School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
The purpose of the study was to examine the disintegration of tablets in media designed to simulate conditions pertaining in the stomach. Although many studies have been performed to determine dissolution rates in these media, little work has been undertaken on the preliminary step in dissolution, namely disintegration. Two tablet formulations were prepared. One disintegrated rapidly (under 25 s in water) and the other more slowly (8 min in water). The disintegration times were measured by the BP 2000 test using discs. For the rapidly disintegrating tablets, disintegration times were similar in all media except for whole milk. This media is used to simulate the fed stomach and disintegration times were over five times longer than in the other media (P < 0.05). A similar effect was seen with the poorly disintegrating tablets in milk, and prolonged times were also observed in some of the other media. For these latter media, there was a good correlation between the penetration rate of the fluid into the tablet and the disintegration time. Penetration rates for milk were also slow which may be a reflection of its relatively high viscosity and low surface tension.
J Pharm Pharm Sci. ;12 (2):218-228 19732499
Department of Pharmacy, National University of Singapore. email@example.com.
Surface chemistry has a large influence in many industries. In the life sciences, surface area is gaining importance in the characterization of materials during their development, formulation and manufacturing. The chemical activity, adsorption, dissolution, and bioavailability of a drug may depend on the surface of the molecule. In order to meet manufacturing challenges and develop new and better performing products with improved qualities, knowledge of surface tension is of utmost importance. An attempt has been made in this paper to review the application of interfacial tension in the key domains of pharmaceutical applications.
Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK.
Purpose. To validate Magnetic Moment Imaging (MMI) for the investigation of gastrointestinal transit and disintegration of solid dosage forms and to correlate the MMI findings with the corresponding gamma scintigraphic data. Materials and Methods. Three magnetic tablets (MT) were investigated using in vitro and in vivo tests.The clinical study was a four-way, cross-over study with the following arms :(a); Immediate release tablets, administered fasted and (b) after 400 mL of Clinutren((R)) ISO; Enteric coated tablets administered fasted (c) and (d) non-disintegrating tablets studied in the lightly-fed state (100 mL of Clinutren((R)) ISO). Results. In both the in vitro and in vivo studies tablets were detected successfully by MMI and scintigraphy. There was a good correlation between gastric residence times and positional data (in the x,y and y, z axis). In addition, MMI revealed early swelling behaviour of the tablet matrix. There was excellent agreement for the disintegration times of MT(A) in the fasted arm (scintigraphy 12.0+/-4.4 min, MMI 11.8+/-4.4 min). In the MT(A) fed arm, onset times determined by scintigraphy were delayed in 3 subjects when compared to the corresponding MMI results. Delayed disintegration was observed with MT(A) after food (p<0.01) in both techniques. Conclusion. The MMI device is a reliable imaging tool for tracking the transit and disintegration of a magnetic tablet through the gastrointestinal tract.
Prediction of Food Effects on the Absorption of Celecoxib Based on Biorelevant Dissolution Testing Coupled with Physiologically-Based Pharmacokinetic Modeling.
Yasushi Shono, Ekarat Jantratid, Niels Janssen, Filippos Kesisoglou, Yun Mao, Maria Vertzoni, Christos Reppas, Jennifer B Dressman
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany; Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Company, Ltd., Osaka, Japan.
Since the rate-determining step of the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial changes in GI physiology, in addition to any specific interactions between drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs. In this study, in vitro dissolution testing using biorelevant media coupled with in silico physiologically-based pharmacokinetic (PBPK) modeling was applied to the prediction of food effects on the absorption of a poorly soluble drug, celecoxib, from 200 mg capsules. A PBPK model was developed based on the STELLA((R)) software using dissolution kinetics, solubility, standard GI parameters and post-absorptive disposition parameters. Solubility, dissolution profiles and initial dissolution rate from celecoxib 200 mg capsules were measured in biorelevant and compendial media. Standard GI parameters (gastric emptying rate and fluid volume) were varied according to the dosing conditions. Disposition parameters were estimated by fitting compartmental models to the oral PK data, since intravenous data are not available for celecoxib. Predictions of food effects and average plasma profiles were evaluated using the AUC and C(max) and the difference factor (f(1)). An approximately 7-fold difference in the maximum percentage dissolved was observed in in vitro dissolution tests designed to represent the fed and fasted states. By contrast, the food effect estimated by simulating the plasma profiles with the PBPK model predicted only a slight delay in the peak plasma level ( approximately 1 h), and modest increases in the C(max) and AUC of approximately 1.9-fold and 1.3-fold in the fed state, respectively. The PBPK approach, combining in silico simulation coupled with biorelevant dissolution test results, thus corresponds much better to food effect observed for celecoxib in vivo. Additionally, point estimates of AUC and C(max) as well as f(1) calculations demonstrated clear advantages of using results in biorelevant rather than compendial media in the PBPK model. In vitro biorelevant dissolution testing coupled within silico simulation technology was applied successfully to predict the modest food effects on absorption from celecoxib 200 mg capsules. Simulated plasma profiles generated from biorelevant media predict plasma profiles of celecoxib in the fasted and fed states much better than those generated with compendial media.
Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses.
Grzegorz Garbacz, Ralph-Steven Wedemeyer, Stefan Nagel, Thomas Giessmann, Hubert Mönnikes, Clive G Wilson, Werner Siegmund, Werner Weitschies
Department of Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Greifswald, Germany.
The prediction of the in vivo drug release characteristics of modified release oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development. A novel dissolution test apparatus that mimics the physical conditions experienced by an oral formulation during gastrointestinal transit was developed. This included the simulation of pressure forces exerted by gut wall motility, shear forces generated during propagation, and loss of water contact when the dosage form is located in an intestinal air pocket. The new apparatus was evaluated using a diclofenac extended release (ER) tablet. The in vitro dissolution profiles were compared between the novel test apparatus and a conventional dissolution apparatus (USP II). These data were compared with the profiles of plasma concentration versus time that were obtained after the administration of an ER tablet to 24 healthy volunteers under fasting conditions. Multiple peaks were observed in individual plasma concentration-time profiles after the intake of the reference ER tablet. Standard dissolution testing showed typical characteristics of an almost continuous release for this formulation; however, dissolution testing with the novel apparatus suggested that the diclofenac release from the ER tablets would be extremely variable and dependent on the applied stress. The data suggest that the observed multiple peaks of plasma concentration after dosing of the ER diclofenac tablets are most probably caused by sensitivity to physical stress events during gastrointestinal transit.
Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
PURPOSE The aim of this study was to update the compositions of biorelevant media to represent the composition and physical chemical characteristics of the gastrointestinal fluids as closely as possible while providing physical stability during dissolution runs and short-term storage. METHODS Media were designed to reflect postprandial conditions in the stomach and proximal small intestine in the "early","middle", and "late" phases of digestion. From these "snapshot" media, general media for simulating postprandial conditions were devised. Additionally, media reflecting preprandial conditions in the stomach and small intestine were revisited. RESULTS A set of four media is presented. A recently published medium to represent the fasted stomach, FaSSGF, needed no further revision. To simulate the postprandial stomach, a new medium, FeSSGF, is presented. Media representing the upper small intestine in the fed and fasted states were fine-tuned according to physicochemical and biochemical characteristics in vivo. All four media proved to be stable under ambient storage conditions for at least 72 h as well as under usual dissolution test conditions. CONCLUSIONS The updated dissolution media can be used to predict formulation performance and food effects in vivo. These media are more physiologically relevant and show better physical stability than their corresponding predecessors.
Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound.
Bena-Marie Lue, Flemming Seier Nielsen, Thomas Magnussen, Hanne Mette Schou, Kim Kristensen, Lene Orup Jacobsen, Anette Müllertz
Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro-in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters (C(max) and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.
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Short-course preoperative radiotherapy prior to abdominoperineal resection for Stage I low rectal cancer; evidence based or defensive medicine?
Palliative excisional surgery for primary colorectal cancer in patients with incurable metastatic disease. Is there a survival benefit? A systematic review.
Department of Colorectal Surgery, Calderdale and Huddersfield NHS Trust, Huddersfield Department of Oncology, Calderdale and Huddersfield NHS Trust, Huddersfield Department of Colorectal Surgery, Lancashire Teaching Hospitals NHS Trust, Preston, UK.
Aim Patients with stage IV colorectal cancer with unresectable metastases can either receive chemotherapy or palliative resection of the primary lesion. In the absence of any randomized data the choice of initial treatment in stage IV colorectal cancer is not based on firm evidence. Method A search of MEDLINE, Pubmed, Embase and the Cochrane Library database was performed from 1980 to 2010 for studies comparing palliative resection in stage IV colorectal cancer with other treatment modalities. Audits and observational studies were excluded. Median survival was the primary outcome measure. The morbidity and mortality of surgical and nonsurgical treatments were compared. Results Twenty-one studies (no randomized controlled trials) were identified. Most demonstrated a survival benefit for patients who underwent palliative resection. Multivariate analysis indicates that tumour burden and performance status are both major independent prognostic variables. Selection bias, incomplete follow up and nonstandardized reporting of complications make the data difficult to interpret. Conclusion The studies indicate that there may be a survival benefit for primary resection of colorectal cancer in stage IV disease. The findings suggest that resection of the primary tumour should be based on tumour burden and performance status rather than on the presence or absence of symptoms alone.
