Intrauterine closure of myelomeningocele defects with primary linear repair versus bipedicle fasciocutaneous flaps: a post-MOMS cohort study with long-term follow-up.

OBJECTIVE: The objective of this study was to determine the effects of in utero bipedicle flaps on maternal-fetal morbidity/mortality, the need for CSF diversion, and long-term functional outcomes. METHODS: Eighty-six patients who underwent fetal myelomeningocele repair from 2011 to 2021 at a single institution were reviewed. Primary outcomes included intrauterine fetal demise, postnatal death, postnatal myelomeningocele repair dehiscence, and CSF diversion by final follow-up. RESULTS: The cohorts were no different with regard to race, ethnicity, maternal age at fetal surgery, body mass index, gravidity, parity, gestational age at fetal surgery, estimated fetal weight at fetal surgery, or fetal lesion level. Of the 86 patients, 64 underwent primary linear repair and 22 underwent bipedicle flap repair. There were no significant differences in rates of intrauterine fetal demise, postnatal mortality, midline repair site dehiscence, or the need for CSF diversion by final follow-up. Operative times were longer (32.5 vs 18.7 minutes, p < 0.001) and gestational age at delivery was lower (232 vs 241 days, p = 0.01) in the bipedicle flap cohort, but long-term functional outcomes were not different. CONCLUSIONS: Analysis of the total cohort affirms the long-term benefits of fetal myelomeningocele repair. In utero bipedicle flaps are safe and can be used for high-tension lesions without increasing perioperative risks to the mother or fetus. In utero flaps preserve the long-term benefits seen with primary linear repair and may expand inclusion criteria for fetal repair, providing life-changing care for more patients.

In vivo Raman spectroscopy monitors cervical change during labor.

BACKGROUND: Biochemical cervical change during labor is not well understood, in part, because of a dearth of technologies capable of safely probing the pregnant cervix in vivo. The need for such a technology is 2-fold: (1) to gain a mechanistic understanding of the cervical ripening and dilation process and (2) to provide an objective method for evaluating the cervical state to guide clinical decision-making. Raman spectroscopy demonstrates the potential to meet this need, as it is a noninvasive optical technique that can sensitively detect alterations in tissue components, such as extracellular matrix proteins, lipids, nucleic acids, and blood, which have been previously established to change during the cervical remodeling process. OBJECTIVE: We sought to demonstrate that Raman spectroscopy can longitudinally monitor biochemical changes in the laboring cervix to identify spectral markers of impending parturition. STUDY DESIGN: Overall, 30 pregnant participants undergoing either spontaneous or induced labor were recruited. The Raman spectra were acquired in vivo at 4-hour intervals throughout labor until rupture of membranes using a Raman system with a fiber-optic probe. Linear mixed-effects models were used to determine significant (P<.05) changes in peak intensities or peak ratios as a function of time to delivery in the study population. A nonnegative least-squares biochemical model was used to extract the changing contributions of specific molecule classes over time. RESULTS: We detected multiple biochemical changes during labor, including (1) significant decreases in Raman spectral features associated with collagen and other extracellular matrix proteins (P=.0054) attributed to collagen dispersion, (2) an increase in spectral features associated with blood (P=.0372), and (3) an increase in features indicative of lipid-based molecules (P=.0273). The nonnegative least-squares model revealed a decrease in collagen contribution with time to delivery, an increase in blood contribution, and a change in lipid contribution. CONCLUSION: Our findings have demonstrated that in vivo Raman spectroscopy is sensitive to multiple biochemical remodeling changes in the cervix during labor. Furthermore, in vivo Raman spectroscopy may be a valuable noninvasive tool for objectively evaluating the cervix to potentially guide clinical management of labor.

A Collaborative Model of a Community Birth Center and a Tertiary Care Medical Center.

