Exploring Canine-Human Differences in Product Performance. Part II: Use of Modeling and Simulation to Explore the Impact of Formulation on Ciprofloxacin In Vivo Absorption and Dissolution in Dogs.

This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection. A mechanistic absorption model was used to predict the in vivo dissolution and absorption characteristics of the oral formulations. Canine ciprofloxacin absorption was constrained to the duodenum/jejunum. This absorption window was far narrower than that seen in humans. Furthermore, while substantial within-individual variability in drug absorption was seen in human subjects, a greater magnitude of variability was observed in dogs. For three sets of data, a lag time in gastric emptying was necessary to improve the accuracy of model-generated in vivo blood level profile predictions. In addition to species-associated dissimilarities in drug solubilization due to human versus canine differences in gastrointestinal fluid compositions, the far more rapid intestinal transit time and potential segmental differences in drug absorption needed to be considered during human-canine extrapolation of oral drug and drug product performance. Through the use of mechanistic models, the data generated in the human and canine studies contributed insights into some aspects of the interspecies differences to be considered when extrapolating oral bioavailability/formulation effect data between dogs and humans.

Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles.

The bolus (or oblet) is a dosage form that can be used for the oral administration of pharmaceutical compounds to ruminating species. Unlike traditional tablets, oral boluses may contain quantities of drug on the order of grams rather than milligrams. Due to its size, it is only recently that USP-like in vitro dissolution methods have been developed for this dosage form. However, whether or not these dissolution tests can predict product in vivo performance has yet to be determined. The importance of this issue is apparent when the U.S. Food and Drug Administration Center for Veterinary Medicine is faced with the decision of whether to require additional in vivo bioequivalence study data to support the approval of changes in product chemistry or manufacturing method. The current study was undertaken to determine whether an in vivo/in vitro correlation can be established for bovine sulfamethazine oral boluses and to acquire insight into the magnitude of changes in in vitro product performance that can occur before corresponding changes are seen in in vivo blood level profiles. Based upon the results of this investigation, it is concluded that marked changes in in vitro sulfamethazine bolus performance can be tolerated before resulting in altered in vivo blood level profiles. However, the data also suggest that rumenal absorption may occur for some compounds. Therefore the degree to which variation in product in vitro dissolution profiles can be tolerated may be compound specific.

Characterization of the interactions between polymethacrylate-based aqueous polymeric dispersions and aluminum lakes.

Instability in film coating formulations can arise from interactions between aluminum lake pigments and aqueous polymeric dispersions. The purpose of this study was to characterize the interactions between three polymethacrylate-based aqueous polymeric dispersions (Eudragit RS 30 D, Eudragit L 30 D-55, and Eudragit NE 30 D) and aluminum lakes. Particle size measurements, pH stability profiles, zeta potential measurements, and microscopy were used to study mixed dispersions of the polymeric latices and the lakes. Interactions leading to dispersion instability were related to the surface charge of the components in the formulation. Interactions between the ionic polymers and the lakes arose from instability of the lakes outside a certain pH range resulting in the release of electrolytes, which led to aggregation of the polymeric particles. Interactions between the nonionic polymer and the lakes were related to the polymer modifying the surface charge of the lakes, resulting in aggregation of the pigment particles.

Estimation of capping incidence by indentation fracture tests.

The purpose of this study was to predict the capping tendencies of pharmaceutical powders by creating indentation fracture on compacts. Three sets of binary mixtures containing different concentrations of each ingredient were used in the study. The binary mixtures were chosen to represent plastic-plastic, plastic-brittle, and brittle-brittle combination of materials. The mixtures were tableted at different pressures and speeds on Prester, a tablet press simulator. These mixtures were also compacted on the Instron Universal Testing Machine 4502. Static indentation tests were done on these compacts at different depths until surface cracking and chipping were observed. The extent of surface cracking and chipping was observed from light microscope and scanning electron microscope images. A rank order correlation was observed between lamination susceptibility and the depth at which indentation failure occurred. It was concluded that indentation fracture tests could provide a useful estimate of lamination properties of pharmaceutical powders.

Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic and spectroscopic investigation.

