Comparison of the Bioavailability of oral and Rectal forms of Diphenylhydantoin Sodium

The bioavailabilities of single 100-mg oral and rectal doses of diphenylhydantoin sodium were studied in five healthy volunteers. The rectal form used was prepared at laboratory conditions and the oral form was a commercial preparation. Blood samples were analysed over a 72-hr period. Evaluation of the AUC, t_max and C_max values have shown that the total absorption after the two routes of administration was the same while the C_max and t_max differed.     

Bioavailability of oral methylnaltrexone increases with a phosphatidylcholine-based formulation

Objective: Methylnaltrexone (MNTX), a peripherally restricted opioid antagonist with mu-opioid receptor selectivity, can reduce opioid activity in the gastrointestinal tract while sparing the pain relief afforded by opioids. Since the bioavailability of oral MNTX is low, it is necessary to explore the oral formulations of MNTX that increase its bioavailability.

Materials and methods: An MNTX-phosphatidylcholine complex (MNTX-PC) formulation was prepared. The physicochemical properties of MNTX-PC were analyzed, and its bioavailability was evaluated in rats. After 250?mg/kg of oral MNTX-PC, plasma samples were collected up to 9?h. The concentrations of the compound in rat plasma were quantified using LC/MS/MS.

Results: Two MNTX plasma concentration peaks were observed at 120 and 180?min for the MNTX-PC group and control (MNTX in a water solution). T_max was 180?min, C_max was 1083.7?±?293.9?ng/mL, and T_1/2 was 496?min for the MNTX-PC group. For control, T_max was 180?min, C_max was 448.4?±?126.0?ng/mL, and T_1/2 was 259?min. The AUC_{0–540 min} for the MNTX-PC group was 5758.2?±?1474.2?ngh/mL; for control, 1405.9?±?447.8?ngh/mL. Thus, the relative bioavailability after the oral administration of MNTX-PC was 410% compared to that of control.

Conclusion: MNTX-PC formulation significantly enhanced the oral bioavailability of MNTX.     

Preparation and Evaluation of Mucin-Gelatin Mucoadhesive Microspheres for Rectal Delivery of Ceftriaxone Sodium

ABSTRACT

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.     

Bioavailability assessment of oral coenzyme Q10 formulations in dogs

The purpose of this investigation was to compare the bioavailability of three coenzyme Q10 (CoQ10) formulations in dogs using an open, randomized, multiple-dose crossover design. The formulations included a powder-filled capsule (A, control) and two soft gelatin formulations (Q-Gel as the water-miscible form of CoQ10, B and Q-Nol as the water-miscible form of ubiquinol, the reduced form of CoQ10, C). Formulations were evaluated in pairs, allowing a washout period of 14 days prior to crossing over. Blood samples were collected from each animal prior to dosing to determine the endogenous plasma CoQ10 concentrations. Serial blood samples were collected for 72 hr and plasma CoQ10 concentrations were determined by high-performance liquid chromatography. Plasma concentration-time profiles were corrected for endogenous CoQ10 concentrations. Results showed that the relative bioavailabilities of formulations B and C were approximately 3.6 and 6.2-fold higher than that of control formulation A. The AUC(microgram.hr/mL) +/- SD, Cmax(microgram/mL) +/- SD, and Tmax(hr) +/- SD for formulations A, B, and C were 1.695 +/- 0.06, 6.097 +/- 0.08, and 10.510 +/- 0.10; 0.096 +/- 0.035, 0.169 +/- 0.038, and 0.402 +/- 0.102; and 4.2 +/- 1.48, 4.1 +/- 1.57, and 4.5 +/- 0.58, respectively. While no significant differences were observed between Tmax values of the three formulations, the AUC and Cmax values for formulations B and C were significantly higher than those of the control (p < 0.05). The present investigation demonstrates that soft gelatin capsules containing water-miscible CoQ10 formulations B (Q-Gel) and C (Q-Nol) are superior to powder-filled formulations with regard to their biopharmaceutical characteristics.     

Effectiveness of Rectal Insulin Suppositories Containing Sodium Cholate in Normal and Insulin Dependent Diabetic Subjects

The effectiveness of 100-U porcine insulin suppository containing 5% sodium cholate was examined in 3 normal volunteers (controls) and 15 diabetics. The hypoglycaemic response, in controls, started at 15 min, peaked at 30 min and returned to the initial level after 45 min, while in diabetics, started at 15 min, peaked at 120 min and persisted for the duration of the study (150 min). The maximum percent reduction in plasma glucose was found to be significantly greater in controls than in diabetics, while the AUC for percent glucose reduction was greater in diabetics than in controls. This was accompanied by a significant rise in serum insulin in controls than in diabetics. The serum insulin peaked at 15 min and remained above the initial value for 45 and 120 min, post administration, in controls and diabetics, respectively. Thus, rectal insulin could be considered as alternative to existing therapies.     