OBJECTIVE: To describe the development, implementation, and evaluation of a collaborative model between a freestanding birth center and a tertiary care medical center. METHODS: An interdisciplinary team developed a freestanding accredited birth center in collaboration with a tertiary care medical center in the southeast United States. We performed a retrospective cohort study of all women obtaining care at the birth center and assessed the rate (and 95% CIs) of cesarean delivery, patient transfers, and adverse maternal and neonatal events. RESULTS: Between January 2017 and December 2018, 1,394 women initiated prenatal care at the birth center. The study cohort consisted of 1,061 women who continued their prenatal care and planned to deliver at the birth center, of whom 358 (34%) were subsequently transferred before admission and 703 (66%) presented to the birth center in labor. Of those, 573 (82%) were subsequently delivered vaginally in the birth center, and 130 (18%) were transferred for hospital birth. Of those admitted to the birth center in labor, 41 ultimately underwent cesarean delivery for an overall cesarean delivery rate of 6% (95% CI 4-8%). Maternal transfers for postpartum hemorrhage occurred in eight patients (1%; 95% CI 1-2%). There were 39 neonatal intensive care admissions (6%; 95% CI 4-8%), eight cases (1%; 95% CI 0.5-2%) of 5-minute Apgar scores less than 7, and two previable neonatal deaths (0.3%; 95% CI 0-1%). CONCLUSION: We describe a collaborative model between a freestanding birth center and a tertiary care medical center, which provided women with access to a traditional birth center experience while maintaining access to the specialized care provided by a tertiary care medical center. We believe that the model may facilitate options for maternity care in regional perinatal systems.

In vivo Raman spectroscopy for biochemical monitoring of the human cervix throughout pregnancy.

BACKGROUND: The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications. OBJECTIVE: The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair. STUDY DESIGN: In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6-week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses. RESULTS: Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm-1) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm-1) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm-1) and cholesterol (1447 cm-1) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals. CONCLUSION: Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth.

Trial of Labor Compared With Cesarean Delivery in Superobese Women.

OBJECTIVE: To examine whether labor compared with planned cesarean delivery is associated with increased maternal and neonatal morbidity. METHODS: We conducted a retrospective cohort study of all women with body mass indexes (BMIs) at delivery of 50 or greater delivering a live fetus at 34 weeks of gestation of greater between January 1, 2008, and December 31, 2015. Pregnancies with multiple gestations and major fetal anomalies were excluded. The primary outcome was a composite of maternal and neonatal morbidity and was estimated to be 50% in superobese women based on institutional data. A sample size of 338 women determined the study period and was selected to show a 30% difference in the incidence of the primary outcome between the two groups. Multivariate logistic regression adjusted for potential confounders. RESULTS: There were 344 women with BMIs of 50 or greater who met eligibility criteria, of whom 201 (58%) labored and 143 (42%) underwent planned cesarean delivery. Women who labored were younger, more likely to be nulliparous, and less likely to have pre-existing diabetes. Among women who labored, 45% underwent a cesarean delivery, most commonly for labor arrest (61%) or nonreassuring fetal status (28%). Composite maternal and neonatal morbidity was reduced among women who labored even after adjusting for age, parity, pre-existing diabetes, and prior cesarean delivery (adjusted odds ratio 0.42, 95% CI 0.24-0.75). In the subgroup of women (n=234) who underwent a cesarean delivery, whether planned (n=143) or after labor (n=91), there were no differences in maternal and neonatal morbidity except that severe maternal morbidity was increased in women (n=12) who labored (8.8% compared with 2.1%, relative risk 4.2, 95% CI 1.14-15.4). CONCLUSION: Despite high rates of cesarean delivery in women with superobesity, labor is associated with lower composite maternal and neonatal morbidity. Severe maternal morbidity may be higher in women who require a cesarean delivery after labor.

The bending strength of tablets with a breaking line--Comparison of the results of an elastic and a "brittle cracking" finite element model with experimental findings.

