The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

PURPOSE: Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies. METHODS: Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared. RESULTS: In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome. CONCLUSIONS: The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.

Delivery of a therapeutic antibody to the lower gastrointestinal tract for the treatment of Clostridium difficile infection (CDI).

The colonic delivery system of toxin neutralizing antibody is a promising method for treating Clostridium difficile infection (CDI) and has some advantages over the parental administration of a neutralizing antibody. However, colonic delivery of biologics presents several challenges, including instability of biologics during encapsulation into the delivery system and harsh conditions in the upper GI tract. In this work, we described a multi-particulate delivery system encapsulating a tetra-valent antibody ABAB-IgG1 with the potential to treat CDI. This work first approved that the cecum injection of ABAB-IgG1 into the lower GI tract of mice could relieve the symptoms, enhance the clinical score, and improve the survival rate of mice during CDI. Then, the antibody was spray layered onto mannitol beads and then enteric coated with pH-sensitive polymers to achieve colon-targeting release. The in vitro release of antibody from the multi-particulate system and the pH-sensitive release of antibody was monitored. The in vivo efficacy of this system was further examined and confirmed in mice and hamsters. In summary, the findings of this study should provide practical information and potential treatment options for CDI through colonic delivery of antibody therapeutics to the lower GI tract using a multi-particulate delivery system.

Development and Validation of a Stability-indicating UPLC-DAD Method for the Simultaneous Determination of Ivermectin and Praziquantel in Pharmaceutical Tablets and Dissolution Media.

Currently, there is no single rapid and accurate stability-indicating quantitative method that can simultaneously determine both ivermectin and praziquantel and their related compounds. Thus, the goal of this research is to develop and validate a new rapid, accurate, and stability-indicating ultra-performance liquid chromatography (UPLC) method. The method uses a water, acetonitrile, and methanol gradient. The chromatographic separation was achieved on a C18 (1.7 µm, 2.1 × 50 mm) column with a flow rate of 0.7 mL/min, and the column temperature was maintained at 40°C. Analytes are detected at 245 nm. The method was validated in accordance with ICH Q2R1 guidelines. The linearity (R2) was >0.9987 and 0.9997 for praziquantel and ivermectin, respectively. The corresponding accuracy ranged between 98.0 and 102.0%. Intermediate precision (assessed as inter-day precision) was determined by calculating the cumulative %CV of eighteen assay preparations and was less than 2.0% for both praziquantel and ivermectin. The specificity of the method was shown by the resolution of the two active pharmaceutical ingredients (APIs) from any interfering excipients, impurities, or degradation products. The limit of detection and quantitation for ivermectin was 26.80 ng/mL and 81.22 ng/mL, respectively. The limit of detection and quantitation for praziquantel was 1.39 µg/mL and 4.22 µg/mL, respectively. The robustness study proved that method performance is stable against small variations in sample processing parameters (shaking, sonication time, and acetonitrile % in solvent solution) and also against small variations in the initial % of mobile phase components and gradient slope. Using ICH Q2R2 criteria, the method was demonstrated to be specific, accurate, stability indicating, and robust to small variations of chromatographic variables.

Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans.

PURPOSE: Despite no broad, direct evidence in humans, there is a potential concern that surfactants alter active or passive drug intestinal permeation to modulate oral drug absorption. The purpose of this study was to investigate the impact of the surfactant polysorbate 80 on active and passive intestinal drug absorption in humans. METHODS: The human (n = 12) pharmacokinetics (PK) of three probe substrates of intestinal absorption, valacyclovir, chenodeoxycholic acid (CDCA), and enalaprilat, were assessed. Endogenous bile acid levels were assessed as a secondary measure of transporter and microbiota impact. RESULTS: Polysorbate 80 did not inhibit peptide transporter 1 (PepT1)- or apical sodium bile acid transporter (ASBT)-mediated PK of valacyclovir and CDCA, respectively. Polysorbate 80 did not increase enalaprilat absorption. Modest increases in unconjugated secondary bile acid Cmax ratios suggest a potential alteration of the in vivo intestinal microbiota by polysorbate 80. CONCLUSIONS: Polysorbate 80 did not alter intestinal membrane fluidity or cause intestinal membrane disruption. This finding supports regulatory relief of excipient restrictions for Biopharmaceutics Classification System-based biowaivers.

