified Franz diffusion cells. The skin fluxes of fentanyl from silicone-2920 and PIB adhesives were 6.3 +/- 0.7 and 3.1 +/- 0.3 micrograms/cm2/h, respectively. On the other hand, the skin fluxes of fentanyl from acrylate and silicone-2675 adhesive matrices were about 1 microgram/cm2/h. The effect of drug loading on skin flux was investigated using PIB as a model adhesive. The drug released in the phosphate buffer (pH = 6.0) increased linearly as the drug loading in the PIB was increased from 1% to 4%; and as the drug loading exceeded 4%, an initial burst effect followed by a zero-order release was observed. The skin flux of fentanyl increased proportionally as the drug loading in the PIB adhesive was increased from 1 to 4%, and a plateau was reached beyond 4% drug loading. These results suggest that fentanyl concentration in the PIB adhesive might have reached saturation above 4% drug loading and that the optimum skin flux was accomplished from such a system because of attainment of maximum thermodynamic activity.

Transdermal delivery of ketorolac tromethamine: permeation enhancement, device design, and pharmacokinetics in healthy humans.

Transdermal delivery of ketorolac tromethamine, a potent non-narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure-sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure-sensitive adhesive onto a microporous membrane. Three liquid-reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD-A (microporous membrane/acrylic adhesive), TD-B (microporous membrane/silicone adhesive), and TD-C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 microgram/mL for TD-A, TD-B, and TD-C, respectively. The total AUC values for the concentration-time curves were TD-C > TD-A > TD-B, and the terminal half-life ranged from 6.6 to 9.7 h.

Permeability of pure enantiomers of ketorolac through human cadaver skin.

The permeability of pure enantiomers of ketorolac acid, a potent non-narcotic analgesic, through human cadaver skin was evaluated. The melting temperature of each enantiomer was 20 degrees C higher than that of the racemic compound. As expected, the solubility of the racemic compound in water and isopropyl alcohol/water/isopropyl myristate (IPA/water/IPM, 50:50:1.5) was roughly 2 times higher than that of the enantiomers. The permeability of the enantiomers through poly(ethylenevinyl acetate) (EVA) synthetic membrane and human cadaver skin was determined with a side-by-side diffusion cell. The skin flux of the racemic compound was about 1.5 times higher than those of the enantiomers. On the other hand, no significant differences in the intrinsic permeability coefficient of the racemic compound and the enantiomers in the EVA membrane and human cadaver skin was observed. An excellent agreement between the predicted and experimental flux ratio of the racemic compound and enantiomer in the EVA membrane and cadaver skin was observed. The IPA/water/IPM (50:50:1.5) provided the highest in vitro skin flux of the S enantiomer among the three vehicle formulations studied. The skin flux of the active pure S enantiomer was ca. 34% higher than that of the impure S enantiomer in the racemic mixture. Furthermore, about 14% intersubject variability in the in vitro skin flux of the S enantiomer was observed. The required skin flux of the S enantiomer as calculated from the pharmacokinetic parameters was about 32 micrograms/cm2/h from a 25 cm2 transdermal patch, which was readily achievable from the IPA/water/IPM (50:50:1.5) ternary vehicle system.

Absorption of transdermally delivered ketorolac acid in humans.