Bioavailability of clarithromycin cyclodextrin ternary complexes upon oral administration to healthy beagle dogs

The dissolution profiles of clarithromycin (CLM) and its beta-cyclodextrin-citric acid ternary complexes (CTC) were examined. CTC showed an enhanced dissolution rate in pH 6.8 phosphate buffers. The relative bioavailability was evaluated by comparing area under the plasma concentration-time curve (AUC) of the pure CLM with that of its cyclodextrin-citric acid ternary complexes those were filled into hard gelatin capsules. To compare the pharmacokinetic behavior, both plasma levels of parent compound and the active metabolite 14-OH-CLM concentrations were estimated. The relative bioavailability value as the ratios of CLM of mean total AUC for CTC relative to CLM was 120.3%. The relative bioavailability value as the ratios of 14-OH CLM of mean total AUC for CTC relative to CLM was 95.3%. The results suggest that the absorption of CTC in beagle dogs was slightly improved because of the enhanced dissolution rate of CTC at pH 6.8.     

Overview of compendial standards for solid oral dosage forms

Compendial standards define acceptable articles at the time of use, in contrast to process control and product release strategies. The establishment of drug names and the setting of requirements for identity, strength, quality, purity, packaging, storage, and labeling are addressed by compendial standards. Because the solid oral dosage forms of drugs are used most frequently in drug therapy, it is crucial to examine how the attributes of these forms affect the development of quality standards. Compendial selections of tests for identity, dose uniformity, dissolution/disintegration, and limits and of assays to confirm content are surveyed in this article. Also discussed are the packaging and storage standards established by the compendia and the relationships between drug names and labeling requirements.     

Overview of compendial standards for solid oral dosage forms

Abstract

Compendial standards define acceptable articles at the time of use, in contrast to process control and product release strategies. The establishment of drug names and the setting of requirements for identity, strength, quality, purity, packaging, storage, and labeling are addressed by compendial standards. Because the solid oral dosage forms of drugs are used most frequently in drug therapy, it is crucial to examine how the attributes of these forms affect the development of quality standards. Compendial selections of tests for identity, dose uniformity, dissolution/disintegration, and limits and of assays to confirm content are surveyed in this article. Also discussed are the packaging and storage standards established by the compendia and the relationships between drug names and labeling requirements.     

Dissolution of omeprazole from delayed-release solid oral dosage forms

The evaluation of the biopharmaceutical quality of omeprazole enteric-coated products (granules in capsules) with respect to its dissolution characteristics is not specifically regulated in any of the most common official pharmacopoeia. USP 23 includes a general monograph for enteric-coated products. This paper reports the evaluation of the medium pH effect on the dissolution rates of omeprazole from four omeprazole-containing products of different manufacturers. It is concluded that the USP 23 recommended dissolution procedure for enteric-coated products is not suitable due to the degradation of omeprazole under such conditions. Furthermore, the medium with pH 8.0 showed different dissolution rates not observed at pH 7.4, allowing discrimination between products of different manufacturers.     

Stability of pharmaceutical salts in solid oral dosage forms

Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid-state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them to avoid and solve the instability issues of pharmaceutical salts in the product design.     

Comparison of the fatigue behaviour of two different forms of PMMA

This study investigates the fatigue behaviour of two forms of polymethylmethacrylate (PMMA): pure PMMA in the form of acrylic glass and PMMA-based bone cement. Acrylic glass demonstrated superior fatigue strength compared to hand-mixed porous bone cement but was significantly weaker than pore-free bone cement. The greater fatigue strength of bone cement in comparison to acrylic glass was attributed to its composite-like microstructure, containing pre-polymerized beads which are absent in the amorphous structure of acrylic glass. In tests conducted on notched specimens, the porous bone cement demonstrated superior fatigue strength to acrylic glass. The results could be predicted using the theory of critical distances, with errors no larger than 14%. This approach allowed us to show that, although porosity had a negative influence on the fatigue strength of the plain specimens in comparison to acrylic glass, the presence of porosity had no effect when the samples contained a notch or a hole. This finding is interesting when considering the effort put into removing porosity from bone cement during surgical operations, where it is used in situations where there are sharp stress concentrations in the form of protruding bone and the design features of artificial implants.     

Comparison of linear forms of the radiative transfer equation with analytic Jacobians

Determining the Jacobians of the radiative transfer equation (RTE) is important to the qualities of the simultaneous retrieval of geophysical parameters from satellite radiance observations and the assimilation of radiance data into a numerical weather prediction system. Two linear forms of the RTE with analytic Jacobians are formulated. The first linear form has approximate analytic Jacobians, which involves some monochromatic approximation applied to a fast transmittance model. Unlike previous research, which lacks the transmittance Jacobian with respect to the atmospheric temperature profile, this form is complete in the sense that the transmittance Jacobians with respect to atmospheric temperature and absorbing constituent profiles are both present. The second linear form has exact analytic Jacobians derived consistently from the same fast transmittance model without using any monochromatic approximation. By numerical comparison between the two linear forms for the NOAA-12 High-Resolution Infrared Sounder, we show significant errors in the linear form with approximate analytic Jacobians. The relative absolute linearization error from the linear form with approximate analytic Jacobians is shown to be 2-4 orders of magnitude larger than that from the linear form with exact analytic Jacobians, even for the case of a 0.1% perturbation of the U.S. Standard Atmosphere. The errors unnecessarily complicate the ill-posed retrieval problem of atmospheric remote sensing and can be avoided if the correct linear form of the RTE with exact analytic Jacobians is adopted.     