PURPOSE: To determine the influence of hydrogen bonding and solubility parameter on the glass transition temperature (T(g)) of various drug-poly(vinylpyrrolidone) blends. METHODS: The T(g) of PVP films containing either acetaminophen, naproxen, salicylamide, carbamazepine, griseofulvin or propranolol hydrochloride were measured using differential scanning calorimetry. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction was used to characterize the specific interactions between the drug-PVP blends and the physical state of the films, respectively. The total solubility parameter and its individual components were calculated using the method of Van Krevelen. RESULTS: Salicylamide displayed the greatest plasticizing effect, depressing the T(g) to the minimum. This was consistent with the FTIR data, which indicated the presence of hydrogen bonding with PVP. Griseofulvin showed the least plasticizing effect due to lack of interaction with PVP. All the drugs except griseofulvin were amorphous within the film up to 30% (w/w) drug composition. The correlation between the various components of the solubility parameters and the plasticizing effect of drugs was very poor. CONCLUSIONS: Spectroscopic investigation for the presence of interaction between the drugs and PVP proved to be extremely predictive of the plasticizing effect of various drugs. In contrast, solubility parameters appeared to be far less sensitive indicators of drug-PVP miscibility.

The influence of excipients on the stability of the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose.

The purpose of this study is to test the hypothesis that in tablet formulations, moisture-sensitive drugs formulated with lactose monohydrate have the same stability as formulations containing anhydrous lactose, and to characterize the kinetics of niacinamide degradation in the solid state. Aspirin and niacinamide decomposition were used as indicators of stability. Aspirin and niacinamide tablets containing either lactose monohydrate or anhydrous lactose were separately investigated at different temperatures and relative humidities; the stability tests were done at 25 degrees C--60% RH, 40 degrees C--80% RH, 60 degrees C--60% RH, 60 degrees C--80% RH, and 80 degrees C--80% RH. Official U.S. Pharmacopeia methods were used for the aspirin and niacinamide assays. Statistical analysis showed that tablets containing lactose monohydrate have the same stability as tablets containing anhydrous lactose, which means that even though water is present in the crystal structure, the bound water does not influence the reaction rate. In addition, niacinamide degradation in the solid-state can be described by a third order rate equation.

Design and validation of an annular shear cell for pharmaceutical powder testing.

An annular shear cell was constructed for powder flow testing, the influence of design and process parameters was characterized, and the results were compared with other flow methods. The shear cell was designed with interchangeable parts to mimic other shear cells. The texture of the powder-metal interface and the gap distance between the lid and side wall of the trough were varied, and the effects of shear rate, powder bed thickness, and consolidation times were tested. Shear parameters, such as cohesion, angles of friction, and flow factors, were measured for microcrystalline cellulose, anhydrous lactose, spray-dried lactose, mannitol, dibasic calcium phosphate dihydrate, anhydrous theophylline, and theophylline monohydrate powder. The results were then compared with the Carr index, mass flow rate, and flowability index. Design parameters such as surface texture and the gap distance significantly affected the shear call results, whereas for the process parameters studied, the shear rate, consolidation time, and powder bed height had a minimal effect on the shear cell results. Of the shear parameters obtained, the angles of friction best represented the known flow properties of powders and were in general agreement with those from other flow tests.

Covering the uninsured through TennCare: does it make a difference?

Tennessee created TennCare in 1994 to address the needs of "poor and uninsured citizens ... excluded from the health care system." Under TennCare, Tennessee implemented managed care in its Medicaid program and used savings anticipated from the switch to expand insurance coverage to uninsured and uninsurable adults and children. Our analysis of the expansion suggests that it improved access to care, reduced unmet need, and encouraged use of preventive services, particularly for children. These changes coincided with higher levels of satisfaction with care among TennCare beneficiaries.

Practical limitations of tableting indices.

The purpose of this study was to utilize tableting indices to distinguish between materials with varying degrees of compactibility by establishing a quantitative relationship between indices and compactibility. Compactibility in this study is restricted to tablet strength and friability alone. Nine mixtures with varying degrees of compactibility were tableted and the tensile strength and friability of the tablets were determined. The tableting indices of these mixtures were determined using an Instron Universal testing machine. An artificial neural network program was used to establish a quantitative relationship between indices and tablet strength and friability. Six new powders were used to validate the models describing the relationship between indices and tablet strength and friability. These powders were compressed into tablets and their strength and friability were determined. Their indices were also determined. The established models were used to predict tablet strength and friability from index values. The predicted values were compared with the experimentally determined values. There was little correlation between the predicted and experimentally determined values for tablet strength and friability. It was also found that materials or mixtures having almost similar indices had remarkably different compactibilities. It was concluded that models created to predict compactibility using one set of materials may not be able to successfully predict the compactibility of a new material. This calls into question the practicality of indices.

