<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status

Purpose

To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status.

Methods

A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent.

Results

Erosion was best described by a Michaelis–Menten type model. The maximal HPMC release rate (V_MAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of V_MAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm).

Conclusions

The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

     

Influence of HPMC K100LV and Compritol® HD5 ATO on Drug Release and Rheological Behavior of HPMC K4M Matrix Tablets

Purpose

The objectives of this study were to develop once-a-day oral controlled-release tablets of quetiapine fumarate (QF) and to determine the effect of polymer type, viscosity grade, polymer ratio, and polymer rheological properties on the rate of QF release from hydroxypropyl methylcellulose (HPMC) matrix tablets.

Methods

Tablets were prepared from low-viscosity-grade HPMC K100LV (K100LV), high-viscosity-grade HPMC K4M (K4M), Compritol® HD5 ATO (PEGylated glyceryl behenate (PGB)), and binary combinations of these polymers. In vitro drug release from all tablets was evaluated over 24 h.

Results

In vitro drug release studies revealed that formulations containing K100LV/K4M and PGB/K4M at a ratio of 170:70 resulted in similar release profiles which extended for 24 h (f2 > 50). QF release kinetics followed either diffusion, anomalous transport, case II transport, or super case II transport, as fitted by the Korsmeyer-Peppas model. Tablet swelling and erosion studies were consistent with dissolution profiles. A linear relationship between % swelling and % QF released was observed in tablets containing K4M alone or in combination with K100LV or PGB, indicating the direct role of polymer swelling in controlling the mechanism of drug release. The viscoelastic properties of single and binary polymeric gels made with the three polymers (K100LV, K4M, and PGB) corroborated the in vitro release studies of QF tablets.

Conclusions

Our results provide evidence that blending polymers with different viscosities and hydrophilicities can result in unique matrices with tunable release profiles.

     

Development of a Clinically Relevant Dissolution Method for Metaxalone Immediate Release Formulations Based on an IVIVC Model

Purpose

The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC).

Methods

Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method.

Results

Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability.

Conclusion

The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.

     

Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations

Purpose

The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.

Methods

The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.

Results

Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.

Conclusions

Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.

     

HPMC-Eudragit-Based Gastro-retentive Hydrodynamically Balanced System—Suitable for Sparingly Soluble and Freely Soluble Drugs: an In Vitro Study

Purpose

In this study HPMC-eudragit based hydrodynamically balanced capsules of two model drugs; propranolol HCl and ofloxacin were prepared with the aim to have the gastric retention of the systems for longer periods of time with desired sustained/ controlled drug release.

Methods

Gastro-retentive capsules were prepared by simple physical blending of various low density polymers and filling into capsules. These capsules were subjected to in vitro buoyancy/ matrix integrity and dissolution studies. Weight variation, content uniformity test, UV spectral analysis and placebo interaction studies were also performed.

Results

Preliminary studies revealed that high soluble drug required higher polymer ratios to sustain drug release and maintain matrix integrity/ buoyancy than low soluble drug. In both the cases, with increase in HPMC and eudragit S100 levels there was an increase in matrix integrity and decrease in drug release rate, however much higher levels of eudragit S100 decreased matrix integrity and buoyancy. Lactose (release rate modifier) decreased matrix integrity, buoyancy and increased drug release. Mechanism of release in the both cases was found to be anomalous "non-fickian".

Conclusion

From this research and the literature available on the eudragit and HPMC matrix systems, it is evident that different categories of drugs (suitable for gastric retention), ranging from freely soluble to sparingly soluble can be suitably formulated as HPMCeudragit based GR HBS capsules with desired drug release characteristics, provided no chemical instability/ incompatibility occurs between the drug and the polymers.

     

Determining The Pressure-Generating Capacity of The Classical and Alternative In Vitro Dissolution Methods Using a Wireless Motility Capsule

Purpose

In vitro dissolution tests are an important tool for prediction of in vivo behavior of pharmaceutical dosage forms. One of the main reasons behind poor in vitro-in vivo correlation is the lack of knowledge about the true in vivo conditions and the failure to replicate them adequately in vitro. The objective of this study was to investigate the conditions during the dissolution testing in terms of their capability to generate the biorelevant pressure values that orally administered dosage forms are exposed to in vivo.