A method for the tribological assessment of oral pharmaceutical liquids.

OBJECTIVE: Patient acceptance of pediatric formulations is critical to compliance and consequently therapeutic outcomes; thus, having an in vitro method to evaluate sensory perception of pharmaceutical products would be beneficial. The objective of this research is to develop a sensitive and reproducible tribological method to characterize pharmaceutical suspensions at low force and sliding speeds. METHODS: The discriminating potential of the method was examined using tribology profiles (coefficient of friction (COF) vs. sliding speed) for commercially available products and products made for this study with widely varying sweetness, thickness, and grittiness; these formulations were used to judge the sensitivity of the method. Samples were measured using 3M Transpore™ surgical tape to simulate the tongue surface, steel half ring geometry, constant gap setting, target axial force of 2 N in a 600 s exponential ramp for rotation speed. RESULTS: The COF ranged from 0.1 to 0.6. For the speeds studied, the high viscosity commercial suspension ibuprofen drops and acetaminophen suspension show a classic Stribeck curve with an increasing COF at the higher rotation speeds, which indicates these formulations entered the hydrodynamic lubrication phase, while the lower viscosity suspensions only reached the mixed lubrication phase. CONCLUSION: The contribution of particles affects the COF in a dynamic tribologic pattern compared to products that are categorized as either low gritty or high viscosity. These results are important as they provide a potentially rapid in vitro method for screening pediatric medications and help to identify the factors that affect the palatability of pediatric formulations.

Formulation of smokeless tobacco products with a wide range of pH to study nicotine pharmacokinetics and pharmacodynamics.

The rate of nicotine absorption from tobacco products is a determinant of addiction potential and other detrimental health effects. Oral nicotine bioavailability from moist snuff smokeless tobacco (ST) is influenced by nicotine content, pH, flavors, and tobacco cut. For use in a clinical study testing the effect of pH on nicotine pharmacokinetics, four investigational ST products that differed only in pH were produced. A commercial ST product (Copenhagen Long Cut Original, pH 7.7) was modified with citric acid monohydrate (23 mg/g tobacco) or sodium carbonate (4.6 and 11 mg/g) to create products with pH 5.0, 8.2, and 8.6, respectively. All products - including the original product with pH 7.7 - were individually packaged (approximately 2 g) in aluminum foil pouches and stored frozen (-20 °C); pH, nicotine, tobacco-specific nitrosamines, moisture content, and mold and yeast counts were tested for up to 19 months to verify stability. Remarkable stability was demonstrated in this packaging/storage combination. For example, pH from all products were within 0.1 pH units and never exceeded 0.2 units. Nicotine concentration averaged 9.07 mg/g at baseline, maximal deviations from baseline in the four products averaged 0.30 mg/g. Similarly, TSNA, moisture content, yeast, and mold did not materially change. This study illustrates a method of investigational tobacco products formulation by manipulating a single design feature (or component) with the purpose of independently and systematically assessing its influence on nicotine bioavailability in a clinical study.

Cholecalciferol complexation with hydroxypropyl-ß-cyclodextrin (HPBCD) and its molecular dynamics simulation.

The focus of the current study is to investigate cholecalciferol (vitamin D3) solubilization by hydroxypropyl-ß-cyclodextrin (HPBCD) complexation through experimental and computational studies. Phase solubility diagram of vitamin D3 (completely insoluble in water) has an AP profile revealing a deviation from a linear regression with HPBCD concentration increase. Differential scanning calorimetry (DSC) is the best tool to confirm complex formation by disappearance of cholecalciferol exothermic peak in cholecalciferol-HPBCD complex thermogram, due to its amorphous state by entering HPBCD inner hydrophobic cavity, similarly validated by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). AP solubility diagram profile can be associated with cholecalciferol-HPBCD complex instability in liquid phase requiring spray drying to bring it to a solid dispersion state (always more stable) illustrated by scanning electron microscopy (SEM). Computational studies led to a deeper understanding and clarification, at molecular level, of the interactions within cholecalciferol-HPBCD complex. Thermodynamics and geometry of the complex were investigated by molecular dynamics (MD) simulation.

Surface Characterization as a Tool for Identifying the Factors Affecting the Dissolution Rate of Amorphous Solid Dispersion Tablets.

