Ethical observations on the choice of parenteral solvents. Choice of parenteral solvent...

The parenteral administration of insoluble drugs leads to the use of biologically active solvents inducing effects associated with ethical cause of concern including pain and pharmacological interactions. Selected vehicles currently used were ethically and scientifically reviewed. Our investigations allowed reinforcing the formulation decision tree with an ethical point of view. The last generation of cyclodextrin appears to be the safest solvent. Second choice could be lipidic emulsions, third choice being co-solvents, and finally non-ionic surfactants because of their hypersensitivity reactions. Screening tests including pH, osmolality measurements, cytotoxicity, and hemotoxicity, should allow to check the formulation tolerance before the animals' administration.     

Aerosol-based efficient delivery of telithromycin,a ketolide antimicrobial agent,to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections

Purpose: The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration. Method: The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer®. Results and discussion: The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values. Conclusion: This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.     

Employee privacy: legal and research developments and implications for personnel administration

The contemporary emphasis on privacy has created a myriad of complex personnel problems and associated approaches to handle them. These privacy-oriented problems generally involve social, ethical, legal, managerial, and even political considerations. Personnel administrators are constantly confronted with the privacy issue. This article attempts to synthesize privacy information relevant to personnel administration, and to provide personnel administrators with managerial guidance for handling employee privacy problems in the work environment. It places particular emphasis on differentiating between ethical and legal aspects of privacy in our society, and, accordingly, on clarifying existing confusion over the impact of so-called "privacy laws" on personnel administration.     

Thermoelastic wave characteristics in a hollow cylinder using the modified wave finite element method

This paper represents a modified formulation of the wave finite element (WFE) method for propagating analysis of thermoelastic waves in a hollow cylinder without energy dissipation. The 2D-high-order spectral element with the Gauss–Legendre–Lobatto integration is applied into the WFE method, which produces the diagonal mass matrix. Based on the assumption of harmonic displacement fields by Fourier series expansion, the general discretization wave equation is simplified from the 3D problem to 2D. Dispersion properties of elastic wave propagation in the hollow cylinder are computed considering the choice of the spectral element orders, and the results indicate the high efficiency and high accuracy of the modified formulation compared with that of the software Disperse. Then, using the modified formulation, the thermoelastic dynamic equation of the cylinder is derived from the generalized thermoelasticity theory. The propagation of the thermoelasticwave (including two kinds of wave modes) in the cylinder without energy dissipation is discussed in differentcases. Finally, wave structures along the radial direction of thermoelastic wave modes are shown at thenondimensional frequency 1.25, which can be used for the recognition of different modes.     

Development of microemulsion of mitotane for improvement of oral bioavailability

Background: Mitotane (o,p′-DDD) is considered to be the drug of choice in the treatment of nonresectable and metastasized adrenocortical carcinoma. However, mitotane has poor solubility in the gastrointestinal tract and very low bioavailability. Consequently, to achieve therapeutic plasma level, high cumulative doses (4–6 g/day) of mitotane were usually used during 3–5 months. To shorten this equilibration time and reduce gastrointestinal side effects, a self-microemulsifying drug delivery system (SMEDDS) of mitotane has been developed. Method: First time, the solubility of mitotane was determined in various oils and surfactants; then, the influence of oils, surfactants, and cosurfactants on the formation of SMEDDS was investigated by constructing ternary phase diagrams. SMEDDS was characterized by morphological observations and droplet size measurements. Intestinal drug permeation of SMEDDS of mitotane (3 mM) was assessed in an Ussing-type apparatus and the bioavailability was determined in a rabbit model. Results: The optimum formulation consisted of a mixture of Capryol®, Tween®, and Cremophor® EL (33:33:33). The formulation was found to pass through the intestinal barrier much faster than a solution of mitotane (14.85 ± 0.8 versus 3.03 ± 0.2 μmol/cm²). Moreover, after oral administration in rabbits, the relative bioavailability was 3.4, compared with that of the conventional form (Lysodren®). Conclusion: This SMEDDS can now be considered as a very good candidate to optimize the administration of mitotane.     

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. Method: Gels formed by solutions containing methylcellulose (1.0–2.0%) and pectin (0.5–2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. Results: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. Conclusions: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.     

