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.

     

3D Printed “Starmix” Drug Loaded Dosage Forms for Paediatric Applications

Purpose

Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print “candy – like” formulations by imitating Starmix® sweets to prepare paediatric medicines with enhanced palatability.

Methods

Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix® objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug – excipient interactions and the content uniformity.

Results

Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60 min.

Conclusions

3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix® designs.

     

Immediate Release 3D-Printed Tablets Produced Via Fused Deposition Modeling of a Thermo-Sensitive Drug

Purpose

Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium.

Methods

Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures.

Results

Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min.

Conclusions

The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.

     

Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying

Purpose

The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders.

Methods

Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray drying process. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders.

Results

XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio.

Conclusions

Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.

     

Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament

Purpose

The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM.

Methods

A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments.

Results

Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts.

Conclusion

The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer.

     

Visualization and Non-Destructive Quantification of Inkjet-Printed Pharmaceuticals on Different Substrates Using Raman Spectroscopy and Raman Chemical Imaging

Purpose

The purpose of this study was to investigate the applicability of Raman spectroscopy for visualization and quantification of inkjet-printed pharmaceuticals.

Methods

Haloperidol was used as a model active pharmaceutical ingredient (API), and a printable ink base containing lactic acid and ethanol was developed. Inkjet printing technology was used to apply haloperidol ink onto three different substrates. Custom-made inorganic compacts and dry foam, as well as marketed paracetamol tablets were used as the substrates.

Results

Therapeutic personalized doses were printed by using one to ten printing rounds on the substrates. The haloperidol content in the finished dosage forms were determined by high-performance liquid chromatography (HPLC). The distribution of the haloperidol on the dosage forms were visualized using Raman chemical imaging combined with principal components analysis (PCA). Raman spectroscopy combined with modeling by partial least squares (PLS) regression was used for establishment of a quantitative model of the haloperidol content in the printed dosage forms. A good prediction of the haloperidol content was achieved for the inorganic compacts, while a slightly poorer prediction was observed for the paracetamol tablets. It was not possible to quantify haloperidol on the dry foam due to the low and varying density of the substrate.

Conclusions

Raman spectroscopy is a useful tool for visualization and quality control of inkjet printed personalized medicine.

     

Three-Dimensional Printing of Cell Exclusion Spacers (CES) for Use in Motility Assays

Purpose

Cell migration/invasion assays are widely used in commercial drug discovery screening. 3D printing enables the creation of diverse geometric restrictive barrier designs for use in cell motility studies, permitting on-demand assays. Here, the utility of 3D printed cell exclusion spacers (CES) was validated as a cell motility assay.

Methods

A novel CES fit was fabricated using 3D printing and customized to the size and contour of 12 cell culture plates including 6 well plates of basal human brain vascular endothelial (D3) cell migration cells compared with 6 well plates with D3 cells challenged with 1uM cytochalasin D (Cyto-D), an F-actin anti-motility drug. Control and Cyto-D treated cells were monitored over 3 days under optical microscopy.

Results

Day 3 cell migration distance for untreated D3 cells was 1515.943μm?±?10.346μm compared to 356.909μm?±?38.562μm for the Cyt-D treated D3 cells (p?<?0.0001). By day 3, untreated D3 cells reached confluency and completely filled the original voided spacer regions, while the Cyt-D treated D3 cells remained significantly less motile.

Conclusions

Cell migration distances were significantly reduced by Cyto-D, supporting the use of 3D printing for cell exclusion assays. 3D printed CES have great potential for studying cell motility, migration/invasion, and complex multi-cell interactions.

     

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

Purpose

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.

Method

Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.

Results

Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.

Conclusions

SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

     

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology

Purpose

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles.

Methods

NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references.

Results

NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C _max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation.

Conclusion

Controlled release of integral NLCs is achieved by the osmotic pump strategy.

     

Valvejet Technology for the Production of a Personalised Fixed Dose Combination of Ramipril and Glimepiride: an Investigative Study on the Stability of Ramipril

Purpose

To use valvejet technology for printing a fixed dose combination of ramipril and glimepiride, and to investigate the stability profile of ramipril, which is susceptible to a range of processing and storage conditions.

Methods

Inks of ramipril and glimepiride were formulated and printed on to HPMC film and the films were evaluated for the chemical and solid-state integrity of the APIs using HPLC and XRPD. The stability of the APIs in the inks and in the printed samples was investigated using Raman and NMR techniques.

Results

The printed samples demonstrated excellent precision and accuracy in the doses of APIs deposited. Both drugs were chemically intact in the freshly printed samples and ramipril was found to be in its amorphous form. Ramipril in the printed samples has transformed into ramipril diketopiperazine when stored at 40°C with 75% RH, but remained stable when stored in a desiccator. Results from the stability study of ramipril ink show that the API has undergone degradation when stored both at room temperature and at 40°C but remained stable when stored in a refrigerator.