An amorphous solid dispersion (ASD) is a commonly used approach to enhancing the dissolution of poorly aqueous soluble drugs. Selecting the desired polymer and drug loading can be time-consuming. Surface properties, such as surface composition and wetting behavior, are essential factors controlling the dissolution of ASD tablets. Thus, our study aims to use surface characterization to understand the factors that affect the dissolution rate of ASD tablets. In this work, we prepared ASDs with itraconazole and hypromellose acetate succinate (HPMCAS) using spray drying. ASDs were prepared using three grades of HPMCAS and different drug loading levels (10%, 30%, and 50%). We prepared ASD tablets with two porosities. For each tablet, contact angles were measured using the Drop Shape Analyzer; surface free energies, disperse, and polar fractions were calculated based on the contact angles. We conducted near-infrared (NIR) and dissolution measurements of ASD tablets. Principal component analysis (PCA) was carried out to investigate the NIR spectra further. The relative PCA scores were reported with other sample properties. A partial least square (PLS) model using NIR scores, tablets' wetting properties, and dissolution rates revealed that water and buffer contact angles, surface free energy, and polar fraction are the most significant factors attributing to the dissolution rate of ASD tablets. This work understood the interplay between the surface properties and the dissolution rate of ASD tablets. Moreover, surface characterization can be the tool to screen the formulation and compaction process of ASD tablets in early development.

Understanding the impact of magnesium stearate variability on tableting performance using a multivariate modeling approach.

The objective of this research is to understand how the properties of magnesium stearate (MgSt) affect product performance in a quantitative manner using a multivariate modeling approach. In addition, we explored the feasibility of using NIR and Raman spectra as a surrogate measurement of physiochemical properties in prediction of performance in tablet direct compression. Partial least square models to predict performance attributes (PAs) from MgSt properties or spectra were developed and validated. The model input variables are MgSt physiochemical properties, spectra, key formulation and process parameters. Material physiochemical properties include fatty acid composition, loss on drying, densities, particle size distribution, specific surface area, and solid state properties. The key formulation and process parameters include MgSt concentration, filler type and compression force. The output variables are PAs including tablet ejection force, breaking force and disintegration time. It was found that the prediction of MgSt performance from its properties greatly depends on filler type and PAs of interest. NIR spectra successfully predicted lubricant performance in lactose tablet; however, predictions from Raman spectra were not acceptable. In the cases that the contributing physiochemical properties in performance prediction are sufficiently captured in the spectra, the spectra can be used as an alternative tool to predict excipient performance.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900 min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60 min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60 min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

Probing Thermal Stability of Proteins with Temperature Scanning Viscometer.

Thermal stability is essential for the understanding of protein stability and is a critical quality attribute of therapeutic biologics, including enzymes, fusion proteins, monoclonal antibodies, etc. The commonly used analytical methods, such as differential scanning calorimetry (DSC), differential scanning fluorimetry (DSF), and circular dichroism (CD), have their limitations in measuring protein thermal stability. Through this work, we described a novel method to probe the thermal stability of proteins in various formulations using a temperature scanning viscometer. The viscosity of the material was plotted against the temperature, and the peak in the first derivative of the viscosity versus temperature was shown to be related to the protein melting temperature. The measured melting temperature of bovine serum albumin (BSA) at a concentration of 1 mg/mL in phosphate buffer was 63 °C, which was close to the value of 64 °C obtained by DSC. The unfolding of BSA was confirmed using orthogonal techniques of second derivative ultraviolet-visible (UV-vis) spectroscopy and dynamic light scattering (DLS). This method was also able to reveal the microenvironment changes of proteins, including formulation effects. Other multiple domains proteins including lysozyme and IgG were also tested using this method and showed comparable melting temperatures with DSC. This work showed the feasibility of using a temperature scanning viscometer to measure the thermal stability of proteins in diverse formulation matrices with wider protein concentration ranges.

Prediction of Dissolution of Sustained Release Coated Ciprofloxacin Beads Using Near-infrared Spectroscopy and Process Parameters: a Data Fusion Approach.

