Showing papers in "Pharmaceutical Research in 1988"

Oligonucleotide Analogues as Potential Chemotherapeutic Agents

Abstract: Oligonucleotides specifically bind to complementary sequences of either genomic DNA or genomic RNA through hydrogen bonding of base pairs. In principle, relatively short oligomers (<20 bases) can specifically hybridize with DNA or RNA and thus be used for novel drug design strategies involving targeted interference of genetic expression at the level of transcription or translation. Conceivable chemotherapeutic applications predicated on sequence-specific hybridization (“antisense” inhibition) require oligonucleotide analogues that are resistant to in vivo degradation by enzymes such as nucleases. Nuclease-resistant analogues having modified internucleoside linkages (e.g., methylphosphonates or phosphorothioates) or modified nucleosides (e.g., 2′-0-methylribose or α-anomers) are now readily available by means of automated synthesis, and there are various classes of pendant groups (e.g., alkylating or intercalating agents) that can be attached to increase the efficacy of these analogues. The present account reviews this area of research by classifying structures and mechanisms of action, with comments on stereochemistry. Biological studies are briefly summarized, and pharmaceutically related topics of interest are noted.

Estimating Human Oral Fraction Dose Absorbed: A Correlation Using Rat Intestinal Membrane Permeability for Passive and Carrier-Mediated Compounds

Abstract: Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P eff *, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P aq * is not rate controlling gives the following equation for fraction dose absorbed: F = 1− e −2 P*w. The correlation between fraction dose absorbed in humans and P w * determined from steady-state perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P w * is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.

Drug/Polymer Matrix Swelling and Dissolution

Abstract: The swelling and dissolution behavior of pharmaceutical systems containing a drug and a polymer can be analyzed by a mathematical model which predicts the drug released and the gel layer thickness as a function of time It is possible to approximate the values of several of the physicochemical parameters of this model in order to obtain an order-of-magnitude analysis of the tablet dissolution process Selected experimental results of tablet dissolution and drug release are analyzed and conclusions are made about the importance of the drug and polymer content and solubility in the release behavior

In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell.

Abstract: A new diffusion cell, derived from the Ussing chamber, was developed for the measurement of tissue permeability. This cell incorporates the attributes of using a single material and laminar flow across the tissue surface. In addition, the design allows the cell to be manufactured in a wide range of sizes to allow optimization of surface area to volume for a variety of tissues. The apparatus is applicable to the evaluation of transport of compounds through mucosal/epithelial barriers, i.e., gastrointestinal tissue. Active transport, permeability enhancers, enzymatic degradation, and absorption in various tissue sections can be explored. Preliminary data are consistent with the expected effects of molecular size and partition coefficient of a transported molecule on permeability in epithelial tissue. In addition, active transport of D-glucose and inhibition by phloridzin and ouabain can be demonstrated.

Turbuhaler: a new powder inhaler for administration of drugs to the airways.

Abstract: A metered-dose powder inhaler system has been developed. It is a multidose system that is easy to load and handle for the patient and that does not demand coordination between activation and inhalation. In addition, the new inhaler system is free of propellants, carriers, and other drug additives. Terbutaline sulfate has been selected as a suitable compound for evaluation of this inhaler. Clinical tests with the Turbuhaler have been performed and it has been compared with the conventional terbutaline pressurized metered-dose inhaler (MDI). The new powder inhaler can even be used at low inspiratory flow rates such as those present during acute asthma attacks.

Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques.