Department of General and Colorectal Surgery, Huddersfield Royal Infirmary, Calderdale and Huddersfield NHS Trust, Huddersfield HD3 3EA.
The enhanced recovery programme in colorectal surgery is an exciting and innovative new approach for pre- and postoperative management of surgical patients. It challenges some of the non-evidence-based practices and myths which have been entrenched in the minds of clinicians for decades.
Department of Urology, Services Institute of Medical Sciences, Jail Road, Lahore 54660, Pakistan. firstname.lastname@example.org
This was a retrospective study conducted to assess the nature, presentation, mode of insertion, diagnosis and management of foreign bodies in the urinary bladder. Between January 1998 and December 2007, 20 patients with foreign bodies in their urinary bladder were treated at our centre. The records of these patients were reviewed and analysed for their symptoms, mode of insertion, diagnosis, management and complications. A total of 20 foreign bodies were recovered from the urinary bladders during the study period. These included JJ stents with calculi, intrauterine contraceptive devices with stones, a rubber stick, ribbon gauze, encrusted pieces of Foley catheter, proline thread with calculus, a suture needle, broken cold knives, the ceramic beak of a paediatric resectoscope, a knotted suprapubic tube, a hair clip, a nail, an electrical wire and a hairpin. The common presenting features were dysuria and haematuria. The diagnosis was established radiologically in most of the cases. The circumstances of insertion were variable; iatrogenic in 16 (80.0 percent) cases, sexual stimulation in two (10.0 percent), accidental insertion by a child in one (5.0 percent) and physical torture in one (5.0 percent). 17 (85.0 percent) foreign bodies were recovered endoscopically, and cystolithotomy was required in three (15.0 percent) patients. The instances of foreign bodies in the urinary bladder are uncommon. A diagnosis is usually made radiologically. Iatrogenic foreign bodies were found to be the most frequent type of insertion encountered. Endoscopic retrieval is usually successful, with minimal morbidity.
Br J Surg. 2010 Sep ;97 (9):1456 20683879
Adverse effects of polyvinylidene fluoride-coated polypropylene mesh used for laparoscopic intraperitoneal onlay repair of incisional hernia (Br J Surg 2010; 97: 1140-1145).
Department of Surgery, Huddersfield Royal Infirmary, Huddersfield, UK.
Eye (Lond). 2010 Aug ;24 (8):1366-75 20414259
Department of Ophthalmology, University Hospitals Leicester, Infirmary Square, Leicester, UK. email@example.com
Prostate Research Group, The Chancellors Building, University of Edinburgh, Edinburgh, UK.
Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.
Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
Recent developments in the study of host-pathogen interactions have fundamentally altered our understanding of the nature of Staphylococcus aureus infection, and previously held tenets regarding the role of the granulocyte are being cast aside. Novel mechanisms of pathogenesis are becoming evident, revealing the extent to which S. aureus can evade neutrophil responses successfully by resisting microbicides, surviving intracellularly and subverting cell death pathways. Developing a detailed understanding of these complex strategies is especially relevant in light of increasing staphylococcal virulence and antibiotic resistance, and the knowledge that dysfunctional neutrophil responses contribute materially to poor host outcomes. Unravelling the biology of these interactions is a challenging task, but one which may yield new strategies to address this, as yet, defiant organism.
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Radio-labeled hydrogel beads, based on amidated pectin, have been produced by adding droplets of an amidated pectin solution to calcium chloride. Incorporation of model drugs into the beads and measurement of the dissolution rate showed that the properties of the beads were unaffected by the incorporation of the radiolabel. The labeled beads were used to carry out an in vivo study of their behavior in the gastrointestinal tract using human volunteers. The volunteers were given the beads after an overnight fast and images were obtained at frequent intervals during transit through the upper gastrointestinal tract and the colon. The beads exhibited rapid gastric emptying and proceeded to pass through the small intestine individually before regrouping at the ileo-caecal junction. Once in the colon, the beads again proceeded as individuals and evidence of the degradation of the beads was observed.