The aim of the work is to develop a data fusion model using near-infrared (NIR) and process parameters for the predictions of drug dissolution from controlled release multiparticulate beads. Using a design of experiments, ciprofloxacin-coated beads were manufactured and critical process parameters such as air volume, product temperature, curing temperature, and curing time were measured; environmental humidity was monitored using a Pyrobuttons®. The NIR spectra were decomposed using principal component analysis (PCA). The PCA scores were fused with process measurements and all variables were autoscaled. The autoscaled variables were regressed against measured dissolution data at 1 h and 2 h time points; the PLS regression used quadratic and cross terms. The NIR spectra only model using data collected at the end of bead curing generated a PLS model using 5 latent variables with R2 equal to 0.245 and 0.299 and RMSECV 13.23 and 13.12 for the 1 h and 2 h dissolution time points, respectively. The low R2 and high root mean square error of cross validation (RMSECV) values indicate that NIR spectra alone were insufficient to model the drug release. Similar results were obtained for NIR model using data collected at the end of spraying phase. Models with fused spectral and process data yielded better prediction with R2 above 0.88 and RMSECV less than 5% for the 1 h and 2 h dissolution time points. The data fusion model predicted dissolution profiles with an error less than 10%.

Decision Support for Excipient Risk Assessment in Pharmaceutical Manufacturing.

Excipients have always been a key input into pharmaceutical products, profoundly affecting product quality. Currently, most of our knowledge of excipient critical quality attributes is empirical, gained through experience, and shared through publications and other sources. The behavior of excipients is complicated, with many different failure modes that depend on the type of dosage form. Even within the same dosage form, there can be multiple failure modes depending on the manufacturing method. This complex behavior creates many possible combinations to assess when designing a formulation or evaluating regulatory submissions. Formulation science could be improved if data from different sources could be made widely available through an interactive system using a consistent, structured format to help formulators and regulators assess the risk of excipient usage for a particular dosage form with a particular manufacturing method. This paper describes a decision support system that was created for assessing excipient risk in different types of formulations and considering different types of manufacturing methods, dosage forms, and excipient functionality. The Excipient Risk Assessment System consists of a database that stores knowledge about factors that affect formulation design and a decision support processor that manages selections for creating formulation scenarios and assigning risk. Formulation and risk assessment data are provided by formulation science experts. This enables the system to assess compatibility among excipients, functionality, dosage forms, and manufacturing methods selected for formulations. The interface guides users through the creation of formulation scenarios and displays customized, interactive risk assessment reports for users to search and explore.

Utility of Films to Anticipate Effect of Drug Load and Polymer on Dissolution Performance from Tablets of Amorphous Itraconazole Spray-Dried Dispersions.

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.

Investigation of Polymer/Surfactant Interactions and Their Impact on Itraconazole Solubility and Precipitation Kinetics for Developing Spray-Dried Amorphous Solid Dispersions.

Methods were developed to systematically screen different polymer-surfactant combinations for the purpose of enhancing amorphous active pharmaceutical ingredient (API) solubility while maintaining its physical stability. Itraconazole (ITZ) was chosen as the model API mostly due to its low aqueous solubility. Special attention was paid to determine the effect of a reduction in the critical micelle concentration (CMC) by specific polymer/surfactant combinations on the ITZ solubility and physical stability. However, only a slight correlation was actually found. Only the polymer/surfactant combinations with the smallest effect on CMC improved solubility and stability of ITZ in simulated intestinal fluids (SIF). Surfactants were found to negate the stabilizing effects of polymers. ITZ crystallization tendency generally depended on the degree of supersaturation and the type of polymer/surfactant combinations used. In general, we found that instead of focusing solely on reducing the CMC, a systematic screening of systems that maintain high ITZ supersaturation proved to be a successful approach.

Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS).