Plasma Levels of lormetazepam after Sublingual and Oral Administration of 1 MG to Humans

Abstract

A new galenical formulation containing 1 mg lormeta-zepam (LMZ) for sublingual administration (“sleeping wafer”, see Figure 1) has been developed. In an open-cross over design the plasma lormetazepam levels were monitored radioimmunologically in 16 volunteers. Subjects received the sublingual formulation and an oral tablet (Noctamid^R-1) in a randomized sequence at weekly intervals. After sublingual administration the mean plasma lormetazepam levels were significantly higher between 7.5 and 25 minutes than after administration of the tablet. The earlier rise in plasma LMZ levels is also reflected in partial areas under the plasma level curve up to 45 minutes. LMZ was completely absorbed from both formulations as shown in total AUCs.

It is anticipated that sublingual administration of the new formulation will lead to a 40 - 50 % reduction of sleep latency. Possibilities for therapeutic application of the new formulation are discussed.     

Plasma Levels of lormetazepam after Sublingual and Oral Administration of 1 MG to Humans

A new galenical formulation containing 1 mg lormeta-zepam (LMZ) for sublingual administration (“sleeping wafer”, see Figure 1) has been developed. In an open-cross over design the plasma lormetazepam levels were monitored radioimmunologically in 16 volunteers. Subjects received the sublingual formulation and an oral tablet (Noctamid^R-1) in a randomized sequence at weekly intervals. After sublingual administration the mean plasma lormetazepam levels were significantly higher between 7.5 and 25 minutes than after administration of the tablet. The earlier rise in plasma LMZ levels is also reflected in partial areas under the plasma level curve up to 45 minutes. LMZ was completely absorbed from both formulations as shown in total AUCs.

It is anticipated that sublingual administration of the new formulation will lead to a 40 - 50 % reduction of sleep latency. Possibilities for therapeutic application of the new formulation are discussed.     

CALCULATION OF HYPERELASTIC RESPONSE OF FINITELY DEFORMED ELASTIC-VISCOPLASTIC MATERIALS

The objective of this paper is to present a numerical algorithm for calculating hyperelastic constitutive equations characterizing the thermomechanical response of elastically isotropic elastic-viscoplastic materials. The algorithm is developed within the context of an alternative formulation of plasticity in which elastic distortional deformation is determined directly by integrating an evolution equation which includes the current velocity gradient and quantities that depend only on the present state of the material. Consequently, the formulation is independent of the particular choice of a measure of plastic deformation, the reference configuration, and the total deformation gradient from the reference configuration. These features allow the constitutive equations to be easily implemented into computer codes which currently use a hypoelastic formulation for calculating plasticity.     

Prospect theory based estimation of drivers’ risk attitudes in route choice behaviors

This paper applied prospect theory (PT) to describe drivers’ route choice behavior under Variable Message Sign (VMS), which presented visual traffic information to assist them to make route choice decisions. A quite rich empirical data from questionnaire and field spot was used to estimate parameters of PT. In order to make the parameters more realistic with drivers’ attitudes, they were classified into different types by significant factors influencing their behaviors. Based on the travel time distribution of alternative routes and route choice results from questionnaire, the parameterized value function of each category was figured out, which represented drivers’ risk attitudes and choice characteristics. The empirical verification showed that the estimates were acceptable and effective. The result showed drivers’ risk attitudes and route choice characteristics could be captured by PT under real-time information shown on VMS. For practical application, once drivers’ route choice characteristics and parameters were identified, their route choice behavior under different road conditions could be predicted accurately, which was the basis of traffic guidance measures formulation and implementation for targeted traffic management. Moreover, the heterogeneous risk attitudes among drivers should be considered when releasing traffic information and regulating traffic flow.     

SELECTION OF VARIABLES FOR LINEARIZED TRUSS OPTIMIZATION

Three possible variable selections for linearized truss optimization are compared. The available evidence shows that a variable choice of member stresses and member cross-sectional areas is inferior to either of the other two variable combinations, member stresses and reciprocal areas or member forces and cross-sectional areas. The properties of the member force/area variable choice are determined analytically and it is suggested that this selection may well be at least equally as powerful as the member stress/reciprocal area formulation.     

A flux limiter strategy for solving the saturation equation in RTM process simulation

The main aim of this work is the proposal of a numerical procedure for solving the saturation equation in RTM process simulation. In order to analyze in more detail the progressive impregnation of a fibrous preform by a fluid resin, the numerical model here proposed considers the flow through a partially saturated medium, including the dependence of permeability on the saturation degree. The model consists of an elliptic equation governing the pressure distribution and a transport hyperbolic equation governing the evolution of the saturation. A global flux limiter fixed mesh strategy is proposed for solving the transport equation with source term which describes the saturation evolution in RTM process. The flux limiter method has the ability to limit the extra numerical diffusion introduced by standard first-order schemes. This formulation could be an appealing choice for improving RTM flow simulations and optimize injection processes. Some preliminary numerical results are presented in order to validate the proposed numerical strategy.     