Abstract: Microspheres containing methylene blue and prednisolone acetate were prepared by one of three methods: freeze-drying, evaporation, and solvent-extraction-precipitation. An extremely porous structure was obtained by the freeze-dry and solvent-extraction-precipitation procedures. The specific surface area of 6.33-µm particles was 20.6 m2/g, or 35 times that of a particle devoid of pores, and the void space was 59–61%. The sphericity, size, and yields of the microspheres were influenced by the preparation procedure, surfactant type and concentration, temperature of the continuous phase, polymer concentration in the dispersed phase, and ratio of marker to polymer. The most suitable processing conditions were a polymer concentration of 5–10%, a marker loading of 10%, 0.1% sorbitan sesquioleate as the surfactant, and temperature adjustment of the continuous phase from 15 to 50°C following the addition of the dispersed phase. Complete release of the highly water soluble methylene blue occurred within 72 hr, while the less soluble prednisolone acetate released much more slowly, i.e., 90% after 7 days. The microspheres remained relatively intact during the in vitro release of methylene blue, confirming that the incorporated agent was confined to the walls of the porous network. Collapse of the polymer structure was evident after 7 days. The release therefore was believed to be governed principally by the solubility of the drug and the porosity of the matrix.

The role of protein and lipid domains in the uptake of solutes by human stratum corneum.

Abstract: The uptake of a series of hydrocortisone esters varying in lipophilicity from water into untreated and delipidized human stratum corneum has been determined. The partition coefficients of solutes into fully hydrated stratum corneum are postulated to represent the separate contributions of three structurally distinct domains—the extractable lipids, protein, and the solvent domain. The solvent domain was assumed to have the properties of bulk water. The relative affinities of the protein and lipid domains of stratum corneum for solutes varying in structure were determined by comparing solute uptake in untreated and delipidized stratum corneum. Partitioning into the extracted lipids was also examined. Solute uptake into stratum corneum may be governed by the protein domain, the lipid domain, or a combination of the two, depending on solute lipophilicity. Due to differences in the selectivity of the two domains, a change in uptake mechanism occurs with increasing solute lipophilicity from protein-dominated uptake for hydrophilic solutes to lipid domain-dominated uptake for lipophilic solutes. The stratum corneum lipid content, which varies dramatically from individual to individual (3–46% in this study), is an important determinant of the affinity of the stratum corneum for highly lipophilic solutes but has no effect on the uptake of hydrophilic solutes.

Effects of Gender, Posture, and Age on Gastric Residence Time of an Indigestible Solid: Pharmaceutical Considerations

Abstract: We have recently reported the effect of varying food composition on the gastric residence time (GRT) of an indigestible solid, the Heidelberg capsule (HC). The purpose of the present evaluation was to evaluate the reproducibility and the effect of gender, posture, and age on the GRT of the HC. The reproducibility in measurement of the GRT of the Heidelberg capsule was evaluated in two trials separated by 1 week. Mean GRT values obtained in nine healthy men on day 1 were not statistically different from those on day 8 (3.5 ± 0.6 vs 3.5 ± 0.7 hr, P > 0.05). To evaluate the influence of gender on the GRT of the HC, 12 healthy male volunteers and 12 age (±3 years)- and race-matched female counterparts entered into a randomized study. Each subject was served a standardized 500-kcal breakfast 30 min prior to oral ingestion of the HC. The mean (± SD) ambulatory GRT in the males was significantly faster than in the females (3.4 ± 0.6 vs 4.6 ± 1.2 hr, P 0.05). The effect of age on the GRT of the HC was evaluated in 12 healthy elderly males (>65 years) with no prior gastrointestinal complications. The mean value of the GRT 30 min after a 500-kcal breakfast was significantly prolonged compared to that of the young male volunteers (4.5 ± 1.1 vs 3.4 ± 0.6 hr, P 70 years old.

Site dependence of absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery.