The aim of this work was to ascertain the influence of the position of the breaking line of bevel-edged tablets in a three-point bending test. Two different brands of commercially available, flat-round, bevel-edged tablets with a single central breaking line were studied. Breaking line positions tested, relative to the upper loading roll, were 0°, 22.5°, 45°, 67.5° and 90°. The breaking line faced either up- or downwards during the test. The practical results were compared with FEM results simulating similar test configurations. Tablets failed mainly across the failure plane, resulting in two tablet halves. An exception to this was found for tablets where the breaking line faced down and was positioned at an angle of 22.5° relative to the loading plane. Here the crack followed the breaking line in the centre of the tablets and only diverged towards the loading plane position at the edges of the tablets. The breaking line facing upwards resulted in a significantly higher tensile strength of the tablets compared to it facing downwards. However, with one exception, the orientation of the breaking line relative to the loading plane appeared not to affect the tensile strength values. A fully elastic FEM model indicated that both the position of the breaking line relative to the loading plane and as to whether the breaking line faced up- or downwards during the bending test would result in considerably different failure loads during practical experiments. The results also suggested that regardless of the breaking line position, when it is facing down crack propagation should start at the outer edges propagating towards the midpoint of the discs until failure occurs. Failure should hence always result in equal tablet halves, whereby the failure plane should coincide with the loading plane. Neither predictions fully reflected the practical behaviour of the tablets. Using a brittle cracking FEM model significantly larger tensile stresses for tablets with the breaking line positioned downwards at 0° or 22.5° relative to the loading plane were still predicted, but the differences between model and experimental values was greatly reduced. The remaining differences are more likely due to the inadequacy of the equation available to calculate the experimental tensile strength values. This equation cannot account for the presence of a breaking line and overestimates the thickness of the loading plane by the depth of the breaking line when in 0° or 22.5° position. If the depth of the breaking line is taken into account, the model predictions and the experimental findings are comparable. Also, in the brittle cracking FEM simulations the predicted crack propagation patterns were similar to those found in the experiments, and the model stress distributions across the lower surfaces were much more homogeneous and streamlined parallel to the loading plane. The brittle cracking model hence reflected the practicalities of the bending test more closely. The findings suggested that with the breaking line facing down fracture should always start in the centre of a tablet at its lower surface, initiated by the breaking line. Due to simultaneous development of larger stresses along the y-axis the tablet should still break into two equal halves along the loading plane, unless the position of the breaking line relative to the loading plane was 22.5°. In this case the tablet would fail by a mixed process, whereby failure would occur mainly along the breaking line, but due to simultaneous crack formation at the lower surface close to the bevel edge parallel to the loading plane the final breaking pattern would deviate from the breaking line about half-way from its centre, as seen in the practical experiments.

Theoretical investigations into the influence of the position of a breaking line on the tensile failure of flat, round, bevel-edged tablets using finite element methodology (FEM) and its practical relevance for industrial tablet strength testing.

Flat, round tablets may have a breaking ("score") line. Pharmacopoeial tablet breaking load tests are diametral in their design, and industrially used breaking load testers often have automatic tablet feeding systems, which position the tablets between the loading platens of the machine with the breaking lines in random orientation to the applied load. The aim of this work was to ascertain the influence of the position of the breaking line in a diametral compression test using finite element methodology (FEM) and to compare the theoretical results with practical findings using commercially produced bevel-edged, scored tablets. Breaking line test positions at an angle of 0°, 22.5°, 45°, 67.5° and 90° relative to the loading plane were studied. FEM results obtained for fully elastic and elasto-plastic tablets were fairly similar, but they highlighted large differences in stress distributions depending on the position of the breaking line. The stress values at failure were predicted to be similar for tablets tested at an angle of 45° or above, whereas at lower test angles the predicted breaking loads were up to three times larger. The stress distributions suggested that not all breaking line angles would result in clean tensile failure. Practical results, however, did not confirm the differences in the predicted breaking loads, but they confirmed differences in the way tablets broke. The results suggest that it is not advisable to convert breaking loads obtained on scored tablets into tablet tensile strength values, and comparisons between different tablets or batches should carefully consider the orientation of the breaking line with respect to the loading plane, as the failure mechanisms appear to vary.

Borderline amniotic fluid index and its relation to fetal intolerance of labor: a 2-center retrospective cohort study.