Methods

Using the SmartPill®, three classical dissolution systems (USP 1–3) were subjected to the pressure measurements. With USP 3, the addition of plastic beads was also examined. Additionally, two novel in vitro dissolution models capable of simulating the peristaltic action were also investigated, namely, the advanced gastric simulator (AGS) and the intestine model for simulating the peristaltic action (IMSPA).

Results

The USP 1 and USP 2 systems showed no significant pressure readings, while the USP 3 (and especially its combination with plastic beads) showed measurable pressure peaks but still below the reported in vivo values. The AGS and the IMSPA, on the other hand, offered precise and repeatable controlled contractions of a silicone container resulting in the maximum pressure values very close to the reported in vivo measurements by the SmartPill® device.

Conclusions

The results therefore support the in vivo relevance of the newly developed AGS and IMSPA models and present their potential for further optimization of dissolution testing methods.

     

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine

Introduction

Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations.

Methods

An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations.

Results

In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG.

Conclusion

The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

     

Iron-Based Metal-Organic Frameworks as a Theranostic Carrier for Local Tuberculosis Therapy

Purpose

The purpose of the study was initial evaluation of applicability of metal organic framework (MOF) Fe-MIL-101-NH₂ as a theranostic carrier of antituberculous drug in terms of its functionality, i.e. drug loading, drug dissolution, magnetic resonance imaging (MRI) contrast and cytotoxic safety.

Methods

Fe-MIL-101-NH₂ was characterized using X-ray powder diffraction, FTIR spectrometry and scanning electron microscopy. The particle size analysis was determined using laser diffraction. Magnetic resonance relaxometry and MRI were carried out on phantoms of the MOF system suspended in polymer solution. Drug dissolution studies were conducted using Franz cells. For MOF cytotoxicity, commercially available fibroblasts L929 were cultured in Eagle’s Minimum Essential Medium supplemented with 10% fetal bovine serum.

Results

MOF particles were loaded with 12% of isoniazid. The particle size (3.37–6.45 μm) depended on the micronization method used. The proposed drug delivery system can also serve as the MRI contrast agent. The drug dissolution showed extended release of isoniazid. MOF particles accumulated in the L929 fibroblast cytoplasmic area, suggesting MOF release the drug inside the cells. The cytotoxicity confirmed safety of MOF system.

Conclusions

The application of MOF for extended release inhalable system proposes the novel strategy for delivery of standard antimycobacterial agents combined with monitoring of their distribution within the lung tissue.

     

Velocity Field Visualization in USP Dissolution Apparatus 3 Using Particle Image Velocimetry

Purpose

The hydrodynamics in USP dissolution apparatus 3, at five different dip rates, was characterized by analyzing phase-averaged velocity fields obtained using Particle Image Velocimetry (PIV).

Methods

Phase locked 2 Component-PIV (2C–PIV) measurements were recorded on a typical dissolution apparatus 3 configuration with a black painted tablet fixed at the center of the bottom porous screen of the reciprocating cylinder. A trigger mechanism was employed to capture data over 12 phase positions for each reciprocation cycle. Data were captured over a fixed number of cycles, based on dip rate, and the resultant images were post-processed to obtain phase-averaged velocity fields at each phase.

Results

For all dip rates studied, the sinusoidal nature of the cylinder’s reciprocating motion was evident in the images. The phase positions, in which the cylinder was completely submerged, were characterized by recirculation of liquid through the cylinder, top fitting cap, vessel-cylinder annulus, and bottom fitting cap. The direction of recirculation was opposite for phase positions during the up- and downstrokes. The end positions of the up- and downstrokes were characterized by vortices below and above the cylinder respectively. Increasing dip rates led mainly to increasing velocity magnitudes while all flow characteristics, in general, were retained.

Conclusions

The hydrodynamics in typical USP dissolution apparatus 3 is characterized by cyclic phase-dependent flow fields. Specifically, the velocity field distribution within dissolution apparatus 3 is greatly influenced by the relative position of the top cap to the liquid level in the cylinder.

     

Evaluations of the Effect of Sodium Metabisulphite on the Stability and Dissolution Rates of Various Model Drugs from the Extended Release Polyethylene Oxide Matrices

Purpose

This study examines the effect of sodium metabisulphite (SMB) as an antioxidant on the stability and release of various model drugs, namely, propranolol HCl, theophylline and zonisamide from the polyethylene oxide (PEO) tablets. The antioxidant was used to minimise degradation and instability of the manufactured tablets when stored at 40 °C (55 ± 5% RH) over 8 weeks.

