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The authors conclude that the persistence of aluminum hydroxide at the site of intramuscular injection is a novel finding which has an exact significance that remains to be established fully. It seems mandatory to evaluate possible long-term adverse effects induced by this compound, because this issue has not been addressed (in the past, aluminum hydroxide was believed to be cleared quickly from the body). If safety concerns about the long-term effects of aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to rescue vaccine-based strategies should be proposed to ensure the enormous benefit for public health that these vaccines provide worldwide.

The aim of this study was to test the hypothesis that polyvinylpyrrolidone (PVP) would increase the critical micelle concentration (CMC) of nonoxynol-9 (N-9), providing a reduction in its irritation potential, while maintaining essential spermicidal activity. Solid coprecipitates of N-9 with PVP were manufactured with the use of a modified lyophilization process. The irritation potential of N-9 was estimated by an in vitro assay, monitoring the extent of hemolysis of red blood cells. CMCs of N-9 were measured in the presence of various concentrations of PVP. A modified Sander-Cramer assay was implemented to measure the spermicidal activity of N-9 and the N-9/PVP coprecipitates. With the use of the lyophilization process and more suitable solvents, solid coprecipitates of N-9/PVP were manufactured with no residual organic solvents. The irritation potential of N-9 was reduced when in the presence of PVP-50% hemolysis values increased from 0.054 mM to more than 0.2mM. N-9 CMC values increased in the presence of PVP from 0.085 mM (0% PVP) to 0.110 mM (3.5% PVP) and 0.16 6mM (10% PVP). However, spermicidal activities ranged from 0.213 mM to 0.238 mM, N-9 remaining steady regardless of the amount of PVP. By use of N-9/PVP coprecipitates, the self-association properties and irritation potentials of N-9 were altered. This result suggests a process to produce a spermicidal product that reduces the detrimental implications to the vaginal epithelium while maintaining the essential spermicidal activity.

Many patients find it difficult to swallow powdery preparations like granules and because of this do not take their medication as prescribed. The difficulty is experienced in particular with dysphagic and geriatric patients, in addition to pediatric patients, especially those who find it difficult to deal with the bitter taste of medicine. It is possible that such problems result in a high incidence of noncompliance and ineffective therapy. In contrast, it is generally known that gelatinous foods like jelly are a favorite with the elderly and infants because their rheological properties make them easy to swallow. We have developed a deglutition aid jelly that can change almost all solid preparations into gelatinous dosage form preparations, which poses no risk of aspiration or spilling from the mouth, and thus is safe. To evaluate the pharmaceutical utility of this jelly, sensory tests and videofluoroscopic assessments were performed in 10 healthy adult volunteers (20-60 years of age). During the sensory tests, this jelly showed significant improvement in diffusion of the powdery preparation in the mouth and of adhesion to the oropharynx and prolonged the time until the bitter taste of the medicine was perceived. During the videofluoroscopic assessments, there were significant changes in the total oropharyngeal transit time (mean -13.04 s) and oral transit time (mean -10.69 s) in the group that received the jelly, suggesting improvement in the initiation of pharyngeal contractions and reduction in the time required for the bolus to transverse the pharynx. In addition, significant improvement in the oral onset of swallowing and a significant reduction in pharyngeal swallowing delay and in the frequency of aspiration were observed in some hospitalized patients with dysphagia. This jelly could therefore contribute to improved compliance in patients who feel burdened by taking oral medications.

This study examined the rheological and mucoadhesive properties of polymeric systems composed of the bioadhesive copolymer poly(methylvinylether-co-maleic anhydride), PMVE/MA and poly(vinylpyrrolidone, PVP) as candidate platforms for improved drug delivery to the oral cavity. Aqueous, neutral formulations were prepared containing PMVE/MA (10 or 15% w/w) and PVP (0-9% w/w). The rheological properties were examined at 20 +/- 0.1 degrees C using both oscillatory rheometry (0.01 to 1.0 Hz at a constant strain of 1.0 x 10(-3) rad) and controlled stress flow rheometry using a Carri-Med CSL(2)-100 rheometer. The mechanical properties were examined using texture profile analysis (15-mm depth of insertion, 9 mm s(-1) rate of insertion, 15 s delay period between the end of the first and beginning of the second compressions). The interaction of the various formulations with mucin was examined using oscillatory rheometry. All formulations exhibited pseudoplastic flow with minimal thixotropy. Increasing the concentration of each polymeric component increased the zero-rate viscosity (calculated using the Cross model), hardness, compressibility, the storage (G') and loss (G") moduli, and decreased the loss tangent. These observations may be due to greater polymeric entanglement between adjacent polymer chains. Specifically, rheological synergy was observed between PMVE/MA and PVP, evidence of complexation between these two polymers. From the relationship between the viscoelastic properties and oscillatory frequency, and the mathematical comparison of steady and oscillatory shear response of formulations using the Cox-Merz equation, it may be concluded that formulations containing 15% w/w PMVE/MA and either 6 or 9% w/w PVP exhibited rheological properties that were consistent with gel behavior. All other formulations exhibited rheological properties that resembled polymeric liquids. Increasing the concentrations of PMVE/MA and PVP significantly increased the interaction with mucin, the rheological synergy between the polymeric formulations and mucin and, in addition, the adhesiveness of the formulations. This is evidence of the muco/bioadhesive properties of the formulations. Conversely, the time of contact between each formulation and mucin did not affect their resultant interaction. In conclusion, this study has uniquely described the rheological and mucoadhesive properties of aqueous systems composed of PMVE/MA and PVP. In particular, the concentrations required for gel formation have been defined and the interaction between these two polymeric components illustrated using rheological methods. Furthermore, the simultaneous analysis of rheological, mechanical, and mucoadhesive data provided an insight into their potential utility as platforms for drug delivery systems for application to the oral cavity.

Asymmetric membrane-coated capsules with in situ formation of a delivery orifice were examined for their improved osmotic effects. The release mechanisms were investigated for drugs with both moderate to high water solubility and those with poor water solubility. The capsule wall membrane was produced by a phase-inversion process, in which an asymmetric membrane was formed on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quenching solution. In situ formation of a delivery orifice in the thin membrane was proven by visualization of a jet stream of chlorophyll being released from the capsule. The release mechanism for drugs with moderate to high water solubility was mainly controlled by the osmotic effect, which is a function of the drug's solubility. Permeability across the asymmetric membrane of the capsule was determined to be 4.28 x 10(-6) cm(2)/h-atm at 37 degrees C for drugs with water solubilities in a moderate to high range. Accordingly, the poorly water-soluble drug, nifedipine, was unable to create enough of an osmotic effect to activate drug release. Solubilization either by the addition of the solubility enhancer, SLS, or by a solid dispersion with HPMC could increase the solubility of nifedipine to a sufficient extent to activate drug release. It was found that the suspending ability induced by the viscous nature of HPMC further interacted with SLS to synergistically increase the maximal percent release and the release rate of nifedipine. The osmotic effect of this suspension ability was proposed as the underlying mechanism responsible for the release of poorly water-soluble drugs, i.e. nifedipine, from this system.