Abstract: The site dependence of the absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin was studied in rats. Insulin absorption was estimated on the basis of the cumulative hypo-glycemic response from 0 to 4 hr postdose, relative to that after intramuscular insulin. Insulin was administered with or without adjuvants to isolated rectal, nasal, and buccal absorption sites. Laureth-9, a nonionic surfactant which irreversibly removes membrane proteins or lipids, promoted insulin absorption from each site. The rectal, nasal, and buccal routes were 30% as effective as the i.m. route. The enhancing effects of Na salicylate and Na2EDTA, which have reversible mechanisms of permeability enhancement, were specific for rectal absorption. With these adjuvants, rectal insulin was 30–40% as effective as i.m. insulin, but nasal and buccal doses were less than 5% as effective as i.m. doses. This specificity can be at least partly explained by considering the site-to-site differences in membrane histology, although differences in pore size and membrane biochemistry might also contribute. The protease inhibitor aprotinin was ineffective in increasing insulin efficacy via each route, either alone or in combination with laureth-9.

The Role of Tumor Necrosis Factor and Interleukin 1 in the Immunoinflammatory Response

Abstract: Monocytes and tissue macrophages produce at least two groups of protein mediators of inflammation, interleukin 1 (IL-1) and tumor necrosis factor (TNF). Recent studies have emphasized that TNF and IL-1 modulate the inflammatory function of endothelial cells, leukocytes, and fibroblasts. Although these cytokines share a number of biologic properties, they have quite distinct gene and protein structures. It is our purpose to focus on the role of these mediators in inflammation.

Enhancement of colonic drug absorption by the transcellular permeation route.

Abstract: The effects of sodium caprate and sodium caprylate on transcellular permeation routes were examined in rats The release of membrane phospholipids was significantly increased only by caprate, while protein release did not change from the control in the presence of caprate or caprylate, indicating that the extent of membrane disruption was insufficient to account for enhanced permeation Using brush border membrane (BBM) vesicles prepared from colon, with their protein and lipid component labeled by fluorescent probes, the perturbing actions of caprate and caprylate toward the membrane were examined by fluorescence polarization Caprate interacted with membrane protein and lipids, and caprylate mainly with protein, causing perturbation to the membrane The release of 5(6)-carboxyfluorescein previously included in BBM vesicles was increased by caprate but not by caprylate These results suggest that caprate enhances permeability via the transcellular route through membrane perturbation

Heterogeneity Effects on Permeability–Partition Coefficient Relationships in Human Stratum Corneum

Abstract: The relationship between the permeability of solutes undergoing transport via the lipid pathway of the stratum corneum and the degree to which the same solutes partition into the stratum corneum has been explored by measuring the permeability coefficients and stratum corneum/water partition coefficients of a series of hydrocortisone esters varying in lipophilicity. Isolated human stratum corneum, used in both the permeability and the uptake experiments, was shown to resemble full-thickness skin in its overall resistance and selectivity to solute structure. As with full-thickness skin, delipidization destroys the barrier properties of isolated stratum corneum. Although a linear relationship is frequently assumed to exist between permeability coefficients and membrane/water partition coefficients, a log–log plot of permeability coefficients versus the intrinsic stratum corneum/water partition coefficients for the series of hydrocortisone esters studied is distinctly nonlinear. This nonlinearity arises from the fact that the transport of these solutes is rate limited by a lipid pathway in the stratum corneum, while uptake reflects both lipid and protein domains. From the relative permeability coefficients of 21-esters of hydrocortisone varying in acyl-chain structure, group contributions to the free energy of transfer of solute into the rate-limiting barrier microenvironment of the stratum corneum lipid pathway are calculated for a variety of functional groups including the −CH2−, −CONH2, −CON(CH3)2, -COOCH3, −COOH, and −OH groups. These are compared to contributions to the free energies of transfer obtained for the same functional groups in octanol/water, heptane/water, and stratum corneum/water partitioning experiments. The group contributions to transport for polar, hydrogen-bonding functional groups are similar to the values obtained from octanol/water partition coefficients. This similarity suggests that complete loss of hydrogen bonding does not occur in the transition state for passive diffusion via the lipid pathway.

pH-Dependent Swelling and Solute Diffusion Characteristics of Poly(Hydroxyethyl Methacrylate–CO–Methacrylie Acid) Hydrogels