Transdermal delivery of ketorolac acid, a potent analgesic, through human skin in vitro and in vivo was evaluated. The following three transdermal solutions were selected to study the in vitro skin permeation rate of ketorolac acid: formulation A, isopropyl alcohol: water: isopropyl myristate (IPA/water/IPM; 11:7:1); formulation B, ethanol: propylene glycol:isopropyl myristate (ET/PG/IPM; 11:7:2); and formulation C, IPM/capmul (glyceryl mono- and dicaprylate; Monoctanoin). The permeation of ketorolac acid through cadaver skin from a saturated drug solution was evaluated at 32 degrees C with a modified Franz diffusion cell. The in vitro skin fluxes were 180, 177, and 14 micrograms/cm2/h for formulations A, B, and C, respectively. The systemic bioavailability of ketorolac acid from three transdermal formulations was evaluated in nine healthy subjects in a randomized three-way crossover fashion. Hill Top chambers were used as prototype dermal delivery devices to load the drug solution. This procedure was followed by the immediate application of devices to human subjects for 24 h. Blood samples were collected at various time intervals up to 48 h, and the samples were assayed by HPLC. The basic pharmacokinetic parameters were derived from the drug plasma concentration versus time plot. The maximum drug plasma concentrations were 1.265, 0.696, and 0.092 micrograms/mL for formulations A, B, and C, respectively. Formulation A provided the highest in vitro and in vivo transdermal delivery rate among the three formulations studied. An excellent correlation between the in vitro steady-state skin flux and the area under the curve of in vivo plasma drug concentration versus time was observed for all the three formulations.

Transdermal delivery of narcotic analgesics: comparative metabolism and permeability of human cadaver skin and hairless mouse skin.

The permeation of hairless mouse skin and human cadaver skin by narcotic analgesics was investigated to determine the interspecies variation. Permeability coefficients of morphine, fentanyl, and sufentanil across full-thickness hairless mouse skin were 1 order of magnitude higher than those found for human epidermis. The permeability coefficient of morphine for stripped hairless mouse skin was 500-fold higher than that for intact skin, showing the stratum corneum to be the principal barrier to its penetration. The permeability coefficient of fentanyl for stripped hairless mouse skin was also raised, but stripping caused an inappreciable increase in the permeation rate of sufentanil. The thick dermis of excised mouse skin obviously offered a significant resistance to the permeation of these lipophilic compounds. In comparison, the permeability coefficients of fentanyl and sufentanil through stripped cadaver epidermis (n > or = 25) were 67 and 37 higher than for intact human epidermis, respectively. The skin metabolism of the narcotics was investigated. No significant metabolic degradation of morphine, fentnayl, and sufentanil was observed in either fresh human cadaver skin or hairless mouse skin homogenates in the presence of NADPH cofactor, suggesting a low monooxygenase enzyme presence in skin. Moreover, no measurable glucuronidation of morphine took place in human skin or hairless mouse skin. Both processes proceeded rapidly in liver homogenates (mouse) under identical circumstances. It thus appears that these drugs pass through in intact form.

Permeability of ketorolac acid and its ester analogs (prodrug) through human cadaver skin.

The in vitro skin permeabilities of ketorolac acid (KA), a potent nonsteroidal analgesic, and its two ester analogs as prodrug through human cadaver skin were investigated. The two esters of KA, namely, the ethyl ester (KEE) and [(N,N-dimethylamino)carbonyl]methyl ester (KDAE), were selected. The melting temperature of the two esters was significantly lower than that of ketorolac free acid. The partition coefficients (KO/W) were 600, 3541, and 124 for KA, KEE, and KDAE, respectively. The enzymatic hydrolysis of KEE and KDAE by human pooled serum at 37 degrees C was investigated. The esters were hydrolyzed to KA by the serum esterases; the metabolic rate constants were 0.0418 and 0.0148 min-1 for KDAE and KEE, respectively. The serum half-life of KDAE was about 3 times shorter than KEE. When split-thickness cadaver skin was incubated with ester solution at 32 degrees C, the enzymatic hydrolysis of these esters was observed. The metabolic rate in the skin, however, was significantly lower than in the human pooled serum. The skin permeations of KA, KEE, and KDAE through heat-separated epidermis from propylene glycol (PG), PG/glyceryl monocaprylate (GMC) (9:1), and PG/Azone (19:1) vehicle mixtures were evaluated using modified Franz flow-through diffusion cells. The skin fluxes of KA, KEE, and KDAE from PG/GMC (9:1) were 50 +/- 10, 15 +/- 4, and 57 +/- 6 micrograms/cm2/h, respectively. KA was detected in the receiver compartment, albeit to a lesser extent. In conclusion, KDAE appeared to be a better ester prodrug than KEE because it exhibited relatively higher skin flux and faster enzymatic hydrolysis by human serum to liberate the parent drug.