Background and Objectives The accumulation of platelet-derived cytokines in platelet concentrates (PC) during storage may contribute towards non-haemolytic transfusion reactions (NHTR). We investigated the effect of platelet storage medium on platelet activation, complement activation and cytokine levels in leucocyte-reduced PC. Materials and Methods Hyperconcentrated platelets (3000–6000 × 109/l) were collected by apheresis and diluted in 100% plasma, 70% PASIII, or 70% or 80% PASIII supplemented with magnesium and potassium (PAS IIIM). Results Levels of transforming growth factor-β (TGF-β) and regulated on activation, normal, T-cell expressed, and secreted (RANTES) increased during storage, as did the expression of P-selectin (CD62P), and were highest in PC stored in PASIII. In PC stored in PASIIIM, however, levels of TGF-β and RANTES were not significantly different from PC stored in plasma. Levels of CD62P expression, however, remained higher in PASIIIM PC than in those stored in plasma by day 5, but were lower than PC stored in PASIII. C3a des arg levels increased during storage in all media with the exception of PASIII and, on day 7, were higher in PC stored in plasma compared to PC stored in the other media. Conclusions Our results indicate that replacing plasma in PC with unmodified PASIII for storage results in higher levels of platelet-derived cytokines in PC. Furthermore, it appears that the nature of the medium used for storage of PC has a significant impact on platelet activation and cytokine levels of the PC. These implications should be taken into account when considering replacement of plasma with PAS.

Se desarrolló la caracterización de suspensiones de recubrimiento de núcleos placebos en sistemas acuosos que tenían como base polycoat 2 blanco, las que fueron coloreadas con 3 colorantes Lake diferentes. Se evaluó la densidad de estas suspensiones con diferentes porcentajes de sólidos dispersos (10-20 %), y se observó un aumento de estas con el incremento de sólidos dispersos. Se realizó el recubrimiento de núcleos placebos de diferentes tamaños de troquel y a las tabletas recubiertas se les efectuó un estudio de estabilidad del color a la luz, mediante la evaluación de su densidad óptica, estableciéndose el orden amarillo > azul > rojo. Se llevó a cabo un estudio de ganancia de humedad de las tabletas recubiertas a diferentes humedades relativas en hidrostatos estabilizados, y se confirmó la eficacia del sistema de recubrimiento para la protección de las tabletas en condiciones normales de humedad relativa. Los parámetros físico-químicos evaluados en núcleos placebos y tabletas recubiertas cumplen con los límites establecidos y se discuten algunos de ellos.The characterization of suspensions for coating placebo nuclei was developed in aqueous systems with white polycoat 2 as a base. The suspensions were colored with 3 different Lake coloring matters. The density of these suspensions was evaluated with diverse percentages of disperse solids (10-20 %). An increase of them was observed with the increment of disperse solids. The coating of placebo nuclei of different die sizes was carried out and the coated tablets were submitted to a study on the stability of color to light by evaluating their optical density. The following order was established: yellow > blue > red. A study on the humidity gain of the coated tablets was conducted at various relative humidities in stabilized hydrostats and the efficiency of the coating system for protecting tablets under normal conditions of relative humidity was confirmed. The physical and chemical parameters evaluated in placebo nuclei and coated tablets fulfilled the established limits and some of them were discussed.

Longer red blood cell (RBC) storage can improve blood logistics, increase the usefulness of autologous blood storage, and reduce donor exposure in neonatal intensive care. Better RBC storage can prevent membrane loss and preserve the secretion of adenosine 5'-triphosphate (ATP) in response to deformation. Better RBC storage may also reduce the formation of proinflammatory membrane breakdown products that lead to transfusion-related acute lung injury and the systemic inflammatory response syndrome. To improve RBC storage, the authors have attempted to maximize the production of ATP by the manipulation of pH and to minimize membrane loss through the use of membrane protectants and the manipulation of tonicity. Increasing the initial storage pH led to successively higher RBC ATP concentrations until pH 7.2 was reached, when the synthesis of 2,3-diphophoglycerate was initiated at the expense of ATP. Synthesis of ATP could be maintained by buffering the fall of pH with increased storage solution volume or the addition of bicarbonate. Maintaining RBC ATP turns out to be an important way of preventing membrane microvesiculation or blebbing, as does the manipulation of tonicity and the addition of mannitol. These experiments show that it is possible to store RBC in experimental additive solutions containing only saline, adenine, glucose, mannitol, sodium bicarbonate, and disodium phosphate for 11 weeks or longer with little loss of membrane and high in vivo recovery.

Hydrocortisone–PVP composites were successfully prepared using the supercritical fluid gas anti-solvent method (GAS). Analysis by differential scanning calorimetry DSC and powder X-ray diffraction (XRD) indicated that these systems were more crystalline than corresponding systems prepared by spray drying. These systems, prepared by the GAS method were more similar in physicochemical properties to coprecipitates prepared by conventional solvent evaporation. Compressed composites of hydrocortisone–PVP systems, prepared by the GAS method, had dissolution rates lower than those of corresponding systems prepared by the other processing methods but equivalent to those of corresponding physical mixtures.

The aim of this paper was to investigate the electrostatic interactions between multivalent phosphates (phosphate (Phos), pyrophosphate (Pyro) and tripolyphosphate (TPP)) and chitosan, as well as the influence of electrostatic interactions on the properties of chitosan films ionically cross-linked by the above mentioned phosphates. The charge number of Phos was too low to interact with chitosan, while Pyro and TPP with more negative charges showed a significant ability to ionically cross-link chitosan. Solution pH played an important role on the charge numbers carried by Pyro, TPP and chitosan, especially for Pyro/chitosan. For instance, at pH less than 2.0 the interaction between Pyro and chitosan disappeared, while for TPP/chitosan even in solutions at pH less than 0.5 it still existed. Media pH and ionic strength also had a significant influence on the properties of cross-linked chitosan film with multivalent phosphates. Usually these films swelled and drug was released quickly in acidic conditions (such as in simulated gastric fluid) while under neutral conditions (such as in simulated intestinal fluid) they remained in a shrinkage state and drug was released slowly. Compared to TPP/chitosan films, Pyro/chitosan films exhibited much better pH-sensitive swelling and controlled release properties due to their relatively weak electrostatic interaction. The same reasoning was used to explain the significant acceleration of Pyro/chitosan film swelling and model drug release observed on adding sodium chloride. These films may be promising for site-specific drug delivery in the stomach.