C G Wilson, B O'Mahony, S M Connolly, M V Cantarini, M R Farmer, P A Dickinson, R P Smith, H C Swaisland
Bio-Images Research Ltd, Glasgow, Scotland, UK. firstname.lastname@example.org
The selective EGFR tyrosine kinase inhibitor, gefitinib has been shown to be active against certain human carcinomas. It had been noted that a proportion of volunteers consistently had lower gefitinib exposure following oral administration. The shape of the elimination profile in this subset was also different, showing a monophasic elimination pattern rather than the biphasic pattern observed in the majority of subjects. A gamma scintigraphic study was conducted to examine the relationship of gastrointestinal transit and drug absorption in a cohort of rapid clearance subjects (n=5) and normal profile volunteers (n=7). The fasted volunteer panel received a 250 mg gefitinib tablet labelled with [(111)In]-DTPA together with 240 mL [(99m)Tc]-labelled water. The rapid clearance cohorts were shown to have a faster mean gastric emptying T90 (37 min vs 74 min) and shorter small intestinal transit time (156 min vs 204 min), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma C(max) was lower (99.2 ng/mL vs 116 ng/mL) and AUC almost half in the rapid clearance group (2162+/-81 ngh/mL vs 4996+/-64 ngh/mL). These data suggest that gastrointestinal transit parameters play a role in the differences in the rapid clearance profile group, also contributing to the biphasic to monophasic switch. However, historical data show, at the recommended dose of 250 mg/day steady-state plasma concentrations adequate for clinical benefit are achieved in patients with non-small cell lung cancer.
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Quality-by-design case study: investigation of the role of poloxamer in immediate-release tablets by experimental design and multivariate data analysis.
Pfizer Inc., Groton, Connecticut 06340, USA. email@example.com
The role of poloxamer 188, water and binder addition rate, on retarding dissolution in immediate-release tablets of a model drug from BCS class II was investigated by means of multivariate data analysis (MVDA) combined with design of experiments (DOE). While the DOE analysis yielded important clues into the cause-and-effect relationship between the responses and design factors, multivariate data analysis of the 40+ variables provided additional information on slowdown in tablet dissolution. A steep dependence of both tablet dissolution and disintegration on the poloxamer and less so on other design variables was observed. Poloxamer was found to increase dissolution rates in granules as expected of surfactants in general but retard dissolution in tablets. The unexpected effect of poloxamer in tablets was accompanied by an increase in tablet-disintegration-time-mediated slowdown of tablet dissolution and by a surrogate binding effect of poloxamer at higher concentrations. It was additionally realized through MVDA that poloxamer in tablets either acts as a binder by itself or promotes binder action of the binder povidone resulting in increased intragranular cohesion. Additionally, poloxamer was found to mediate tablet dissolution on stability as well. In contrast to tablet dissolution at release (time zero), poloxamer appeared to increase tablet dissolution in a concentration-dependent manner on accelerated open-dish stability. Substituting polysorbate 80 as an alternate surfactant in place of poloxamer in the formulation was found to stabilize tablet dissolution.
Faculty of Pharmacy, University of Manitoba, Apotex Centre, Winnipeg, Canada. firstname.lastname@example.org
In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.
Universite Paul Cezanne, UMR CNRS 6263 ISM2, 13397 Marseille Cedex 20, France.
The present study is an experimental investigation of the thermal evolution of millimeter-sized sessile water droplets deposited on heated substrates. Infrared thermography is used to record temperature profiles on the droplet interface in time as evaporation takes place. The local measurements of the interface temperature allowed us to deduce the local evaporation rate and its evolution in time. To our knowledge, this is the first time that such measurements have been performed. The deduced evaporation rate using thermography data has been validated with optical measurements. Temperature evolution is used to reveal the contact line location and transient temperature fields. Temperature differences between the apex of the droplet and the contact line are shown to decrease in time. The rate of local temperature increase at the interface is found to behave linearly with time. The slope of this linear increase turns out to be more pronounced as the substrate temperature is increased. A generalized linear trend, using dimensionless properties for the interface temperature rise, is deduced from the measurements.
College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China.
To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.
Physicochemical Properties and Dissolution Studies of Dexamethasone Acetate-beta-Cyclodextrin Inclusion Complexes Produced by Different Methods.
Mayara M Doile, Keila A Fortunato, Iára C Schmücker, Sacha K Schucko, Marcos A S Silva, Patrik O Rodrigues
Departamento de Farmácia, Universidade da Região de Joinville, Bom Retiro, CEP 88040-900, Joinville, Santa Catarina, Brazil.
Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and beta-cyclodextrin (betaCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of betaCD (33-fold) and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze-dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.