OBJECTIVES: To determine whether a borderline amniotic fluid index (AFI) in the third trimester is associated with an increased rate of cesarean delivery for fetal intolerance of labor, meconium-stained amniotic fluid, and intrauterine growth restriction, among other adverse perinatal outcomes. METHODS: Patients with a diagnosis of a borderline AFI between January 2008 and August 2012 were identified. Antepartum, delivery, and neonatal data were collected and compared to a cohort with a normal AFI. RESULTS: We enrolled 739 patients, including 177 with a borderline AFI (>5 and <10 cm) and 562 with a normal AFI (≥ 10-24 cm); 360 patients delivered at University of Arizona Medical Center, and 379 delivered at St Joseph's Hospital. Combined and individual analyses of each center revealed no significant difference in fetal intolerance of labor (P = .19) or cesarean delivery for fetal intolerance (P = .074) between cohorts. In both settings, patients with a borderline AFI were more likely than those with a normal AFI to undergo antepartum testing (P < .001). A statistically significant increase in intrauterine growth restriction in the borderline AFI group was noted, with a calculated risk ratio of 13.76 (P < .001). There was no difference between groups for meconium-stained amniotic fluid (P = .23), neonatal intensive care unit admission (P = .054), preterm delivery (P = .31), or operative vaginal delivery (P = .45). CONCLUSIONS: The findings of this study suggest that there is no difference in the rate of fetal intolerance of labor in pregnancies with a borderline AFI and those with a normal AFI. Pregnancies complicated by a borderline AFI are more likely to undergo antepartum testing, yet the benefit is unclear. Significantly more patients with a borderline AFI had underlying growth restriction, which may provide a useful tool for risk stratification in the management of a borderline AFI.

Investigations into the tensile failure of doubly-convex cylindrical tablets under diametral loading using finite element methodology.

In the literature various solutions exist for the calculation of the diametral compression tensile strength of doubly-convex tablets and each approach is based on experimental data obtained from single materials (gypsum, microcrystalline cellulose) only. The solutions are represented by complex equations and further differ for elastic and elasto-plastic behaviour of the compacts. The aim of this work was to develop a general equation that is applicable independently of deformation behaviour and which is based on simple tablet dimensions such as diameter and total tablet thickness only. With the help of 3D-FEM analysis the tensile failure stress of doubly-convex tables with central cylinder to total tablet thickness ratios W/D between 0.06 and 0.50 and face-curvature ratios D/R between 0.25 and 1.85 were evaluated. Both elastic and elasto-plastic deformation behaviour were considered. The results of 80 individual simulations were combined and showed that the tensile failure stress σt of doubly-convex tablets can be calculated from σt=(2P/πDW)(W/T)=2P/πDT with P being the failure load, D the diameter, W the central cylinder thickness, and T the total thickness of the tablet. This equation converts into the standard Brazilian equation (σt=2P/πDW) when W equals T, i.e. is equally valid for flat cylindrical tablets. In practice, the use of this new equation removes the need for complex measurements of tablet dimensions, because it only requires values for diameter and total tablet thickness. It also allows setting of standards for the mechanical strength of doubly-convex tablets. The new equation holds both for elastic and elasto-plastic deformation behaviour of the tablets under load. It is valid for all combinations of W/D-ratios between 0.06 and 0.50 with D/R-ratios between 0.00 and 1.85 except for W/D=0.50 in combination with D/R-ratios of 1.85 and 1.43 and for W/D-ratios of 0.40 and 0.30 in combination with D/R=1.85. FEM-analysis indicated a tendency to failure by capping or even more complex failure patterns in these exceptional cases. The FEM-results further indicated that in general W/D-ratios between 0.15 and 0.20 are favourable when the overall size and shape of the tablets is modified to give maximum tablet tensile strength. However, the maximum tensile stress of doubly-convex tablets will never exceed that of a flat-face cylindrical tablet of similar W/D-ratio. The lowest tensile stress depends on the W/D-ratio. For the thinnest central cylinder thickness, this minimum stress occurs at D/R=0.50; for W/D-ratios between 0.10 and 0.20 the D/R-ratio for the minimum tensile stress increases to 0.67, and for all other central cylinder thicknesses the minimum tensile stress is found at D/R=1.00.