Indomethacin (IMC)/polyvinylpyrrolidone systems were prepared under different technological conditions, using co-evaporation, kneading, traditional, and ultrasound (US) compaction. The materials thus obtained were milled and sieved and the powders were analyzed by using scanning electron microscopy to evaluate the morphology of the final particles and the fractal dimension of the particle contour. In the case of US-treated particles, scanning electron micrographs suggest that IMC could have partially covered the excipient granule surface, which appears lustrous and smooth, whereas after co-evaporation, the particles display a stratified structure. The external color of the granules, the hot stage microscopy examination, and the absence of the melting peak of the drug in thermograms supports the idea that IMC converts into an amorphous form under US discharge. Each technological treatment performed on the binary mixtures increases the dissolution rate of the drug, with respect to the pure drug and the physical mixture, but to a lesser extent than US compaction. US compaction and co-evaporation produce comparable results in improving the release of the drug. Polyvinylpyrrolidone offers better results than beta-cyclodextrin in promoting the dissolution of IMC, when both systems are compacted under US.

An amperometric biosensor based on L-aminoacid oxidase is proposed for enantioselective assay of (+)-3,3',5-triiodo-L-thyronine (L-T3) and (+)-3,3',5,5'-tetraiodo-L-thyronine (L-T4), due to the fact that only the L enantiomer has the hormonal activity. The construction of the amperometric biosensor is simple and reproducible. The analytical information obtained from enantioselective analysis are reliable. The RSD

Buccoadhesive erodible disks of cetylpyridinium chloride were prepared using different bioadhesive polymers along with excipients like mannitol. The purpose of designing the erodible disk was to obviate the need for removal of exhausted device. The optimized disk containing 5.0 mg of cetylpyridinium chloride, 2.0 mg of magnesium stearate and 6.0 mg of mannitol along with sodium carboxy methyl cellulose DVP and hydroxypropylmethylcellulose K4M in the ratio of 1:3 was found to release the drug for a period of over 6.0 h without getting dislodged. Maximum in vitro drug release was found to be 94.78% in 6.0-h study. In situ release characteristics were evaluated using a 'flow-through assembly', which simulated the conditions of the human buccal cavity. The drug concentrations in the in situ samples were found to be above minimum inhibitory concentration (MIC) of the drug. The bioadhesive performance and the surface pH of the disks were satisfactory. Cetylpyridinium chloride disks were tested against microorganisms commonly found in oro-dental infections namely Candida albicans, Staphylococcus aureus, Escherichia coli and Streptococcus mutans. The disk as well as the in situ samples showed inhibition of growth of microorganisms. Approval was taken from Jamia Hamdard Review Board (Ethical Board) to perform in vivo studies in healthy human volunteers. In vivo evaluation of buccoadhesive disks revealed adequate comfort, taste, and non-irritation and none of the volunteers reported severe dry mouth/severe salivation or heaviness at the place of attachment. Salivary concentrations were maintained above MIC for 8.0 h. Correlation was found between the drug concentration in situ and concentration of drug in saliva collected in healthy human volunteers. The correlation was found to be positive with a correlation coefficient of 0.9596. It was found to be statistically significant at 5% confidence level (P

The crystallization of drug in a matrix may significantly affect the efficacy and quality of the transdermal drug delivery system. Therefore, the control of drug crystallization is of particular interest in the development of efficient transdermal delivery systems. In this study, we investigated the effects of various additives on the crystallization of ketoprofen in polyisobutylene (PIB) adhesive matrix. The effects of various additives on the permeation of ketoprofen from PIB matrix across hairless mouse skin were also examined. Poly(vinyl pyrrolidone) (PVP) K-30 was found to be the most effective crystallization inhibitor. Also, Poloxamer, Tween 80 and Labrasol significantly inhibited the crystallization of ketoprofen in a PIB matrix. In case of Tween 80, Labrasol, and PVP K-30, the flux of ketoprofen decreased as the loading content of the additives increased. However, the addition of Tween 80, Labrasol, or PVP K-30 significantly reduced the decrease in the flux of ketoprofen within the PIB matrix during a storage time of 3 weeks.

The effects of various vehicles and adhesives on the percutaneous absorption of isosorbide dinitrate (ISDN) were evaluated. Lauroglycol FCC showed the highest flux among vehicles tested. The flux of ISDN from silicone and acrylic adhesive matrices was found to be higher than that from other types of adhesive matrices. No statistically significant relationship between the flux from acrylic PSA and the flux from a solution formulation was observed. A highly cross-linked acrylic adhesive gave higher permeation rates than the other acrylic adhesives examined. N-decylmethyl sulfoxide showed the highest enhancing effect on the flux of ISDN from acrylic adhesive. The relationship between the HLB values of vehicles and the measured flux showed a decrease of flux at HLB values greater than 12.

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2(3) full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t50% (time in which 50% drug is released) and tlag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f2) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f2) values calculated from the data indicated no significant difference among the t50% values and dissolution profiles respectively for all formulations. Within the 3.3-6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f2 values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000-19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.

Many kinds of rapidly disintegrating or oral disintegrating tablets (RDT) have been developed to improve the ease of tablet administration, especially for elderly and pediatric patients. In these cases, knowledge regarding disintegration behavior appears important with respect to the development of such a novel tablet. Ordinary disintegration testing, such as the Japanese Pharmacopoeia (JP) method, faces limitations with respect to the evaluation of rapid disintegration due to strong agitation. Therefore, we have developed a novel apparatus and method to determine the dissolution of the RDT. The novel device consists of a disintegrating bath and CCD camera interfaced with a personal computer equipped with motion capture and image analysis software. A newly developed RDT containing various types of binder was evaluated with this protocol. In this method, disintegration occurs in a mildly agitated medium, which allows differentiation of minor distinctions among RDTs of different formulations. Simultaneously, we were also able to detect qualitative information, i.e., morphological changes in the tablet during disintegration. This method is useful for the evaluation of the disintegration of RDT during pharmaceutical development, and also for quality control during production.

A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin® US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40 °C/75% RH and 25 °C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared.