Abstract: Poly(hydroxyethyl methacrylate-co-methacrylic acid) hydrogels can swell extensively in a high-pH medium where the carboxyl groups are ionized. The swelling equilibrium is a strong function of the methacrylic acid composition of the polymer and pH of the medium. The nonionized gel structure was found to be rather insensitive to the amount of cross-linker, tetraethylene glycol dimethacrylate (TEGDMA), incorporated, within the range of 0.5 to 3%. This result is supportive of the existence of secondary interactions that shield the effect of covalent cross-links. Phenylpropanolamine (PPA) was used as a probe solute to study the diffusion characteristics of the poly(HEMA-co-MA) gels. Its diffusion coefficient in the swollen matrices of different methacrylic acid compositions at various pH's was measured via a desorption method. It is evident that these diffusion coefficients follow Yasuda's free volume theory, which expresses an exponential relationship between the solute diffusivity in a swollen polymer membrane and the reciprocal of the membrane hydration. Although interactions exist between PPA and the hydrogel matrix, these interactions are not significant enough to perturb the free volume relationship established. This observation can be explained by the high ionic strength of the system.

A New System for In Vitro Studies of Iontophoresis

Abstract: This report describes a new iontophoretic diffusion cell that allows both electrodes to be applied to the same side of the same piece of skin. The cell permits a better approximation of the in vivo situation than do conventional side-by-side cells. The unique construction of the cell allows nonliquid material to be applied to the skin surface and makes it possible to investigate horizontal transport paths. Preliminary results utilizing the cell are described. Iontophoretic enhancement of morphine and clonidine delivery across full-thickness hairless mouse skin has been achieved. The importance of pH control in these experiments is apparent. Further experiments with morphine indicate that, for this drug at least, iontophoretically driven lateral transport within the skin is unimportant. Because the cell design allows significant parallels to the use of iontophoresis in vivo, we suggest that it will prove to be a useful tool in the determination of fundamental structure/transport relationships under the influence of an externally applied current.

Solubility and related physicochemical properties of narcotic analgesics.

Abstract: The physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm3)\({\frac{1}{2}}\) for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphine's solubility parameter from its hexane solubility alone and its melting properties gave a corresponding δ2 value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm3)\({\frac{1}{2}}\). For these compounds, experimental solubility parameters agreed with solubility parameters estimated from molar attraction constants. Because meperidine, fentanyl, and sufentanil exhibit low levels of intracrystalline cohesion, as reflected in low melting points and relatively modest heats of fusion, theoretically projected ideal solubilities and actual solubilities in organic solvents measured for them were considerably higher than determined for morphine and its analogues. Consistent with the solubilities, the octanol–water partition coefficients of the two 4-anilinopiperidine analogues and of meperidine were several orders of magnitude larger than those of the opioids, evidencing the fact that meperidine, fentanyl, and sufentanil are substantially more lipophilic than the opioids.

Physicochemical aspects of percutaneous penetration and its enhancement.

Abstract: The classic diffusion model-based interpretation of percutaneous absorption is compared to a simple kinetic analysis. The physicochemical significance and the major deductions of the two approaches are shown to be in general agreement. In particular, the effect of penetrant oil/water partition coefficient on transdermal flux is consistently predicted by the two models. Diffusional and kinetic assessments of skin penetration enhancement are then shown to reveal similar dependencies upon penetrant physical chemistry. It is demonstrated that the requirements for successful promotion of a lipophilic drug's transdermal flux are quite different from those necessary for a hydrophilic penetrant. Finally, in light of published transport data and our increased comprehension of the stratum corneum barrier function, the evidence for (and significance of) different absorption paths across the stratum corneum is considered. In addition, the impact of penetrant “size” on transport is addressed. It is argued that currently held beliefs concerning (i) a putative “polar” route through the stratum corneum and (ii) the dependence of flux on molecular weight warrant considerable further attention before their unequivocal acceptance is appropriate.