Gastric emptying of multi-particulate dosage forms.

The evidence in the literature for the concept that multi-particulate dosage forms below a specific size empty from the stomach as if they were liquids and hence have the potential to provide the best solution to the formulation of controlled release oral dosage forms, has been considered. There is some evidence that particles less than 1.0mm provide a more rapid response than larger size particles but there is also evidence that this is not always the case and that rapid and reproducible gastric emptying of small particles does not always occur when they are administered. There is strong evidence that food can delay the gastric emptying of multi-particulate systems. Some of the misconception for gastric emptying performance of multi-particulate system is shown to be related to the limitation of the study design and limitation of the way the data is processed. Nevertheless, there is clear evidence that multi-particulate systems can provide effective oral controlled release dosage forms. There is still some way to go with experimental techniques which would allow a definitive answer to the issue of how the variability of the gastric emptying of multi-particulate systems of less than 2.0mm arises.

The influence of non-ionic surfactants on the rheological properties of drug/microcrystalline cellulose/water mixtures and their use in the preparation and drug release performance of pellets prepared by extrusion/spheronization.

The influence of adding two concentrations (5 and 25%) of non-ionic surfactants, one hydrophilic and the other hydrophobic, plus mixtures of equal parts of the two, on the rheological properties of a mixture of equal parts of microcrystalline cellulose and ibuprofen with water has been assessed by capillary rheometry. The mixtures were also used to form pellets by extrusion/spheronization and their in vitro dissolution in simulated intestinal fluid was measured. As with previous rheological studies of these types of pastes, the flow was non-Newtonian (shear thinning). Other rheological parameters were determined in terms of die entry angles, extensional flow and elastic parameters of recoverable shear and compliance. By comparisons with previous studies with the model drug, it was found that it was these latter parameters that were indicative of the ability of the formulations to produce satisfactory pellets. The experiments also identified that the level of surfactant as opposed to the type of surfactant determined the rheological properties of the wet mass. All the formulations were able to produce round pellets with a narrow size distribution, whereby their median size increased with the concentration of the surfactant. The 25% level of each of the surfactant formulations provided a rapid release of the drug (100% within 30min), but the 5% level and the mixed surfactant formulations provided lower drug release profiles.

The rheological properties of modified microcrystalline cellulose containing high levels of model drugs.

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.

The gastric emptying of food as measured by gamma-scintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions.

A study in human volunteers has been designed to evaluate the influence of different food regimes on the gastric emptying of 3 mm and 10 mm diameter tablets. Dextrose and beef drinks were used as liquid food; a mixture of minced beef and mashed potato (shepherd's pie) was used as a solid meal. The gastric emptying of these foods was monitored simultaneously with electrical impedance tomography (EIT) and gamma-scintigraphy (GS), and was quantified in terms of the time before gastric emptying started, the lag time, the mean gastric residence time (MGRT) and its variance (VGRT), and the time for complete emptying. The gastric emptying time of the tablets was established by monitoring the position of the tablets, which had been labelled with suitable radio isotopes, by GS. The two systems for monitoring gastric emptying of the foods did not provide equivalent results: times obtained with EIT were generally shorter than those obtained with GS for the liquid foods, but were longer for the solid meal. There was only a slight difference in the emptying times of the two liquid foods, whereas values for MGRT, VGRT and the time for complete emptying were considerably longer for the solid meal. In nearly all instances the tablets emptied after the foods had emptied completely from the stomach. Gastric emptying times were longer for the 3 mm tablets than the 10 mm tablets, whatever food they were taken with. The difference between the median emptying times was significant when the meal was either a dextrose solution or a beef drink, but not when the meal was shepherd's pie. The increase in gastric emptying time of tablets induced by solid food was greater than that associated with the differences in tablet size. By providing a protocol that did not allow the administration of further food until after the tablets had emptied from the stomach, no tablet emptying times exceeded 6 h.

Cyclooxygenase 2 expression in cervical intraepithelial neoplasia and vulvar cancer.