Parenteral antibiotic prophylaxis is the current standard of therapy in clean-contaminated oral cancer surgery. Nevertheless, the incidence of surgical site infection (SSI) in oral oncological surgery is relatively high, especially in major surgery with reconstruction and tracheotomy. The aims of this study were to investigate the perioperative condition related to microorganisms in the oral cavity and to examine the efficacy of the topical administration of tetracycline in reducing the number of bacteria in the oropharyngeal fluid during intubation. The number of oral bacteria was measured during intubation in patients undergoing major oral cancer surgery. The efficacy of the topical administration of tetracycline or povidone iodine gel in reducing the bacteria was then investigated. Bacteria in the oropharyngeal fluid grew from 10(6)CFU/ml to 10(8)CFU/ml during the 3h after intubation (CFU, colony-forming units). When tetracycline was applied to the dorsum of the tongue, oral bacteria decreased immediately to 10(5)CFU/ml, and the number of bacteria in the oropharyngeal fluid was maintained below 10(7)CFU/ml for 7h. The concentration of tetracycline in the oropharyngeal fluid was extremely high for several hours after topical administration. The topical administration of tetracycline could reduce oral bacteria in patients undergoing clean-contaminated oral cancer surgery. This method is expected to be effective in the prevention of SSI.

In this study, the influence of the preparation technique (ball milling, spray drying, and film casting) of a supersaturated amorphous dispersion on the quality of solubility determinations of indomethacin in polyvinylpyrrolidone was investigated by means of statistical analysis. After annealing of the amorphous dispersions above the crystallization temperature for 2 h, the solubility curve was derived from the glass transition temperature of the demixed material using the Gordon–Taylor relationship and fitting with the Flory–Huggins model. The study showed that the predicted solubility from the ball-milled mixtures was not consistent with those from spray drying and film casting, indicating fundamental differences between the preparation techniques. Through formal statistical analysis, the best combination of fit to the Flory–Huggins model and reproducibility of the measurements was analyzed. Ball milling provided the best reproducibility of the three preparation techniques; however, an analysis of residuals revealed a systematic error. In contrast, film casting demonstrated a good fit to the model but poor reproducibility of the measurements. Therefore, this study recommends that techniques such as spray drying or potentially film casting (if experimental reproducibility can be improved) should be used to prepare the amorphous dispersions when performing solubility measurements of this kind. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:44–51, 2015

Diabetes is the fastest growing metabolic disease that fails to utilize glucose properly due to insulin deficiency or insulin resistance. Although several limited studies demonstrated non-invasive means of protein delivery, major hurdles for commercial success such as short half-life, enzymatic degradation and low bioavailability still remain to overcome. Methylcellulose (MC), a hydrophobically-modified cellulose derivative, forms temperature reversible gel in aqueous solution. However, as the gelling temperature of MC is higher than body temperature, it should be lowered to below body temperature for practical clinical application. In order to decrease gelling temperature and increase bio-compatibility and bio-elimination of MC, the molecular weight of MC was decreased using enzymatic degradation method and confirmed by gel permeation chromatography. Bio-elimination of low molecular weight (LMw) MC was confirmed with non-invasive live image and ex vivo experiment. The exenatide and FGF 21 were physically loaded 100% into LMwMC-based thermo-reversible gel and slowly released from gel with no initial bursts. Exenatide-loaded LMwMC gel showed reduction of blood glucose level for a week in type 1 diabetic animal model. FGF 21-loaded LMwMC gel reduced glucose level to normal condition and maintained over 10 days in type 2 diabetic animal model. LMwMC-based thermo-reversible and injectable hydrogel provides a strong potential to be efficient protein drug delivery system for the treatment of type 1 and type 2 diabetes.

An experimental study was conducted to verify that lubrication mixing in commercial-scale bin blenders can be described by a previously-reported lubrication blending process scale-up model. Specifically, the mixing of two placebo formulations (2:1 MCC:lactose, and 2:1 MCC:DCP) with 1% magnesium stearate in 100, 400, and 2000 L bin blenders at 30% and 70% blend fill levels for several extents of lubricant mixing was examined. The lubricated powder blends were assessed for bulk/tapped density and powder flow, as measured by Hausner's ratio. The blends were then compressed into tablets and evaluated for tensile strength, friability, and disintegration. It was observed that the lubrication rate constant, γ, for tablet tensile strength and for bulk specific volume were similar. Furthermore, powder flow, as measured by Hausner's ratio, improved with increased extent of lubrication. Tablet disintegration and tablet friability were both minimally affected as a result of extended lubrication for the placebos blends evaluated in this study. The results of this study confirm that the lubrication mixing model can be applied to scale-up the lubrication blending process from batches made in 30 mL bottle blenders to batches made in 2000 L bin blenders, which is a range of nearly five orders of magnitude.

A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl4-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin.

International audience; In this study, microcrystalline cellulose (Alfa-MCC) was extracted from Alfa fibres using acid hydrolysis method. The molecular weight of the cellulose samples was determined by gel permeation chromatography. The crystallinities were studied by means of X-ray diffraction and solid state cross polarization magic angle spinning C-13 nuclear magnetic resonance spectroscopy, revealing that Alfa-MCC was more crystalline than the native cellulose isolated from Alfa fibres. The morphology of the celluloses was investigated using scanning electron microscopy, showing a compact structure and a rough surface. Furthermore, a good thermal stability was shown for Alfa-MCC. Based on these analyses, Alfa-MCC showed tremendous potential use as composites reinforcing agent, foods stabilizer and pharmaceutical additive.

Polyplasdone of different particle size was used to study the sorption, desorption, and distribution of water, and to seek evidence that larger particles can internalize water. The three samples were Polyplasdone® XL, XL-10, and INF-10. Moisture sorption and desorption isotherms at 25 °C at 5% intervals from 0 to 95% relative humidity (RH) were generated by dynamic vapor sorption analysis. The three products provided similar data, judged to be Type III with a small hysteresis that appears when RH is below 65%. An absent rounded knee in the sorption curve suggests that multilayers form before the monolayer is completed. The hysteresis indicates that internally absorbed moisture is trapped as the water is desorbed and the polymer sample shrinks, thus requiring a lower level of RH to continue desorption. The fit of the Guggenheim-Anderson-de Boer (GAB) and the Young and Nelson equations was accomplished in the data analysis. The W(m), C(G), and K values from GAB analysis are similar across the three samples, revealing 0.962 water molecules per repeating unit in the monolayer. A small amount of absorbed water is identified, but this is consistent across the three particle sizes.