Setting rates for Medicaid managed behavioral health care: lessons learned.

This paper reviews Tennessee's experience setting, monitoring, and updating capitation rates for Medicaid managed behavioral health care, and draws lessons from those experiences for other states. Our review of assumptions about four components of Tennessee's rate-setting process--data, benefit design, savings expectations, and processes for monitoring and updating rates--suggests that the initial rate established by Tennessee was inadequate, and its inadequacy resulted primarily from the way available information was used to set the rate, rather than from the method of rate setting selected. Tennessee's experiences illustrate how difficult rate setting is and illuminate several key lessons about the rate-setting process.

Assessment of polymer-polymer interactions in blends of HPMC and film forming polymers by modulated temperature differential scanning calorimetry.

PURPOSE: To assess the miscibility and phase behavior of binary blends of hydroxypropylmethyl cellulose (HPMC) with hydroxypropyl cellulose (HPC), methylcellulose (MC), and polyvinylpyrrolidone (PVP). METHODS: Polymer-polymer miscibility was assessed by measurement of the glass transition temperature (Tg) and the width of the glass transition temperature (W-Tg), using modulated temperature differential scanning calorimetry (MTDSC). RESULTS: HPMC K4M/PVP and HPMC E5/MC blends were miscible as evidenced by a single, composition dependent, Tg throughout the entire composition range. HPMC/HPC blends were immiscible at all compositions. For the miscible blends, the variation in Tg with blend composition was compared to the values predicted by the Fox and Couchman-Karasz equations. At intermediate blend compositions, HPMC K4M/PVP blends exhibited negative deviations from ideal behavior. The Tg of the HPMC E5/MC blends was found to follow the Fox equation. The W-Tg measurements of the miscible blends gave evidence of phase separation at certain compositions. CONCLUSIONS: MTDSC was shown to be a useful technique in characterizing the interactions between some commonly used pharmaceutical polymers.

Perils of pioneering: monitoring Medicaid managed care.

This article reviews Federal and State oversight of section 1115 Medicaid managed care demonstrations in Hawaii, Oklahoma, Rhode Island, and Tennessee from 1994 to 1998. Under Medicaid managed care, the Federal Government and States have had to shift their focus and resources into oversight functions that barely existed in fee-for-service (FFS) Medicaid. We find that managed care monitoring was slow to begin and not always adequate in these demonstrations. While State and Federal monitoring have improved over time, monitoring is not yet at the point of ensuring access and quality.

Federally qualified health centers: surviving Medicaid managed care, but not thriving.

This article reviews the experiences of federally qualified health centers (FQHCs) in Hawaii, Rhode Island, and Tennessee before and after Medicaid managed care demonstrations began. Adapting to managed care proved challenging, but all FQHCs survived. Overall, FQHCs performed better financially than anticipated, partly because demonstrations expanded coverage to previously uninsured individuals, and because FQHCs in two States formed plans that paid FQHCs more than other plans. Service encounters declined; it is unclear if this is negative, since it may indicate more efficient care delivery. In some cases, supportive State policies aided FQHCs' survival. Continued adaptation is critical for FQHCs' longer term prospects.

Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations.

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed.

Medicaid managed care and the marketplace.

In 1994 and 1995, Tennessee, Hawaii, Rhode Island, and Oklahoma began massive expansions of Medicaid managed care, growing from three health plans covering a few enrollees to 27 plans covering the great majority a year later. Some firms aggressively pursued expansion, while others had very limited business objectives. Although established insurers often dominated the Medicaid markets, newly developed firms, some provider-sponsored, were also important. Despite the relatively low Medicaid capitation rates in the 1996-97 period, Medicaid plans in three states had an average 1% net profit margin.

Powder densification. 2. Viscoelastic material properties in modeling the uniaxial compaction of powders.

A micromechanical model for predicting the densification of particulate matter under hydrostatic loading was developed to account for the time-dependent response of materials to applied loads. Viscoelastic material response used in the analysis was based upon a standard three-parameter rheological model. Compaction data under closed die conditions were collected using an Instron analyzer for different rates of applied load. Densification during the loading phase of PMMA/coMMA powder, a pharmaceutical polymeric coating material, was well predicted by the proposed algorithm, which contrasts with the prediction implied through a static indentation model. Secondary factors which affect compaction such as die-wall friction are also briefly discussed.