Relative Hypoglycemia of Rectal Insulin Suppositories Containing Deoxycholic Acid, Sodium Taurocholate, Polycarbophil, and Their Combinations in Diabetic Rabbits

In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.     

Relative Hypoglycemia of Rectal Insulin Suppositories Containing Deoxycholic Acid,Sodium Taurocholate,Polycarbophil, and Their Combinations in Diabetic Rabbits

In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.     

Comparison of the physical and chemical stability of niclosamide crystal forms in aqueous versus nonaqueous suspensions

In an effort to produce physically stable and pharmaceutically acceptable suspensions of niclosamide, this study reports the differences in physical and chemical stability of aqueous vs. nonaqueous suspensions of a niclosamide anhydrate, two monohydrates HA and HB, a 1:1 niclosamide N,N-dimethylformamide solvate, a 1:1 niclosamide dimethyl sulfoxide solvate, a 1:1 niclosamide methanol solvate, and a 2:1 niclosamide tetraethylene glycol hemisolvate. Evaluation of aqueous and nonaqueous suspensions showed that in aqueous suspensions anhydrous, and solvated niclosamide crystal forms were transformed to a monohydrate, HA, which was reasonably stable but which did eventually transform to the most stable monohydrate HB. The order in which these crystal forms transformed to monohydrate HB were: Anhydrate > N,N-dimethylformamide > dimethyl sulfoxide > methanol > tetraethylene glycol > monohydrate HA. In a nonaqueous propylene glycol vehicle, the transformation to the monohydrous forms was not observed and on desolvation the solvated crystals transformed to the anhydrous form. In all cases, immediately upon desolvation or dehydration, the crystal structures of the desolvated materials were similar to that of the solvated materials. However, the isomorphic structures, formed after desolvation, were unstable and rehydrated or resolvated when exposed to the solvent or converted to the anhydrous form in a dry environment. The crystal forms remained chemically stable in both aqueous and nonaqueous suspensions for the length of the study.     

Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review

Context: Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model.

Objective: The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms.

Methods: Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described.

Results: There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of “from powder to tablet” is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible.

Conclusion: A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production.     

Powdered self-emulsified lipid formulations of meloxicam as solid dosage forms for oral administration

The objectives of this study were to prepare a powdered self-emulsified (SEDDS) formulation of meloxicam and to compare its oral bioavailability against commercial Mobic^® tablets. The SEDDS formulation was prepared by in situ salt formation of meloxicam in a blend of lipid excipients and aqueous tris (hydroxymethyl) aminomethane solution. The liquid SEDDS was subsequently adsorbed on silica powder and was tested for size, flow, and crystal growth. The flowability index of the powdered SEDDS was borderline acceptable. Absence of crystal growth with storage was confirmed by DSC and PXRD studies. Dissolution of meloxicam from the powdered SEDDS was >90% vs. <12% for powdered meloxicam and <80% for the commercial tablets. Stability of the powdered formulations after storage in gelatin and HPMC capsules was also evaluated to study the effect of water migration from the fill into capsule shells. Capsules softened to a different extent as a function of fill material with HPMC capsules showing greater resistance to water migration. Finally, oral bioavailability of the formulations was evaluated in beagle dogs. Powdered meloxicam SEDDS formulation showed a 1.3-fold increase in AUC vs. commercial Mobic^® tablets. Overall, this study described a novel SEDDS formulation of meloxicam and outlined a systematic approach to adsorbing and testing the flow and stability behavior of powdered SEDDS formulations.     

Comparison of the Results of Prediction of Transport Coefficients of Sodium Vapor with Experimental Data

The interatomic interaction potentials derived from new precision spectroscopic data are used to calculate averaged collision cross sections of two sodium atoms. The coefficients of viscosity and thermal conductivity of sodium vapor at temperatures from 700 to 2500 K and pressures from those corresponding to monatomic rarefied gas to the saturation curve (but not exceeding 1 MPa) are predicted. The prediction results are compared with the available experimental data about the transport coefficients of sodium vapor. Possible reasons for observed systematic discrepancy are discussed.     

Bioavailability and pharmacokinetics of acyclovir tablet preparation

The bioavailability of a generic preparation of acyclovir (Avorax) was compared with the innovator product, Zovirax. Twelve healthy volunteers participated in the study, conducted according to a randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration time curve (AUC(0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the Tmax or the logarithmic transformed AUC(0-infinity) and C(max) values of the two preparations. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC(0-infinity) values of Avorax over those of Zovirax was found to lie between 0.85 and 1.06, while that of the logarithmic transformed Cmax values was between 0.95 and 1.25, being within the bioequivalence limit of 0.80-1.25. Moreover, the elimination rate constant (k(e)), elimination half-life (t(1/2)), and apparent volume of distribution (Vd) values obtained with the two preparations were comparable and not significantly different statistically.