Conclusion

An FDC of ramipril and glimepiride was successfully printed using valvejet technology. The significance of inkjet printing in producing amorphous dosage forms from solution based inks and personalised dosage forms of drugs susceptible to processing conditions was demonstrated using ramipril. This study illustrates the significance of examining the stability of the APIs in the inks and the importance of appropriate storing of both the inks and printed samples.

     

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.

     

Lyophilized Nanosuspensions for Oral Bioavailability Improvement of Insoluble Drugs: Preparation,Characterization, and Pharmacokinetic Studies

Purpose

We describe here a novel lyophilized nanosuspension technology in order to improve the dissolution rate and oral bioavailability of the insoluble drug P2X7 receptor antagonist (PRA), which is an effective antagonist to P2X7 receptor for non-steroidal anti-inflammatory.

Methods

PRA-lyophilized nanosuspension (PRA-LNS) was fabricated by anti-solvent precipitation in combination with high pressure homogenization, and then lyophilized for prolonged storage. After preparations, various characterization experiments were performed including particle size, zeta potential, surface morphology, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), in vitro dissolution study, and in vivo pharmacokinetic study.

Results

The re-dissolved particle size of PRA-LNS was about 180~250 nm with uniform distribution, confirmed by TEM image. The drug PRA in nanosuspensions possessed crystalline form evaluated via XRPD and DSC analysis. The solubility of PRA-LNS in water was 1.52 times larger than PRA raw drug; in vitro dissolution tests showed that PRA-LNS could dissolve completely within 5 min, which is a significant improvement compared to the raw drug. The relative bioavailability of PRA-LNS is 290.70% compared to the raw drug and 177.94% compared to the physical mixture.

Conclusions

PRA-LNS could easily re-disperse in water with increased solubility, enhanced oral bioavailability, and controllable production process.

     

Preparation,Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded PLGA-Glucosamine Nanoparticles

Purpose

Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.

Method

Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, ¹H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.

Results

The spectra of ¹H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.

Conclusion

PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.

     

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats

Rationale

It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.

Objectives

The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.

Materials and methods

Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.

Results

Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.

Conclusion

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

     

Subdivision of Tablets Containing Modified Delivery Technology: the Case of Orally Disintegrating Tablets

Purpose

Clinical practice suggests orally disintegrating tablets (ODTs) may be subdivided for dose adjustments, however there are no studies evaluating the effect of this practice in ODTs quality parameters. This work was therefore dedicated to elucidating the impact of the tablet subdivision on ten selected ODTs produced by different technologies.

Methods

Structural properties were assessed using weight; dimensions; image analysis; moisture content and porosimetry evaluations. Functional evaluations were also performed by disintegration and wetting assays. Tablets were evaluated just after subdivision and after an accelerated aging.

Results

Outcomes suggest the manufacturing method plays an important role in the suitability of ODTs for subdivision. While tablets containing granules immersed in a powdered matrix structure showed poor subdivision performance, with high weight variation and weight loss, tablets obtained by freeze-drying or direct compression of powder mixtures showed acceptable levels of these parameters and could be subdivided for immediate use. Aged tablets revealed structural and/or functional damages for all analyzed drug products, which includes softening of their matrices, water uptake and darkening, with loss of their disintegration and wetting capacities, which suggest inadequacy of ODTs subdivision for later use.

Conclusions

The results exposed in this study could be useful for the clinical decision on the subdivision of this tablets category.

     

Pediatric Dispersible Tablets: a Modular Approach for Rapid Prototyping

Purpose

The design of pediatric formulations is challenging. Solid dosage forms for children have to meet the needs of different ages, e.g. high number of dosing increments and strengths. A modular formulation strategy offering the possibility of rapid prototyping was applied. Different tablet compositions and the resulting tablet characteristics were investigated for dispersible tablets using customized analytical methods.

Methods

Fluid bed granules were blended with extragranular components, and compressed to tablets. Disintegration behavior was studied with a Texture Analyzer and a Tensiometer.

Results

Methods for determination of disintegration time and water uptake of tablets were developed with a Texture Analyzer, and a Tensiometer, respectively. Twenty-two different tablet formulations were prepared and analyzed with respect to disintegration time, hardness, friability, and viscosity. Multivariate data analysis revealed a high impact of type and amount of viscosity enhancer on the disintegration behavior of tablets. An optimized formulation was selected with a disintegration time of 24 s.

Conclusion

Methods providing additional information on the disintegration behavior of dispersible tablets compared to standard pharmacopoeia methods were established. Selecting the right type and level of viscosity enhancer and superdisintegrant was critical for developing pediatric tablets with a disintegration time of less than 30 s but still pleasant mouth feel.

     

Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of Letrozole and Celecoxib in Breast Cancer Therapy

Purpose

In the current work, we propose a combined delivery nanoplatform for letrozole (LTZ) and celecoxib (CXB).

Methods

Multi-reservoir nanocarriers were developed by enveloping protamine nanocapsules (PRM-NCs) within drug-phospholipid complex bilayer.