OBJECTIVE: The purpose of this study is to describe the expression of cyclooxygenase (COX) 2 cervical intraepithelial neoplasia (CIN) and vulvar cancer specimens. MATERIALS AND METHODS: Archived tissues from 21 cases including 6 cases negative for CIN (no CIN), 71 low-grade (CIN 1) diseases, 8 high-grade (CIN 2, 3) diseases, and 14 vulvar cancer cases were examined. Immunohistochemistry was evaluated in COX-2 expression in tissue using an isoform-specific COX-2 polyclonal antibody. Specimens were assigned an immunohistochemical score for intensity of staining and the percent of cells stained. The slides were scored by 2 independent pathologists and compared across histological categories. RESULTS: A greater proportion of cells were stained in specimens with high-grade CIN (p = 0.01). Staining intensity was not statistically different among the 3 groups. Higher scores were found for vulvar cancer as compared with normal vulva (p = 0.01). CONCLUSIONS: The increase in COX-2 in cervical cancer precursors may provide a potential target for prevention studies.

The determination of the mechanical strength of tablets of different shapes.

The aim of the study was to investigate the influence of the platen design, on the evaluation of the mechanical strength of tablets of different shapes in terms of the potential of ensuring reproducible failure mechanisms and deriving their tensile strength. Tablets which were circular, square or hexagonal in shape were prepared at a range of formation pressures each from microcrystalline cellulose (Avicel PH102), a direct compression anhydrous beta-lactose (DCL 21) and dicalcium phosphate dihydrate (Emcompress) with a reciprocating single punch tablet machine. The mechanical strength of the tablets has been determined with a three-point bending test and by applying a diametral load across the edges of the tablets with platens of different designs. Many of the tablets tested in three-point bending did not fail in tension. However, with platens to which semi-circular rods of radius 3.0mm were attached and vertically aligned, a test procedure was provided with which a wide range of tablets tested failed in tension, i.e., split into two halves. Where this occurred it was possible to calculate the tensile strength from the breaking load. Although the value of the tensile strength obtained with such platens was generally lower than that obtained for circular tablets when flat platens were used, the ability to be able to use this new configuration for all the tablet shapes provided a practical system for a range of tablet shapes. The tablets of the three shapes tested here were found to have equivalent values for the tensile strength when formed at the same compaction pressure for the three materials tested.

Factorial designed experiment to study the effects of excipients on the mechanical properties of pellets.

The aim of this work was to determine the effects of formulation factors on the mechanical properties of pellets produced by the process of extrusion and spheronisation. A range of properties from a simple fracture load to detailed load/displacement curves were used to study the effects of the levels of lactose monohydrate and glyceryl monostearate on the mechanical properties of pellets in terms of their surface tensile strength, pellet deformability and linear strain. A series of independent 2(2)-factorial designs were employed to establish the relationships between composition of the formulations and pellet properties, whereby the concept of an excess variable was explored. It was found that the spheronisation aid used, microcrystalline cellulose, is the domineering factor in most mechanical properties studied, except for the surface tensile strength, which decreased significantly with an increase in glyceryl monostearate concentration. The change in binder liquid from water to a water/ethanol mixture further changed the behaviour of the systems significantly. The assumption of an excess variable being less critical for the statistical outcome of a factorial experiment has not been found feasible for the systems studied.

The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate.