In vitro model for ciclosporin intestinal absorption in lipid vehicles.

Abstract: The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vitro. The effect of the intestinal lipid digestion was considered on the partition of the drug from olive oil or middle-chain triglyceride (MCT) into phases of simulated intestinal content. The phases obtained after ultracentrifugation were analyzed for their Ciclosporin content and characterized for their lipid classes. For both lipid vehicles the presence of lipolysis products did not promote the partition of the drug into the aqueous phase. The absorption in vivo was not related to the drug amount in the aqueous phase and in the oil phase. Therefore, phase quantification in vitro cannot simulate the dynamics of in vivo absorption events following application of a poorly water-soluble drug in a lipid vehicle.

Controlled gastric emptying. 1. Effects of physical properties on gastric residence times of nondisintegrating geometric shapes in beagle dogs

Abstract: The importance of three physical parameters (size, shape, and flexibility) on gastric retention in fasting dogs was examined to assess the feasibility of designing a dosage form to achieve a consistent and predictable residence in the stomach. Test shapes were molded from Silastic elastomer or made from extruded polyethylene or polyethylene blends and included 15% barium sulfate for X-ray visualization. Beagle dogs were dosed with test shapes administered in gelatin capsules. Gastric retention was monitored by X ray over a 24-hr period. Six shapes (ring, tetrahedron, cloverleaf, disk, string, and pellet) were screened in vivo for their gastric retention potential. The tetrahedrons (each leg 2 cm in length) exhibited 91–100% retention at 24 hr. The rings (3.6-cm diameter) provided 100% retention at 24 hr. Rings and tetrahedrons of varying flexural moduli were prepared by blending low-density polyethylene and ethylene: vinyl acetate copolymer. A positive correlation existed between flexural modulus and gastric retention. The results indicate that it is feasible to design a platform for a dosage form that can be administered to beagle dogs in capsule form and be retained for 24 hr.

Pharmacokinetics of ibuprofen enantiomers in humans following oral administration of tablets with different absorption rates.

Abstract: Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t1/2 values for the enantiomers. There were significant differences between the peak times (Tmax) of the products. The S:R ratios of the concentrations at Tmax of S and AUC also differed; significant positive correlations were found between Tmax and the S:R ratios of Cmax. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.

Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins: Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ

Abstract: The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, J max * = 21.3 (±4.0), K m = 16.1 (±3.6), P m * = 0, and P c *= 1.32 (±0.07); cefadroxil, J max * = 8.4 (±0.8), K m = 5.9 (±0.8), P m * = 0, and P c * = 1.43 (±0.10); cephalexin, J max * = 9.1 (±1.2), K m = 7.2 (±1.2), P m * = 0, and P c * = 1.30 (±0.10); cefatrizine, J max * = 0.73 (±0.19), K m = 0.58 (±0.17), P m * = 0.17 (±0.03), and P c * = 1.25 (±0.10); and cephradine, J max * = 1.57 (±0.84), K m = 1.48 (±0.75), P m * = 0.25 (±0.07), and P c * = 1.06 (±0.08). The colon absorption parameter for cefaclor is P m * = 0.36 (±0.06, where J max * (mM) is the maximal flux, K m (mM) is the Michaelis constant, P m * is the passive membrane permeability, and P c*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.

Transdermal controlled administration of indomethacin. I. Enhancement of skin permeability.

Abstract: It was observed experimentally that indomethacin delivered in an aqueous suspension has a greater skin permeation rate in an ionized form than in a nonionized form. In this investigation, a matrix-type transdermal drug delivery system was developed to deliver indomethacin molecules in nonionized form. The skin permeation rate of nonionized indomethacin molecules from this system could be substantially improved by incorporating skin permeation enhancers, such as straight-chained alkanols, alkanoic acids, and esters. These enhancers form microreservoirs with indomethacin in the lipophilic silicone polymer matrix. By varying the alkyl chain length of alkanol, alkanoic acid, and its ester, the concentration of permeation enhancer, or the loading dose of indomethacin in the polymer matrix, the skin permeation rate of nonionized indomethacin molecules can be enhanced by as much as 30 times, which is almost sevenfold greater than the rate for ionized indomethacin molecules.