Results

Encapsulation of NCs within phospholipid bilayer was confirmed by both size increase from 109.7 to 179.8 nm and reduction of surface charge from +19.0 to +7.78 mV. The multi-compartmental core-shell structure enabled biphasic CXB release with initial fast release induced by complexation with phospholipid shell followed by prolonged release from oily core. Moreover, phospholipid coating provided protection for cationic PRM-NCs against interaction with RBCs and serum proteins enabling their systemic administration. Pharmacokinetic analysis demonstrated prolonged circulation and delayed clearance of both drugs after intravenous administration into rats. The superior anti-tumor efficacy of multi-reservoir NCs was manifested as powerful cytotoxicity against MCF-7 breast cancer cells and marked reduction in the mammary tumor volume in Ehrlich ascites bearing mice compared with free LTZ-CXB combination. Moreover, the NCs induced apoptotic caspase activation and marked inhibition of aromatase expression and angiogenic marker, VEGF as well as inhibition of both NFκB and TNFα.

Conclusions

Multi-reservoir phospholipid shell coating PRM-NCs could serve as a promising nanocarrier for parenteral combined delivery of LTZ and CXB.

     

A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting

Purpose

Although the bonding area (BA) and bonding strength (BS) interplay is used to explain complex tableting behaviors, it has never been experimentally proven. The purpose of this study is to unambiguously establish the distinct contributions of each by decoupling the contributions from BA and BS.

Methods

To modulate BA, a Soluplus® powder was compressed into tablets at different temperatures and then broken following equilibration at 25°C. To modulate BS, tablets were equilibrated at different temperatures. To simultaneously modulate BA and BS, both powder compression and tablet breaking test were carried out at different temperatures.

Results

Lower tablet tensile strength is observed when the powder is compressed at a lower temperature but broken at 25°C. This is consistent with the increased resistance to polymer deformation at lower temperatures. When equilibrated at different temperatures, the tensile strength of tablets prepared under identical conditions increases with decreasing storage temperature, indicating that BS is higher at a lower temperature. When powder compression and tablet breaking are carried out at the same temperature, the profile with a maximum tensile strength at 4°C is observed due to the BA-BS interplay.

Conclusion

By systematically varying temperature during tablet compression and breaking, we have experimentally demonstrated the phenomenon of BA-BS interplay in tableting.

     

Budesonide Loaded PLGA Nanoparticles for Targeting the Inflamed Intestinal Mucosa—Pharmaceutical Characterization and Fluorescence Imaging

Purpose

The purpose of this study was to evaluate the specifically targeted efficiency of budesonide loaded PLGA nanoparticles for the treatment of inflammatory bowel disease (IBD).

Methods

The nanoparticles were prepared by an oil/water (O/W) emulsion evaporation technique. The nanoparticles were characterized for their size, shape and in vitro drug release profile. Solid state characterization was carried out by differential scanning calorimetry (DSC) and X-ray Power diffraction (XPRD). In order to evaluate the targeted efficiency of nanoparticles, a particle localization study in the healthy and in the inflamed colon was determined in vivo. These data were complemented by cryo-sections.

Results

Nanoparticles were 200?±?05 nm in size with a smooth and spherical shape. The encapsulation efficiency was around 85?±?3.5%, which was find-out by both, direct and indirect methods. Release of budesonide from the nanoparticles showed a biphasic release profile with an initial burst followed by sustained release. XPRD data revealed that the drug in the polymer matrix existed in crystalline state. Nanoparticles accumulation in inflamed tissues was evaluated by in-vivo imaging system and it was found that particles are accumulated in abundance at the site of inflammation when compared to the healthy group.

Conclusion

The study demonstrates that the budesonide loaded PLGA nanoparticles are an efficient delivery system for targeted drug delivery to the inflamed intestinal mucosa.

     

Effects of Pump Pulsation on Hydrodynamic Properties and Dissolution Profiles in Flow-Through Dissolution Systems (USP 4)

Purpose

To clarify the effects of pump pulsation and flow-through cell (FTC) dissolution system settings on the hydrodynamic properties and dissolution profiles of model formulations.

Methods

Two FTC systems with different cell temperature control mechanisms were used. Particle image velocimetry (PIV) was used to analyze the hydrodynamic properties of test solutions in the flow-through dissolution test cell. Two pulsation pumps (semi-sine, full-sine) and a non-pulsatile pump were used to study the effects of varied flows on the dissolution profiles of United States Pharmacopeia standard tablets.

Results

PIV analysis showed periodic changes in the aligned upward fluid flow throughout the dissolution cell that was designed to reduce the temperature gradient during pump pulsation (0.5 s/pulse). The maximum instantaneous flow from the semi-sine pump was higher than that of the full-sine pump under all conditions. The flow from the semi-sine wave pump showed faster dissolution of salicylic acid and prednisone tablets than those from other pumps. The semi-sine wave pump flow showed similar dissolution profiles in the two FTC systems.

Conclusions

Variations in instantaneous fluid flow caused by pump pulsation that meets the requirements of pharmacopoeias are a factor that affects the dissolution profiles of tablets in FTC systems.