Method

Multiple batches of tablets weighing 240 mg (50% w/w) with a ratio of 1:1 drug/polymer and 1% (w/w) sodium metabisulphite containing different model drugs and various molecular weights of PEO 750 and 303 were produced.

Results

The results indicated that the use of sodium metabisulphite marginally assisted in reducing drug release and degradation via oxidation in propranolol HCl tablets containing both PEO 750 and 303. In the case of poorly and semi-soluble drugs (zonisamide and theophylline), the formulations with both PEO showed entirely superimposable phenomenon and different release profiles compared to control samples (matrices without SMB). DSC study demonstrated the modifications of the polymer due to degradation and observed the effect of SMB on the thermal degradation of the PEO matrices.

Conclusion

The use of antioxidant has assisted in retaining the stability of the manufactured tablets with different model drugs especially those with the highly soluble drug that are susceptible to rapid degradation. This has been reflected by an extended release profile of various drugs used at various stages of the storage time up to 8 weeks.

     

A Workflow-Based Framework for Curating Product Analytical Data and Statistical Results for Lot Release

Purpose

Demonstrate the use of a knowledge management and data curation (KProMS) system to support a collaborative research project involving the generation of extensive critical product quality data and the investigation of alternative statistical sampling/analysis strategies for product release.

Methods

A suite of workflows was developed for the analytical testing and calibration activities associated with the required USP dissolution, HPLC, weight, hardness, and physical dimension measurements. The workflow library also includes the computational steps in the relevant Bayesian and frequentist statistical analyses. The necessary interfaces enabling the transfer of raw data from the instrument output files into KProMS were also implemented. By virtue of a HUB-based implementation of KProMS, all of the details of both laboratory and statistical procedures as well as the resulting data and analysis are web-accessible to all authorized participants.

Results

The system enabled data generation, sharing and harvesting over the web, and seamless integration of activities between groups located in three different locations.

Conclusions

KProMS can be effectively used in routine management of the dosage form quality data in pharmaceutical operations. This would allow industrial laboratories to seamlessly generate data and populate the knowledgebase to track the analysis for product release and for correlation to process control charting.

     

Cilostazol-Loaded Poly(ε-Caprolactone) Electrospun Drug Delivery System for Cardiovascular Applications

Purpose

The study discusses the value of electrospun cilostazol-loaded (CIL) polymer structures for potential vascular implant applications.

Methods

Biodegradable polycaprolactone (PCL) fibers were produced by electrospinning on a rotating drum collector. Three different concentrations of CIL: 6.25%, 12.50% and 18.75% based on the amount of polymer, were incorporated into the fibers. The fibers were characterized by their size, shape and orientation. Materials characterization was carried out by Fourier Transformed Infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vitro drug release study was conducted using flow-through cell apparatus (USP 4).

Results

Three-dimensional structures characterized by fibers diameter ranging from 0.81 to 2.48 μm were in the range required for cardiovascular application. DSC and XRD confirmed the presence of CIL in the electrospun fibers. FTIR and Raman spectra confirmed CIL polymorphic form. Elastic modulus values for PCL and the CIL-loaded PCL fibers were in the range from 0.6 to 1.1 GPa. The in vitro release studies were conducted and revealed drug dissolution in combination with diffusion and polymer relaxation as mechanisms for CIL release from the polymer matrix.

Conclusions

The release profile of CIL and nanomechanical properties of all formulations of PCL fibers demonstrate that the cilostazol loaded PCL fibers are an efficient delivery system for vascular implant application.

     

Design,Preparation and Evaluation of HPMC-Based PAA or SA Freeze-Dried Scaffolds for Vaginal Delivery of Fluconazole

Purpose

Aim of this work was preparation of bioadhesive gel formulations based on Hydroxypropyl methylcellulose (HPMC), Poly(acrylic acid) (PAA) or Sodium alginate (SA) loaded with anise/fluconazole β-cyclodextrin inclusion complexes in 1:2 and 1:3 ratios intended for vaginal applications.

Methods

Freeze-drying method was effectively utilized and superporous morphology was obtained. The superporous morphology of the lyophilized gels, dynamic water vapor sorption measurements, drug release kinetics studies and their antimicrobial activities are presented.