The development of antibiotics revolutionized human health, providing a simple cure for once dreaded diseases such as tuberculosis. However, widespread production, use, and mis-use of antibiotics have contributed to the next-generation concern for global public health: the emergence of multiple drug-resistant (MDR) infectious organisms (a.k.a. “superbugs”). Recently, nanotechnology, specifically the use of nanomaterials (NMs) with antimicrobial activity, has been presented as a new defense against MDR infectious organisms. We discuss the potential for NMs to either circumvent microbial resistance or induce its development in light of our current state of knowledge, finding that this question points to a need for fundamental research targeting the molecular mechanisms causing antimicrobial activity in NMs. In the context of current microbial nanotoxicology studies, particularly reductionist laboratory studies, we offer suggestions and considerations for future research, using an illustrative example from our work with silver nanoparticles.

Hyacinthaceae familyası Türkiye'de 10 cins ve 140 taksonla temsil edilmektedir ve bunların % 55'i endemiktir. Araştırma alanı olarak Kahramanmaraş ilinin seçilmesindeki neden ilin bu familyanın üyelerinin yetişme ortamlarına uygun olması ve olağanüstü zengin bir floraya sahip olmasıdır. Araştırma alanında yapılan arazi çalışmalarında 450 bitki örneği toplanmış ve ulusal/uluslararası herbaryumlarda 2900 örnek üzerinde incelemeler yapılmıştır. Yapılan araştırmalar sonucunda araştırma alanında Hyacinthaceae familyasına ait 7 cins (Bellevalia, Hyacinthella, Hyacinthus, Muscari, Ornithogalum, Prospero ve Scilla) ve 38 tür, 3 alttürün doğal olarak yetiştiği saptanmıştır. Bu türlerden 14 tanesi endemiktir ve endemizm oranı %35'tir. Bu araştırmada belirlenen 39 taksondan, 11 takson Avrupa Sibirya Elementi, 19 takson Akdeniz Elementi, 8 takson ise İran-Turan Elementi ve 1 taksonun geniş yayılışlı olduğu belirlenmiştir. Yapılan bu tez çalışmasıyla 2 türün (Ornithogalum kayiranii ve Prospero andirenense) bilim dünyası için yeni, 1 türün (Ornithogalum pedicellare) ise Türkiye için yeni kayıt olduğu saptanmıştır. Ayrıca 6 taksonun C6 karesi ve 7 taksonun ise araştırma alanı için yeni kayıt olduğu belirlenmiştir. Kahramanmaraş ilinde yayılış gösteren 39 taksonun 113 farklı lokaliteden toplanan örneklerinin kromozomları sayılmış ve karyotipleri belirlenmiştir. Karyolojik çalışmalar sonucunda bilim için yeni olan iki türün kromozomları da saptanmıştır. 16 taksonun kromozom sayısının literatürdeki kayıtlı kromozom sayılarından farklı olduğu, 21 taksonun daha önceki sonuçlarla uygunluk gösterdiği ve aynı kromozom sayısına sahip olduğu görülmüştür. Araştırma alanındaki 14 endemik ve 4 nadir taksonun IUCN'e göre kategorileri ve tehdit durumları belirlenmiştir. 39 taksona ait fitokimyasal ön deneme çalışmaları yapılmış, 29 taksona ait daha önce herhangi bir çalışma yapılmadığı belirlenmiştir. The family Hyacinthaceae is represented by 10 genera and 140 taxa in Turkey and % 55 of them is endemic. Province of Kahramanmaraş was selected as a research area due to very rich flora and convenient habitat for the members of Hyacinthaceae. In the field studies which are performed in research area about 450 plant speciemens have been collected and in the national/international herbaria 2900 specimens have been investigated. The result of this study 7 genera (Bellevalia, Hyacinthella, Hyacinthus, Muscari, Ornithogalum, Prospero and Scilla) and 38 species, 3 subspecies which are belong to Hyacinthaceae have been determinated to grow naturally in the research area. 14 of these species are endemic and the ratio of endemism is 35%. From the 39 taxa which are determined in this study has been identified as the 11 taxa of European-Siberian Element, the 19 taxa of the Mediterranean Element, the 8 taxa of Iran-Turan Element and one widely distributed taxa. With this study, 2 species (Ornithogalum kayiranii and Prospero andirinense) have been identified as new species for plant science and 1 species (Ornithogalum pedicellare) is new record for Turkey. In addition, 6 taxa for C6 square and 7 taxa for Kahramanmaraş province have been identified as a new record. The chromosome numbers have been counted and karyotypes have been identified of 39 taxa collected 113 different localities in the research area. The result of karyological studies have been shown that chromosome numbers of 2 new species O.rnithogalum kayiranii 2n=16 and Prospero andirinense 2n=16 have been counted at the first time. Chromosome numbers of 16 taxa have been recorded different from the literature data, 21 taxa have been shown to have the same chromosome numbers. Categories and threat status according to IUCN have been detected for 14 endemic and 4 rare taxa in the research area. Phytochemical preliminary studies of 39 taxa have been conducted, it has been defined there is not performed any study for 29 taxa. 429

Adsorption and controlled release of terbinafine hydrochloride (TER-HCl) to and from pH-sensitive poly(N-vinyl 2-pyrrolidone/itaconic acid) P(VP/IA) hydrogels were investigated. P(VP/IA) hydrogels were prepared by irradiating the ternary monomer mixtures of N-vinyl 2-pyrrolidone/itaconic acid/ethylene glycol dimethacrylate in aqueous solution by -rays at ambient temperature. Hydrogels containing antifungal drug TER-HCl, at different drug-to-polymer ratios, were prepared by direct adsorption method. The influence of IA content in the gel on the adsorption capacities of hydrogels and the effect of pH on the releasing behavior of TER-HCl from the gel matrix were investigated. Terbinafine adsorption capacity of hydrogels was found to increase from 6 to 82 mg of TER-HCl per gram of dry gel with increasing drug concentration and amount of IA in the gel system. In-vitro drug-release studies in different buffer solutions showed that the basic parameters affecting the drug-release behavior of hydrogels are the pH of the solution and the IA content of the hydrogel. © 2001 Elsevier Science B.V. All rights reserved.

Solid dispersions of phenytoin in polyethylene glycol 6000 and polyvinylpyrrolidone K-30 with different drug-to-carrier ratios were prepared by the solvent method with the aim of increasing dissolution rate and bioavailability of the drug. These new formulations were characterized in the solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. Drug solubility and dissolution rate are improved by these formulations, particularly with SDPEG 1/20 and SDPVP 1/20 systems. Storage was found to influence the stability of the solid dispersions. By maximal electroshock test, it was found that the intraperitoneal administration in mice of the SDPEG 1/20 and SDPVP 1/20 systems exhibited anticonvulsant activity similar to diphenylhydantoin sodium salt.