Formulation and Physiological and Biopharmaceutical Issues in the Development of Oral Lipid-Based Drug Delivery Systems

The rapidly increasing availability of drug receptor structural characteristics has permitted the receptor-guided synthesis of potential new drug molecules. This synthesis strategy frequently results in the creation of polycyclic and highly hydrophobic compounds, with attendant poor oral bioavailability resulting from low solubility and slow dissolution rate in the primarily aqueous contents of the gastrointestinal (GI) tract. In an attempt to improve the solubility-limited bioavailability associated with these compounds, formulators have turned to the use of lipid excipients in which the compounds can be solubilized prior to oral administration. This new class of excipients presents the pharmaceutical scientist with a number of new challenges at all stages of the formulation development process, beginning with the excipient selection and stability assessment of the prototype formulation, up to and including scale-up and mass production of the final market-image product. The interaction of lipid-based formulations with the gastrointestinal system and associated digestive processes presents additional challenges and opportunities that will be understood more fully as we begin to unravel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wall mediated by p-glycoprotein (PGP). And, it is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formulation development and scale-up issues and the physiological and biopharmaceutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form.     

Formulation and Physiological and Biopharmaceutical Issues in the Development of Oral Lipid-Based Drug Delivery Systems

The rapidly increasing availability of drug receptor structural characteristics has permitted the receptor-guided synthesis of potential new drug molecules. This synthesis strategy frequently results in the creation of polycyclic and highly hydrophobic compounds, with attendant poor oral bioavailability resulting from low solubility and slow dissolution rate in the primarily aqueous contents of the gastrointestinal (GI) tract. In an attempt to improve the solubility-limited bioavailability associated with these compounds, formulators have turned to the use of lipid excipients in which the compounds can be solubilized prior to oral administration. This new class of excipients presents the pharmaceutical scientist with a number of new challenges at all stages of the formulation development process, beginning with the excipient selection and stability assessment of the prototype formulation, up to and including scale-up and mass production of the final market-image product. The interaction of lipid-based formulations with the gastrointestinal system and associated digestive processes presents additional challenges and opportunities that will be understood more fully as we begin to unravel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wall mediated by p-glycoprotein (PGP). And, it is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formulation development and scale-up issues and the physiological and biopharmaceutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form.     

Flow of compressible fluid in porous elastic media

A finite element formulation for flow of fluid in a porous elastic media has been derived from a Gurtin type variational principle. Biot's field equations for porous media have been used in which the constitutive relations include the compressibility of the fluid. It has been shown that by proper choice of the form of the compressibility of the fluid as a function of the state variables, this option of the formulation can be used to treat the partially saturated soil. The method is general with respect to geometry, boundary conditions and material properties. Finally, the results of a series of examples have been presented and compared with exact results to demonstrate accuracy and applicability.     

Application of new error estimators based on gradient recovery and external domain approaches to 2D elastostatics problems

Two new error estimators for the BEM in 2D potential problems were recently presented by the authors. This work extends these two error estimators for 2D elastostatics problems. The first approach involves a local error estimator based on a gradient recovery procedure in which the error function is based on differences between smoothed and non-smoothed rates of change of boundary variables in the local tangential direction. The second approach is associated with the external problem formulation and gives both local and global measures of the error, depending on a choice of the external evaluation point. These approaches are post-processing procedures. Both estimators show consistency with mesh refinement and give similar qualitative results. The error estimator using the gradient recovery approach presents a more general characteristic as its formulation does not rely on an ‘optimal’ choice of an external parameter, such as in the case of the external domain error estimator. Also, the external domain error estimator can be used only for domains in which an exterior region exists. For example, the external domain error estimator cannot be used for an infinite domain with a crack, because a point in the exterior region (inside the crack) will not be at a finite distance to the crack surface.     

Some Problems in the U.K. With the Provision of New Drug Dosage Forms for Pre-Marketing Tests in Man

Provision of dosage forms for studies in man calls for the highest standards of Good Manufacturing Practice. Problems with supply of such materials are classed as scientific/technological, logistic, ethical and legal, and examples are discussed. The role of the formulation pharmacist as an influence on harmonizing the nature of dosage forms used in multi-centre trials on an international basis, and as a person involved in ensuring smooth transition of products from clinical trial status to production for marketing purposes is highlighted.