Pellets have been prepared by extrusion and spheronization containing microcrystalline cellulose (MCC) and four model drugs with decreasing order of solubility, paracetamol (P), diclofenac sodium (D), ibuprofen (IB) and indomethacin (IN) at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). The drugs differed in their response to extrusion in that all formulations containing the drug D had a 'steady state' extrusion profile whereas the other three drugs exhibited 'forced flow' indicating the possibility of water migration during the process of ram extrusion. The presence of GMS did not influence this effect. The drug D also required consistently less water to function than the other three drugs. In spite of these differences in extrusion performance, it was possible to prepare satisfactory pellets from formulations of all the drugs with 0, 30 and 60% GMS combined with 90, 60 or 30% of MCC at a range of water levels. It was also possible to prepare pellets containing the drug D with 70, 80 and 90% GMS, with corresponding quantities of 20, 10 and 0% of MCC. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS, grinding and processing this with MCC and water. Such systems retained the processing characteristics of the composition made by the blending of the powder. The presence of GMS in all cases reduced the quantity of water required for the process to function. The steady state or the mean of the range of the forces observed during forced flow, were dependent on the composition and the quantity of water added. The surface of the extrudate appeared smooth and measurements of surface roughness established that the value of the rugosity R(a) for any of the extrudates did not exceed 6 microm. The extrudate diameter was found to increase with the quantity of GMS in the formulation. The pellets produced were all within a relatively narrow size range (three sieve fractions of a root two progression), the median value of which increased with the level of GMS. For the drug D, there was a linear increase of pellet diameter with increase in the extrudate diameter. For the three other drugs this relationship was less certain but nevertheless there was a similar trend for the pellet diameter to increase as the extrudate diameter increased, suggesting the mechanism of the process is the same irrespective of the composition. Considering the value of the shape factor e(R), all the pellets produced from the various formulations were well within acceptable levels for further processing and the only observable trend in the values was that the formulations with the lower water contents were the least round. The porosity of the pellets of the different formulations generally decreased with the increase in water used to prepare the pellets, the extent of this decrease being dependent on the drug and the level of GMS. The in vitro drug release from the pellets was controlled by the solubility of the drug, the lower the value of the solubility, the longer the mean dissolution time (MDT). This was not influenced by the presence of GMS or the method of incorporation of the drug into the formulation.

The influence of chitosan and sodium alginate and formulation variables on the formation and drug release from pellets prepared by extrusion/spheronisation.

The influence of the incorporation of two oppositely charged hydrophilic natural polymers, chitosan and sodium alginate, alone and in combination, on the ability of formulations containing a model drug (paracetamol) to form spherical pellets by the process of extrusion/spheronisation and the properties of the pellets, has been undertaken. A statistically experimental design was employed to allow the major factors which determined the properties of the pellets, to be identified. A standardised procedure was used to prepare the pellets with a ram producing the extrudate for spheronisation. Statistical analysis of the results indicated that the formulation variables of the type and level of the polymer, the proportion of the model drug, and the proportion of the microcrystalline cellulose influenced (a) the quantity of liquid binder required to produce a good formulation (narrow size range and high value for the shape factor indicating sphericity), (b) the steady-state extrusion force, (c) the pellet perimeter, (d) the apparent pellet density and (e) the porosity of the pellets. The median size of the pellets of the "good formulation" could only be related to the chitosan and sodium alginate content of the formulations. The proportion of the drug, chitosan and sodium alginate content of the formulation significantly influenced the in vitro dissolution of the model drug (paracetamol). The drug release mechanism differed with the formulation variables, although if the pellets remained intact during the dissolution test, diffusion was the controlling mechanism. There was no significant advantage to be gained by using a mixture of the two polymers in terms of retarding drug release.

Amylose formulations for drug delivery to the colon: a comparison of two fermentation models to assess colonic targeting performance in vitro.

The purpose of this study was to develop an enzyme-based fermentation system for the in vitro assessment of colonic digestion of amylose films and coatings, and to compare its performance with a conventional fermentation model inoculated with human faecal bacteria. Amylose and ethylcellulose were mixed in different ratios and cast as isolated films, as well as spray coated onto drug-(5-aminosalicylic acid) loaded pellets. Four commercial amylase enzymes were individually screened for their ability to digest amylose cast films. The enzyme from the bacterium Bacillus licheniformis was found to be the most active against this substrate. Digestion of mixed amylose and ethylcellulose films was also observed, with the extent of digestion being proportional to the quantity of amylose present in the film. In terms of product performance, drug release from coated pellets was accelerated in the presence of the enzyme. The results with the enzyme system were comparable to those obtained from a faecal-based fermentation model, thereby suggesting that such a system has practical potential for in vitro screening of putative amylose formulations for colonic drug delivery.

The use of formulation technology to assess regional gastrointestinal drug absorption in humans.

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.