Transfer of plasmid DNA into mammalian cells has posed major challenges for gene therapy. Most non-viral vectors are known to internalize in the cells by endocytosis. Therefore, low transfection efficiency of non-viral vectors may be due to intracellular degradation of input DNA in the endosomes and/or lysosomes. DNA degradation can be inhibited either by inactivating the lysosomal enzymes or obliterating endosome fusion to lysosomes using lysosomotropic agents. We report here the effects of individual lysosomotropic agents such as chloroquine, polyvinylpyrolidone (PVP) and sucrose on β-gal expression in cultured fibroblasts COS, 293 and CHO. Cell viability was influenced by type, exposure time and concentration of lysosomotropic agents. Exposure to chloroquine at high concentration (1000 μM) or more than 4 h at any concentration (10–1000 microM) caused extensive cell death, however, cytotoxicity due to sucrose (5–500 mM) and PVP (0.01–1 mg/ml) was minimal in the cell lines tested. All the agents utilized in this study enhanced the gene expression and the transfection efficiency followed the order of sucrose>chloroquine>PVP at the concentrations used in all cell lines. Results suggest that lysosomotropic agents can enhance transfection efficiency but the degree of transgene expression may be cell- and agent-specific. Of the agents studied, sucrose appears to be an attractive agent in improving gene expression without toxic effect in the cultured fibroblasts. Thus, it can be used as an excipient in the formulation of new gene delivery systems.

Current NF monographs do not provide tests that reflect on the functionality of Crospovidone NF from multiple sources. Physical characterization studies such as particle size and distribution, surface area, porosity, and surface morphology revealed major differences among the crospovidones from different sources (Shah, U.; Augsburger, L.L. J. Pharm. Dev. Technol. 2001, 6 (1), 39-51). Differences in disintegration and dissolution were also observed for a model drug in an insoluble filler system (see Shah and Augsburger, 2001). The objective of this study was to determine the relationship between physical differences observed and disintegrant functionality and to develop standard performance test. Tests performed included settling volume studies, measurement of initial rate as well as extent of liquid uptake of the loose disintegrant powder, and simultaneous measurement of the axial and radial disintegrating forces along with the rate and extent of liquid uptake of the pure disintegrant compacts. Significant differences among the crospovidones were observed for all tests performed. Settling volume, liquid uptake, and disintegration force are recommended as standard performance tests to determine differences among crospovidones from different sources.

A new method involving in situ complexation between polyvinyl acetate phthalate (PVAP) and polyvinylpyrrolidone (PVP) has been developed for the entrapment of ibuprofen, a bitter tasting anti-inflammatory drug. The procedure involved dissolving ibuprofen in a thoroughly mixed aqueous alkaline solution of PVAP and PVP, and subsequently slowly adjusting the pH of the solution to 1 with dilute HCl. The yield of the entrapped product, and the percent entrapment of ibuprofen, were 85-90%, and 90-98%, respectively. The PVAP-PVP entrapped granules showed no bitter taste due to ibuprofen. The chewable tablets, prepared by mixing the granules with a cherry-flavored directly compressible tableting excipient, exhibited a release of less than 2% of ibuprofen in pH 1.2 buffer over a period of three hours. In pH 7.4, 100% of ibuprofen was released in six hours. The results presented show that in situ complexation between PVAP and PVP may be useful to produce palatable ibuprofen granules suitable for use in the development of chewable tablets.

We analyzed the physicochemical characteristics of solid dispersions of pizotifen malate and povidone (Kollidon 12) at different proportions; we used X-ray diffraction, infrared spectrometry, and differential scanning calorimetry (DSC) and tested the solubility of the solid dispersions in equilibrium. The results were compared with findings for physical mixtures with the same proportions. A solid dispersion with a drug proportion of 16%–17% formed a eutectic mixture. Solubility of pizotifen malate increased with the proportion of drug in the solid dispersion up to a drug:polymer ratio of 40:60. The hydrotropic effect of the polymer also favored solubility: In physical mixtures, this effect was greatest at a drug:polymer ratio of 10:90; solubility at this proportion was equal to that of the solid dispersion at the same proportion.

The glass forming properties of ketoconazole were investigated using differential scanning calorimetry (DSC), by quench cooling liquid ketoconazole from T(m)+10 to 273.1 K, followed by subsequent heating at 5 K/min to T(m)+10 K. It was shown that liquid ketoconazole forms a glass which did not recrystallise following reheating, indicating its stability; T(g) was found to be 317.5+/-0.3 K. However, the presence of a small amount of crystalline ketoconazole was able to convert the amorphous drug back to the crystalline state: the addition of only 4.1% (w/w) of crystalline material converted 77.1% of the glass back to the crystalline state, and this value increased as the amount of added crystals increased. PVP K25 was found to be highly effective in the prevention of such recrystallisation, but only if the amorphous drug was formulated in a solid dispersion, since physical mixing of amorphous ketoconazole with the polymer resulted in recrystallisation of the former compound. Storage of the solid dispersions for 30 days at 298.1 K (both 0 and 52% RH) in the presence or absence of crystals did not result in recrystallisation of the amorphous drug. Solid dispersions formed compatible blends as one single T(g) was observed, which gradually increased with increasing amounts of PVP K25, indicating the anti-plasticising property of the polymer. The values of T(g) followed the Gordon-Taylor equation, indicating no significant deviation from ideality and suggesting the absence of strong and specific drug-polymer interactions, which was further confirmed with 13C NMR and FT-IR. It can be concluded therefore that the physical mechanism of the protective effect is not caused by drug-polymer interactions but due to the polymer anti-plasticising effect, thereby increasing the viscosity of the binary system and decreasing the diffusion of drug molecules necessary to form a lattice.

The rheological oscillatory test parameters have been observed for highly concentrated hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose-sodium (NaCMC) and mixed HPMC/NaCMC hydrogels obtained by swelling of matrix tablets in 0.1 mol cm −3 HCl and pH 6.8 phosphate buffer. The mechanical spectra of the gels have been analysed using theoretical models, i.e. a generalised Maxwell model and an adapted Maxwell model, both based on Ferry and Williams approximations. The relaxation time spectra as well as the parameters characteristic of linear viscoelastic behaviour have been calculated: zero shear viscosity ( η 0 ), plateau moduli ( G N 0 , G 0 ′ and G 0 ″), zero-relaxation time ( τ 0 ) and mean relaxation time ( θ ). The mechanical spectra of mixed HPMC/NaCMC hydrogels differ considerably from those of the pure ones, the type of the spectrum depending on the two polymers’ ratios. In both media, the rheological models applied define the HPMC gels as homogeneous entangled networks, and those of NaCMC and mixed HPMC/NaCMC as heterogeneous physical gels. The relationship between the kinetic constants of water penetration and the mean relaxation times suggests that the molecular relaxation controls the water uptake velocity. With all the systems tested irrespective of pH of the aqueous phase, an inversely proportional dependence between the viscosity and the water penetration velocity has been noted. Since the degree of hydration is one of the factors determining the degree and velocity of drug release from the hydrogel matrices, the relation between the kinetic parameters of water penetration and the viscosity is a characteristic indicator for the gel structure, the degree of swelling and the drug release rate.