[Preparation and release profile of colon-targeting drug delivered as novel one-step dry-coated tablets (OSDrC)].
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan. email@example.com
One-Step Dry-Coated tablets (OSDrC) of a colon-targeting drug were prepared using Eudragit L 100-55 (Eud-L) and chitosan (Chit) as the outer layer. Lag time in the 1st fluid, which simulated the stomach, was affected by differences in the pores occurring as a result of Chit dissolution. The dissolution rate of Chit was decreased by the addition of Eud-L. On the other hand, lag times in phosphate buffer (pH 7.4) simulating the small intestine, and in the 2nd fluid simulating the colon, were affected by differences in the pores occurring as a result of Eud-L dissolution and Chit swelling. The lag time of OSDrC with an outer layer of Eud-L:Chit at a ratio of 3:1 in each test medium was greater than the gastric emptying time in the 1st fluid and the small intestine transit time in phosphate buffer (pH 7.4). Furthermore, lag times were similar when test media were changed sequentially. Therefore, it is possible to deliver colon-targeting drugs as OSDrC with an outer layer of Eud-L:Chit at 3:1.
Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz).
J Zh Gao, M A Hussain, R Motheram, D A B Gray, I H Benedek, W D Fiske, W J Doll, E Sandefer, R C Page, G A Digenis
Bristol-Myers Squibb Company, Biopharmaceutics R&D, New Brunswick, New Jersey 08903-0191, USA. firstname.lastname@example.org
Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption.
Efficacy of electrocautery in different media: air, perfluorodecalin, glycerine, glycine, and electrolyte solution.
Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. email@example.com
BACKGROUND Electrocautery during fetoscopic surgery is impossible in the electrolyte-containing amniotic fluid. Intrauterine insufflation of carbon dioxide may cause lethal hypercapnia and acidosis in the fetus. Therefore, other media must be considered. OBJECTIVE To evaluate the efficacy of electrocautery in different media that have been described for fetoscopic surgery. MATERIALS AND METHODS Using bipolar electrocautery, lesions were made in 16 skin/cartilage specimens from the ears of New Zealand White rabbits in 5 different media: air, 85% glycerine, 1.5% glycine, electrolyte solution, and perfluorodecalin. The efficacy of electrocautery in the different media was compared by calculating mean necrosis indices--the quotient of native to necrosed tissue thickness--and assessing the qualitative histologic changes. RESULTS In all media except the electrolyte solution, the cauterized areas showed clear sequellae of electrocautery such as thinning, loss of tissue architecture, increased stromal staining, and nuclear disintegration. Mean necrosis indices were 1.38 +/- 0.24 for air, 1.37 +/- 0.28 for glycerine, 1.32 +/- 0.23 for perfluorodecalin, 1.31 +/- 0.14 for glycine, and 1.05 +/- 0.10 for electrolyte solution (P < 0.01 for electrolyte solution compared to all other media). No significant differences were detected between the nonconductive substances. CONCLUSION In our tests, air, glycine, glycerine, and perfluorodecalin allowed similarly effective electrocauterization. As expected, bipolar electrocautery in electrolyte solution is ineffective. The perfluorocarbon perfluorodecalin may have other potential advantages as a medium in endosurgery, such as low surface tension, biologic inertia, optical clarity, and insolubility of blood.
The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets.
University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate.
Department of Pharmaceutical Technology, School of Pharmacy, Ankara University, 06100-Tandoğan, Ankara, Turkey.
Piroxicam is a nonsteroidal anti-inflammatory drug that is characterized by low solubility-high permeability. The present study was designed to improve the dissolution rate of piroxicam at the physiological pH's through its increased solubility by preparing semi-solid dispersions of drug using Gelucires and Labrasol. These excipients are essentially characterized by their melting points and HLB (hydrophilic-lipophilic balance) values. The dissolution tests of the preparations were performed in the media with different pH's. Differential scanning calorimetry (DSC), were used to examine the interaction between piroxicam and excipients. Gelucire 44/14 and Labrasol at the concentration of 15% w/v in water provided 20- and 50-fold increase in the solubility of piroxicam, respectively. The semi-solid dispersion containing 1/20 of drug/excipient mixture (20% Gelucire 44/14 and 80% Labrasol in w/w) produced the dissolution not less than 85% of piroxicam within 30 min in each dissolution media (simulated gastric fluid (SGF), pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). DSC analysis of this semi-solid dispersion indicated that there was no chemical reaction between the drug and excipients, and that a solid-state solution of piroxicam with excipient formed.