Transdermal delivery of buprenorphine through cadaver skin.

The skin permeation of buprenorphine base and HCl salt through cadaver skin was investigated. The octanol-water partition coefficient and solubilities of both buprenorphine free base and HCl salt were determined at 32 degrees C. As expected, buprenorphine free base was more lipophilic than its HCl salt and was practically insoluble in aqueous buffer at pH 8.7. The drug solubility decreased exponentially as the pH of the solution increased, whereas the permeability coefficient increased as the donor solution pH decreased. The skin flux of buprenorphine.HCl was significantly higher than that of the free base from propylene glycol/lauric acid vehicle mixtures. Buprenorphine base permeation through tape-stripped epidermis suggested that in addition to stratum corneum, viable epidermis presented a significant diffusion barrier because of the very low aqueous solubility of the free base observed. The mean steady-state skin fluxes of buprenorphine.HCl were 20.3 and 29.7 micrograms/cm2/h from propylene glycol:lauryl alcohol: ethanol (80:15:5) and propylene glycol: propylene glycol monolaurate: water (80:15:5) vehicle mixtures, respectively. The skin flux of buprenorphine.HCl from various monolithic matrix patches was also evaluated. When capric acid, lauric acid, and lauryl alcohol were separately incorporated into an adhesive matrix, the skin flux of buprenorphine.HCl was enhanced by a factor of 2 to 3.5. Finally, based on the total body clearance and minimum effective concentration of buprenorphine, a transdermal delivery rate of 2.5 micrograms/cm2/h from a 20-cm2 patch was estimated. The in vitro skin permeation data clearly suggest that transdermal delivery of buprenorphine is feasible to achieve a desired systemic analgesic effect.

Permeabilities of alkyl p-aminobenzoates through living skin equivalent and cadaver skin.

The in vitro permeabilities of alkyl p-aminobenzoates through living skin equivalent (LSE) and cadaver skin were compared. Methyl, ethyl, and butyl p-aminobenzoates were used as model compounds. The permeabilities of these compounds through LSE and cadaver skin from an aqueous drug suspension were determined with a flow-through diffusion cell. The permeability coefficients of these esters in LSE were an order of magnitude higher than in cadaver skin. This was primarily because of low resistances offered by the outermost layer (i.e., stratum corneum) of LSE. In the case of cadaver skin, the permeability coefficient increased as the carbon chain length increased, whereas no appreciable change in the permeability coefficients of these esters in LSE was observed. These results clearly suggest that the LSE membrane offered very little resistance as opposed to cadaver skin. Therefore, the LSE membrane may not quantitatively represent a good human skin model for evaluating skin permeation of a drug from topical or transdermal formulations.

Effect of receiver fluid pH on in vitro skin flux of weakly ionizable drugs.

In in vitro skin permeation experiments, the pH of viable epidermis is readily conditioned by the receiver fluid. For weakly ionizable compounds, the flux determined experimentally thus depends on the receiver fluid pH. The purpose of the present work is to characterize this pH effect, since nonphysiological conditions have often been used in the receiver fluid to enhance the solubility of the subject compounds. A transport model was developed to analyze the above-mentioned pH effect of the receiver fluid on the steady state flux of weakly ionizable drugs. The results showed that the skin flux had a strong dependence on pH for those compounds with high intrinsic partition coefficients. Experimentally, this pH effect was observed with a model acid and a model base. The skin flux was found to have a profound dependence on the receiver fluid pH. This dependence also correlates with the octanol/water partition coefficient of the molecule. It was concluded that the use of a physiological receiver fluid would be crucial for a realistic estimation of transdermal potential. The results also suggested that, for weakly ionizable compounds with high partition coefficients, the viable epidermis could be a significant transport barrier for systemic absorption.