OBJECTIVE: The monitoring and evaluation of sintering-induced tablet strength of a polyethylene oxide (PEO) based placebo tables was accomplished using infrared spectroscopy (NIRS). SIGNIFICANCE: Evaluation of high molecular weight PEO-based tablet matrices for abuse deterrent formulation applications is an analytical challenge. NIRS is one tool that can provide physical and chemical evaluation of this polymer and tablet system. In addition, the use of NIRS as a process analytical tool (PAT) to monitor oven sintering of pharmaceutical tablets has not been recorded in the literature. The multiplicative scattering correction (MSC) algorithm was also successfully applied as a new and fast way to calculate NIRS spectral slopes and intercepts to build models against tablet tensile strength with respect to sinter time. METHODS: Both spectral slope regression (SSR) and spectral intercept regression (SIR) models were compared to commonly used partial least squares analysis (PLS) to evaluate placebo PEO based pharmaceutical tablets comprised of PEO at 70, 50, 30% w/w that were compressed at two solid fraction (SF) levels. RESULTS: All three regression techniques, PLS, SSR, SIR, were evaluated for robustness and reliability and physical relevancy to the system studied. The methods were ranked in utility with SSR being the best method followed by SIR then PLS. CONCLUSIONS: The MSC algorithm was presented to quickly calculate spectral slopes and intercepts for use in SSR and SIR analysis. SSR models were successfully applied and assessed as the optimal modeling technique to monitor sintering of PEO-based matrix tablets.

In Vitro Assessment of Nasal Insufflation of Comminuted Drug Products Designed as Abuse Deterrent Using the Vertical Diffusion Cell.

In vitro evaluation of abuse deterrent formulations (ADFs) is a challenge since real abuse situations are variable and ADF technology is evolving. Specifically, an assessment of an ADF to deter nasal insufflation would be valuable. In this study, a vertical diffusion cell (VDC) was used to evaluate polyethylene oxide (PEO)-based tablets manipulated by three different forces. The commercially available products Oxycontin®, an ADF, Opana®, and metoprolol tartrate tablet formulations made in our laboratory were studied. Particle size distribution and percent recovery of manipulated tablets were measured. Grinding produced the lowest recovery and the smallest particle size distribution. Drug release was examined using a VDC by placing the dry comminuted particles on an enclosed wetted cellulose membrane. Dispensing dry particles on a VDC is atypical but includes some key features associated with an abuse situation where once the particles are snorted, the moisture in the nasal mucosa activates hydration and swelling of the polymers in the formulation, retarding drug release. Drug release from OxyContin®, Opana®, and metoprolol tablets were analyzed for the cutting, grinding, and milling modes of abuse. The analysis showed that in most cases, the mode of abuse produced different particle sizes with different release rates. Statistically different release rates were observed for metoprolol tablets made with different molecular weight PEO and with different porosities. These results indicate that within detection limits, the VDC can be used to quantitate release differences due to various modes of abuse used in this study.

Comparing a Statistical Model and Bayesian Approach to Establish the Design Space for the Coating of Ciprofloxacin HCl Beads at Different Scales of Production.

The primary objective of this study was to compare two methods for establishing a design space for critical process parameters that affect ethylcellulose film coating of multiparticulate beads and assess this design space validity across manufacturing scales. While there are many factors that can affect film coating, this study will focus on the effects processing conditions have on the quality and extent of film formation, as evaluated by their impact coating yield and drug release. Ciprofloxacin HCl layered beads were utilized as an active substrate core, ethylcellulose aqueous dispersion as a controlled release polymer, and triethyl citrate as a plasticizer. Thirty experiments were conducted using a central composite design to optimize the coating process and map the response surface to build a design space using either statistical least squares or a Bayesian approach. The response surface was fitted using a linear two-factor interaction model with spraying temperature, curing temperature, and curing time as significant model terms. The design spaces established by the two approaches were in close agreement with the statistical least squares approach being more conservative than the Bayesian approach. The design space established for the critical process parameters using small-scale batches was tested using scale-up batches and found to be scale-independent. The robustness of the design space was confirmed across scales and was successfully utilized to establish process signature for the coating process.

A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

PURPOSE: There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn's Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads. METHODS: In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT® FS 30 D to develop a colonic delivery system. The secondary and tertiary structure change and aggregation of BSA during spray layering process was examined. The BSA layered beads were then challenged in an accelerated stability study using International Council for Harmonization (ICH) conditions. The in vitro release of BSA from enteric coated beads was examined using United States Pharmacopeia (USP) dissolution apparatus 1. RESULTS: No significant changes in the secondary and tertiary structure or aggregation profile of BSA were observed after the spray layering process. Degradation of BSA to different extents was detected after storing at 25°C and 40°C for 38 days. Enteric coated BSA beads were intact in acidic media while released BSA in pH 7.4 phosphate buffer. CONCLUSION: We showed the feasibility of delivering proteins to colon in vitro using multiparticulate system.

A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process.

The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.