Results

HPMC content influences especially the sorption/desorption behaviour of HPMC-based PAA gels and the morphology of the gel formulations with fluconazole/β-cyclodextrin inclusion complexes, due to the interactions among the gel networks absorbing water molecules. It was found that fluconazole release kinetics correspond to quasi-Fickian, Fickian diffusion and non-Fickian mechanisms for the studied hydrogels. The tested vaginal formulations with β-cyclodextrin inclusion complexes exhibited selectivity toward S. aureus ATCC 25923 and all tested Candida strains in comparison with the gel formulation without β-cyclodextrin.

Conclusions

The fluconazole/β cyclodextrin inclusion complexes ensure a controlled release of fluconazole over a few days, the highest amount of drug release (92%) being observed after 43 h. These bioadhesive gel formulations could be very promising topical alternative for treatment of vaginal fungal infections.

     

Real-Time UV Imaging of Nicotine Release from Transdermal Patch

Purpose

This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.

Methods

The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.

Results

Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.

Conclusion

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

     

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions

Purpose

Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution.

Methods

Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier.

Results

The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner.

Conclusions

Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.

     

A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Purpose

The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.

Methods

Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.

Results

Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.

Conclusions

Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

     

Nimodipine Ophthalmic Formulations for Management of Glaucoma

Purpose

Preparation and evaluation of topical ophthalmic formulations containing nimodipine-CD complexes prepared using HP-β-CD, SBE-β-CD and M-β-CD for the management of glaucoma.

Methods

Nimodipine-CD complexes were prepared using a freeze-drying method. Two different molar ratios (NMD:CD) were used for each cyclodextrin. The inclusion complexes were characterized using DSC, FTIR, yield (%), drug content and in vitro release characteristics. NMD-CD complexes incorporated into chitosan eye drops and a temperature-triggered in situ gelling system were evaluated for their pH, viscosity and in vitro release characteristics. We determined the intraocular pressure (IOP) lowering effect of NMD-hydroxypropylmethylcellulose (HPMC) eye drops through a single dose response design using C57BL/6J mice. The minimum effective concentration (MEC) of nimodipine was further applied to mice that vary in the parental allele of Cacna1s, the drug target of nimodipine. Cytotoxicity was also evaluated.

Results

Our ophthalmic formulations possessed pH and viscosity values that are compatible with the eye. In vitro release of nimodipine was significantly increased from chitosan eye drops containing NMD-CD complexes compared to uncomplexed drug. Administration of nimodipine can lower IOP significantly after a single drop of drug HPMC suspension. The IOP-lowering response of the MEC (0.6%) was significantly influenced by the parental allele of Cacna1s.

Conclusions

Nimodipine can be used as a promising topical drug for management of glaucoma through ocular delivery.

     

Controlled Release from Zein Matrices: Interplay of Drug Hydrophobicity and pH

Purpose

In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine.

Methods

Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from a zein based matrix for drug delivery.

Results

Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models.

Conclusion

The drug state and pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used to influence release kinetics release, thereby broadening the horizon for zein as a tuneable release agent.

     

A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein

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.

     

An Investigation into Formulation and Processing Strategies to Drive Gastroretention of Gabapentin Tablets

Purpose

The aim of the present work was to develop gastroretentive drug delivery system of gabapentin from different matrices prepared by hot melt or conventional wet granulation, which may enhance drug bioavailability. The influence of core type, granulation process, and coating level on the drug release rates was investigated.

Methods

Tablet cores were prepared from hydrophilic system of hypermellose, carboxy melthyl celloulse, and Avicel or hydrophobic system of ethyl cellulose, alginic acid, and stearic acid. The tablets were coated by Eudragit RL with triethyl citrate and compressed directly. These tablets were evaluated according to their in vitro dissolution profiles and release mechanisms.

Results

Hydrophobic matrices allowed the control of drug release. Hot melt granulation was an effective tool over wet granulation or coating for slowing release rates from hydrophobic tablets. Both hydrophobic polymer ratio and coating level influenced the drug release mechanism. The drug release of samples with minor proportion of ethyl cellulose and stearic acid or low Eudragit RL level was driven by anomalous transport and the increase of their proportions contributed to the erosion of the matrix.

Conclusions

Hydrophobic core tablet prepared from hot melt granulation and coated by Eudragit RL has shown to be a promising formulation intended to gastroretentive gabapentin delivery system.