Paracetamol particles crystallized in the presence of polyvinylpyrrolidone (PVP) exhibited an obvious improvement in their compression properties compared to untreated paracetamol. Paracetamol particles crystallized in the presence of 0.5% w/v PVP 10000 or PVP 50000 produced tablets with improved crushing strength with no tendency to cap even at high compression speeds. The very low values of strain rate sensitivity (SRS) and the lack of reduction in crushing strength with increasing compression speed for these particles, were indicative of a high degree of fragmentation during compression. The results of elastic recoveries and elastic energies of tablets were indicative of much less elastic behaviour of these particles than untreated paracetamol. The low elastic energy/plastic energy (EE/PE) ratio for paracetamol crystallized in the presence of PVP indicated that, contrary to untreated paracetamol, a minor portion of compression energy was utilized as elastic energy.

UNLABELLED Propofol (Diprivan(TM); AstraZeneca, Wilmington, DE) is a commonly used drug for the induction of general anesthesia in the ambulatory setting. With the availability of a new bisulfite-containing generic formulation of propofol, questions have arisen regarding its cost effectiveness and safety compared with Diprivan(TM). Two hundred healthy outpatients were randomly assigned, according to a double-blinded protocol, to receive either Diprivan(TM) or bisulfite-containing propofol 1.5 mg/kg IV as part of a standardized induction sequence. Maintenance of anesthesia consisted of either desflurane (4%-8% end-tidal) or sevoflurane (1%-2% end-tidal) in combination with a remifentanil infusion (0.125 microg x kg(-1) x min(-1) IV). Patient assessments included pain on injection, induction time, hemodynamic and bispectral electroencephalographic changes during induction, emergence time, and incidence of postoperative nausea and vomiting. The two propofol groups were comparable demographically, and the induction times and bispectral index values during the induction were also similar. However, the bisulfite-containing formulation was associated with less severe pain on injection (5% vs 11%), with fewer patients recalling pain on injection after surgery (38% vs. 51%, P

PURPOSE: Povidone-iodine is a commonly used intrarectal tumoricidal agent in patients undergoing colorectal surgery. The aim of this study was to assess systemic absorption of total iodine and its effect on thyroid function after intrarectal application. METHODS: Twenty patients with carcinoma of the rectum received intraoperative irrigation with either povidone-iodine (Group A; n=10) or physiologic saline (Group B; n=10). Ten patients with carcinoma of the sigmoid colon (group C) were treated the same as Group A. Electrolyte, total iodine, triiodothyronine, thyroxine, and thyroid-stimulating hormone values were measured in serum preoperatively and before intraoperative irrigation and immediately, ten minutes, 1 hour, 6 hours, 24 hours, and two weeks after irrigation. RESULTS: No significant changes occurred in serum electrolytes. A significant uptake of the total iodine was demonstrated in each group. Total iodine levels examined immediately, ten minutes, and one hour after irrigation in Group C were significantly higher than those examined in Group B. Maximum values were obtained one hour after irrigation in Groups A and B and six hours after irrigation in Group C. No significant changes occurred in triiodothyronine, thyroxine, and thyroid-stimulating hormone levels among the three groups. The decrease in triiodothyronine levels after surgery was demonstrated in each group. We noted a decrease after surgery in thyroxine levels for Groups A and B and in thyroid-stimulating hormone levels for Group B. Those hormones were not affected by the administration of povidone-iodine. CONCLUSION: High serum levels of iodine did not cause organ toxicity, suggesting that a single use of intraoperative bowel irrigation with povidone-iodine may be performed with practically negligible risk.

Objective We assessed the pharmacokinetics and tolerability of 5 mg loratadine syrup (1 mg/mL) in children aged 2 to 5 years. Methods Two studies were undertaken. A single-dose, open-label bioavailability study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine. Plasma concentrations of loratadine and desloratadine were determined at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after a single administration of 5 mg loratadine syrup to 18 healthy children (11 male, 7 female; 12 black, 5 white, 1 other; mean age ±SD, 3.8 ± 1.1 years; mean weight ± SD, 17.4 ± 4.4 kg) In addition, a randomized, doubleblind, placebo-controlled, parallel-group study was performed to assess the tolerability of 5 mg loratadine syrup after multiple doses. Loratadine (n = 60) or placebo (n = 61) was given once daily for 15 days to children with a history of allergic rhinitis or chronic idiopathic urticaria. In the loratadine group, 27 boys and 33 girls (52 white, 8 black) were enrolled, with a mean age ± SD of 3.67 ±1.13 years and a mean weight ± SD of 17.2 ±3.8 kg. In the placebo group, 27 boys and 34 girls (53 white, 7 black, 1 Asian) were enrolled, with a mean age ± SD of 3.52 ± 1.12 years and a mean weight ± SD of 17.3 ± 2.9 kg. Tolerability was assessed based on electrocardiographic results, occurrence of adverse events, changes in vital signs, and results of laboratory tests and physical examinations. Results: The peak plasma concentrations of loratadine and desloratadine were 7.78 and 5.09 ng/mL, respectively, observed 1.17 and 2.33 hours after administration of loratadine; the areas under the plasma concentration-time curve to the last quantifiable time point for loratadine and desloratadine were 16.7 and 87.2 ng·h/mL, respectively. Single and multiple doses were well tolerated, with no adverse events occurring with greater frequency after multiple doses of loratadine than after placebo. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically meaningful changes in other tolerabihty assessments. Conclusion Loratadine was well tolerated in this small, selected group of children aged 2 to 5 years at a dose providing exposure similar to that with the adult dose (ie, 10 mg once daily).

The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, l -cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100±8 and 1280±84 μmol thiol groups per gram, respectively (means±S.D.; n=6–8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.

Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults.