Dissolution of ionizable drugs in buffered and unbuffered solutions.

Abstract: The dissolution kinetics of ionizable drugs (weak acids or bases) are analyzed with a mathematical model derived from the theory of mass transfer with chemical reaction. The model assumes that the overall process is diffusion limited, that all the reactions are reversible and instantaneous, and that dissolution and reaction are limited to the stagnant fluid film adjacent to the solid phase. Dissolution into buffered and unbuffered aqueous solutions are considered separately, with covenient analytical solutions obtained in both cases. In addition, equations for the time to partial and complete dissolution are derived. The dissolution rate is shown to be dependent on the pK a and intrinsic solubility and the medium properties, i.e., pH, buffer capacity, and mass transfer coefficient. Equations of a form analogous to the nonionized case are derived to account explicitly for all these factors, with dissolution rates expressed in terms of the product of a driving force (concentration difference) and resistance (inverse of mass transfer coefficient). The solutions are in an accessible analytical form to calculate the surface pH and subsequently the surface concentrations driving the drug dissolution. Numerical examples to illustrate dissolution into unbuffered and buffered media are presented and the results are shown to be in accord with experimental data taken from the literature.

Carrier-Mediated Transport of Baclofen Across Monolayers of Bovine Brain Endothelial Cells in Primary Culture

Abstract: The mechanism of transport of baclofen, a centrally acting muscle relaxant, across the blood-brain barrier (BBB) was studied using an in vitro model. The model consisted of a monolayer of bovine brain endothelial cells grown in primary culture on a porous regenerated cellulose membrane. The transport of baclofen across the monolayer expressed time and concentration dependency and was saturable. Transport data were corrected for diffusion and fitted to the Michaelis-Menten Vmax model: Km = 58.5 microM, Vmax = 0.23 nmol/min. The results validate the use of the in vitro BBB model as described and support the hypothesis that baclofen penetrates the BBB by means of a carrier-mediated transport system.

Kinetics of release from enteric-coated tablets

Abstract: Controlled and localized release of drugs in the intestine can be achieved by enteric coating. The design of enteric-coated tablets has so far remained empirical, in part because of the lack of a quantitative description of the drug release kinetics. In this paper, a mathematical model is presented that describes the dissolution of the polymer coating and release kinetics of weakly acidic drugs from enteric-coated tablets in buffered media. This model can also be used to predict the time of onset of core disintegration. The model assumes that the release rate is limited by diffusion, and furthermore, all the reactions are considered as reversible and instantaneous. Dissolution and reaction are assumed to take place in the polymer layer and a hypothetical stagnant liquid film adjacent to the polymer layer (the classical film theory approach). The dissolution of the enteric coating is found to depend on the intrinsic solubilities and pKa's of the drug and polymer and the medium properties. The release rate of the drug is found to depend on the intrinsic solubilities and pKa's of drug and polymer, the medium properties, i.e., pH and buffer capacity, and a mass transfer coefficient. Explicit relationships between the release rates and all these factors are derived. Successful prediction of experimental data indicates that the model provides an adequate description of release from enteric coated tablets. Limitations of the model and its potential application to the design of appropriate in vitro testing conditions and to the formulation of enteric coated tablets are also discussed.

Approaches to radiolabeling of antibodies for diagnosis and therapy of cancer.

Abstract: The development of monoclonal antibodies of high affinity and selectivity for tumor antigens has supported the development of radiolabeled antibodies for diagnostic localization and targeted delivery of therapeutic radionuclides. Several radionuclide chelating agent systems have been developed for indium-111 and technetium-99m that have shown good sensitivity and specificity for tumor detection in patients. Feasibility for therapy has been shown in animal models and a few patient studies with iodine-131 and yttrium-90. This review covers selection of radionuclides and chemistry of antibody radiolabeling.

Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions.

Abstract: The delivery of particles as small as possible (preferably <5 µm) to the respiratory tract should be the aim of those formulating metered dose inhalers (MDIs) This may be facilitated by the formulation of solution, rather than suspension-type, pressurized aerosol units Two series of MDIs were compared; one contained suspended micronized disodium fluorescein (01%, w/v), while the other contained the same concentration of dissolved salicylic acid Either oleic acid, L-α-phosphatidylcholine, or sorbitan trioleate was incorporated at 015% (w/v) as suspending agent (disodium fluorescein) or solubilizing agent (salicylic acid) The propellant blend was 70% (w/w) Freon 12 and 30% (w/w) Freon 11 in all cases This exhibited a vapor pressure of 506 psig (4447 kPa) at 21°C The output particle size distribution of the aerosol reaching the cascade impactor showed a mass median aerodynamic diameter (MMAD) of approximately 4 and 2 µm for the suspension and solution formulations respectively, regardless of the surfactant used Larger MMADs were observed for solution aerosols formulated with oleic acid (232 µm) compared to those containing L-α-phosphatidylcholine (193 µm) or sorbitan trioleate (207 µm) Possible reasons for these observations are discussed

Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs.

Abstract: Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.

The measurement of warfarin enantiomers in serum using coupled achiral-chiral, high-performance liquid chromatography (HPLC)

Abstract: An assay for the serum concentration of the enantiomers of warfarin, R-warfarin and S-warfarin, has been developed using a bovine serum albumin chiral stationary phase (BSA-CSP) coupled to a Pinkerton internal-surface reverse-phase (ISRP) achiral column. The ISRP column is used to separate R,S-warfarin from the serum components and warfarin metabolites and to quantitate the total R,S-warfarin concentration. The eluent containing R,S-warfarin is then selectively transferred to the BSA-CSP, where the enantiomers are stereochemically resolved (α = 1.19) and the enantiomeric composition is determined. This system is sensitive and accurate, does not require extensive precolumn manipulations, and can be automated for use in large-scale clinical studies.

Free radicals and oxygen toxicity

Abstract: Most organisms are constantly exposed to molecular oxygen, and this has become a requirement of life for many of them. Oxygen is not totally innocuous, however, and it has long been known to be toxic to many organisms, including humans. The deleterious effects of oxygen are thought to result from its metabolic reduction to highly reactive and toxic species, including superoxide anion radical and hydroxyl radical. Peroxidation of lipids is a major consequence of exposure to these species and the cell possesses various enzymes, including superoxide dismutase and catalase, as well as cellular antioxidants which are able to scavenge oxygen free radicals and repair peroxidized lipids. These aspects of oxygen toxicity are reviewed, as well as the involvement of oxygen free radicals in the toxicity of the herbicide paraquat.

Thiol Reduction of 3′-Azidothymidine to 3′-Aminothymidine: Kinetics and Biomedical Implications

Abstract: The ability of thiols to reduce 3′-azidothymidine (AZT) to 3′-aminothymidine has been investigated. Incubation with glutathione, dithiothreitol (DTT), or mercaptoethanol at pH 7.2 and 37°C leads to quantitative reduction of the azido moiety to an amine. The reaction is first order in AZT and first order in reducing agent (mono- or dithiol). The second-order rate constants are 2.77 × 10−3, 6.55 × 10−5, and 6.35 × 10−6M−l sec−1 for the dithiothreitol, glutathione, and mercaptoethanol reductions, respectively. The thiol reduction of alkyl azide to amine under mild conditions is a synthetic method particularly suitable for water-soluble azido compounds that are sensitive to catalytic hydrogenation. The potential for the mono- or dithiol-mediated reduction of alkyl azides under biological conditions must be considered when conducting studies of azido drugs.