This study examined the effects of adding a macromolecule, polyvinylpyrrolidone (10% PVP) and a sugar (0.3 M trehalose) to vitrification solutions (VS) containing either one (40% ethylene glycol [EG], two (25% EG+25% DMSO) or three (20% EG+20% DMSO+10% 1, 3-butanediol [BD]) permeable cryoprotectants on the survival and hatching of IVP bovine embryos, following vitrification, warming and in-straw cryoprotectant dilution. Grade 1 and 2 compact morulae and blastocysts were selected on Day 7 (Day 0=IVF) of culture in SOFaaBSA and equilibrated for 10 min at room temperature in 10% EG. Following exposure, for up to 1 min at 4 degrees C, to one of the above VS (with or without PVP+trehalose), the embryos were loaded into straws and immersed in liquid nitrogen. Following warming and in-straw cryoprotectant dilution, the embryos were cultured for 48 h to assess hatching. There was no effect of VS on the survival of embryos after 24 h, however fewer compact morulae than blastocysts survived after 24 h (24% vs. 75%; P

We previously developed an in vivo pharmacokinetic model that accounts for the corneal diffusion in albino rabbits and predicts the concentration of beta-blockers in the anterior segments. The purpose of this study is to pharmacokinetically predict the ocular absorption and characterize the systemic absorption of instilled drug with ophthalmic viscous vehicle to assist in its design and evaluation. Tilisolol and carboxymethylcellulose sodium salt (CMC) were used as the model ophthalmic drug and viscous polymer, respectively. After instillation of tilisolol with CMC vehicle in rabbits, the disposition of the drug in tear fluid, aqueous humor, and plasma were determined by HPLC. The ocular and systemic absorption were analyzed by a mathematical model including a diffusion process and a two-compartment model with first-order absorption, respectively. CMC vehicle increased the area under the concentration-time curve (AUC) of tilisolol in the tear fluid and aqueous humor and slightly reduced the AUC in plasma. The concentrations of tilisolol in the aqueous humor after instillation with CMC vehicle were accurately predicted from the tear concentrations by using the in vivo ocular pharmacokinetic model. CMC vehicle improved the ocular delivery of tilisolol.

In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a moisture-absorbing substance. In the experiments described below, acetaminophen (APAP) was the model drug; polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) served as the binder and moisture-absorbing material, respectively. Water was used as the granulating fluid. Comparison of the MGT with direct compression (DC) and wet granulation (WG) methods was accomplished by sieve analysis (particle size) and density measurements. Moist granulation yielded an increase in particle size compared to direct compression; these results are comparable to those from the traditional wet granulation after drying and screening. Based only on the particle size, moist granulation appears comparable to conventional wet granulation for this formula. The moist granulation technique appears to have potential for the development of controlled-release formulations.

The size dependent and size independent contributions to the mechanical properties of poly(ethyleneglycol) microspheres with encapsulated air, made for medical ultrasound imaging, have been studied. A relation between the size of microspheres in a reference group and their acoustic attenuation efficacy was derived by partial least square regression. The developed model was used to estimate acoustic attenuation as a function of the measured size distribution for various preparations made during formulation and process studies. The ratio between the measured attenuation and model estimated attenuation was then used to evaluate variations in the mechanical properties of the polymer shell and the contribution of such variations to the acoustical properties of the substance. The statistical parameter was compared with results for the mechanical compressibility derived from a theoretical approach and the results from the two methods mutually confirmed each other. The statistical procedure outlined has been found applicable for studies of other particulate products with size dependent in vitro or in vivo properties.

The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.

This paper examines the effect of water content, water activity, and glass transition temperature (T(g)) on the deamidation of an asparagine-containing hexapeptide (VYPNGA; Asn-hexapeptide) in lyophilized poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) at 50 degrees C. The rate of Asn-hexapeptide deamidation increases with increasing water content or water activity and, hence, decreasing T(g). The rate of deamidation is more sensitive to changes in these parameters in PVA than in PVP. Deamidation is clearly evident in the glassy state in both formulations. In the glassy state, the peptide is more stable in PVA than in PVP formulations but is less stable in the rubbery state. No single variable (water content, water activity, or T(g)) could account for the variation in deamidation rates in PVA and PVP formulations. Deamidation rates were correlated with the degree of plasticization by water (distance of T(g) from the dry intrinsic glass transition temperature); coincident curves for the two polymers were obtained with this correlation. Deamidation in PVA and PVP was closely correlated with the extent of water-induced plasticization experienced by the formulation relative to its glass transition at 50 degrees C, suggesting that the physical state of formulations could be used to predict chemical stability.

Distribution of salicylic acid in human stratum corneum from treatment of six different formulations was assessed by quantitation of drug content in sequentially tape-stripped stratum corneum after a single 2-h dose was applied unoccluded to skin on the ventral forearm of four female subjects. The profile and total amounts of stratum corneum removed in 20 tape-strips varied among different types of formulations. With or without normalization by the total stratum corneum weights removed, the extent of drug delivery to the stratum corneum decreased in the following order: SA (5%)>>SAC (10%), Duofilm (16.7%)>TSSS (2%)>SAO (10%), Salic (2.5%), the percentage in parentheses indicating the salicylic acid concentration in each formulation. The greatest topical bioavailability was observed for the alcoholic solution containing glycerol (SA). The 10% collodion formulation (SAC) was found to deliver an amount of salicylic acid into the stratum corneum 2-fold greater than 10% ointment formulation (SAO). Use of absorption ointment (TSSS) also increased the uptake of salicylic acid into the stratum corneum in comparison with formulations based on simple ointment (SAO) and oil in water (o/w) cream (Salic). The partitioning of salicylic acid from collodion formulations (SAC and Duofilm) appeared to be concentration-independent. The results of this study indicate that topical bioavailability of salicylic acid in the stratum corneum varies substantially among different formulations.

The mechanistic role of water in the deamidation of a model asparagine‐containing hexapeptide (Val‐Tyr‐Pro‐Asn‐Gly‐Ala) in lyophilized formulations containing poly(vinylpyrrolidone) (PVP) and glycerol was investigated. Glycerol was used as a plasticizer to vary formulation glass transition temperature ( T g ) without significantly changing water content or activity. Increases in moisture and glycerol contents increased the rate of peptide deamidation. This increase was strongly correlated with T g at constant water content and activity, suggesting that increased matrix mobility facilitates deamidation. In rubbery systems ( T > T g ), deamidation rates appeared to be independent of water content and activity in formulations with similar T g s. However, in glassy formulations with similar T g s, deamidation increased with water content, suggesting a solvent/medium effect of water on reactivity in this regime. An increase in water content also affected the degradation product distribution; less of the cyclic imide intermediate and more of the hydrolytic products, isoAsp‐ and Asp‐hexapeptides, were observed as water content increased. Thus, residual water appears to facilitate deamidation in these solid PVP formulations both by enhancing molecular mobility and by solvent/medium effects, and also participates as a chemical reactant in the subsequent breakdown of the cyclic imide.