Recent Advances in Bitterness-Sensing Systems.

Bitterness is one of the basic tastes, and sensing bitterness plays a significant role in mammals recognizing toxic substances. The bitter taste of food and oral medicines may decrease consumer compliance. As a result, many efforts have been made to mask or decrease the bitterness in food and oral pharmaceutical products. The detection of bitterness is critical to evaluate how successful the taste-masking technology is, and many novel taste-sensing systems have been developed on the basis of various interaction mechanisms. In this review, we summarize the progress of bitterness response mechanisms and the development of novel sensors in detecting bitterness ranging from commercial electronic devices based on modified electrodes to micro-type sensors functionalized with taste cells, polymeric membranes, and other materials in the last two decades. The challenges and potential solutions to improve the taste sensor quality are also discussed.

Hot-Melt Extrusion-Based Fused Deposition Modeling 3D Printing of Atorvastatin Calcium Tablets: Impact of Shape and Infill Density on Printability and Performance.

The main objective of the current research was to investigate the effect of tablet shapes (heart-shaped and round tablets) and infill densities (50% and 100%) on the drug release profiles of 3D printed tablets prepared by hot-melt extrusion paired with fused deposition modeling techniques. Drug-loaded filaments of 1.5 mm and 2.5 mm diameters were extruded using a Process 11 mm hot-melt extruder employing atorvastatin calcium as a model drug and Kollicoat® IR, Kollidon® VA64, Kollidon® 12PF, and Kolliphor® P407 as hydrophilic polymers. Filaments of Kollicoat® IR in combination with Kollidon® VA64/Kollidon® 12PF has resulted in successful printing of immediate release tablets. The mechanical properties of drug-loaded filaments were evaluated using a 3-point bend test and stiffness test. The transformation of a crystalline drug to an amorphous form and the absence of drug-polymer interactions were confirmed by differential scanning calorimetry and Fourier transform infrared spectroscopy, respectively. The effect of infill density on drug release profiles was greater than that of tablet shape. The stability of 3D printed tablets was preserved even after storage under accelerated conditions (40 ± 2°C and 75 ± 5% RH) for 6 months. Thus, the 3D printing process of hot-melt extrusion paired with fused deposition modeling serves as an alternative manufacturing approach for developing patient-focused doses.

Subcutaneous Delivery of Albumin: Impact of Thermosensitive Hydrogels.

Albumin demonstrates remarkable promises as a versatile carrier for therapeutic and diagnostic agents. However, noninvasive delivery of albumin-based therapeutics has been largely unexplored. In this study, injectable thermosensitive hydrogels were evaluated as sustained delivery systems for Cy5.5-labeled bovine serum albumin (BSA-Cy5.5). These hydrogels were prepared using aqueous solutions of Poloxamer 407 (P407) or poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), which could undergo temperature-triggered phase transition and spontaneously solidify into hydrogels near body temperature, serving as in situ depot for tunable cargo release. In vitro, these hydrogels were found to release BSA-Cy5.5 in a sustained manner with the release half-life of BSA-Cy5.5 from P407 and PLGA-PEG-PLGA hydrogels at 16 h and 105 h, respectively. Without affecting the bioavailability, subcutaneous administration of BSA-Cy5.5-laden P407 hydrogel resulted in delayed BSA-Cy5.5 absorption, which reached the maximum plasma level (Tmax) at 24 h, whereas the Tmax for subcutaneously administered free BSA-Cy5.5 solution was 8 h. Unexpectedly, subcutaneously injected BSA-Cy5.5-laden PLGA-PEG-PLGA hydrogel did not yield sustained BSA-Cy5.5 plasma level, the bioavailability of which was significantly lower than that of P407 hydrogel (p < 0.05). The near-infrared imaging of BSA-Cy5.5-treated mice revealed that a notable portion of BSA-Cy5.5 remained trapped within the subcutaneous tissues after 6 days following the subcutaneous administration of free solution or hydrogels, suggesting the discontinuation of BSA-Cy5.5 absorption irrespective of the formulations. These results suggest the opportunities of developing injectable thermoresponsive hydrogel formulations for subcutaneous delivery of albumin-based therapeutics.

Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies.

The objective of this study was to formulate aripiprazole (ARI)-loaded pH-modulated solid dispersions (SD) to enhance solubility, dissolution, and bioavailability via hot-melt extrusion (HME) technology. Kollidon® 12 PF (PVP) and succinic acid (SA) were selected after solubility screenings of various polymers and acidifiers. Several formulations, varying in screw speed and drug/polymer/acidifier ratios, were extruded using an 11 mm twin-screw extruder and were investigated for the effect of these variables. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to perform solid-state characterizations of the pure drug and extrudates. The aqueous solubility and dissolution were evaluated for the pure drug and milled extrudates. Among the prepared formulations, N6 was chosen for in vivo absorption studies. Solid-state characterization demonstrated the transformation of the crystalline ARI to an amorphous state in the formulations. Each formulation showed increased solubility and dissolution compared to the drug powder. The oral bioavailability (Cmax and AUC0-12) of N6 was significantly improved when compared to the pure ARI. This novel study not only discusses the incorporation of acidifiers in SDs but also the preparation of SDs using HME technology as effective techniques to improve drug release and bioavailability.

Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine.

OBJECTIVE: The aims of the current research project were to investigate the efficiency of various polymers to enhance the solubility and increase the systemic absorption of piperine using hot melt extrusion technology. METHODS: Piperine 10-40% w/w and Eudragit(®) EPO/Kollidon(®) VA 64 or Soluplus(®) were mixed, and the resulting blends were extruded using a twin-screw extruder (Process 11, Thermo Fisher Scientific). Drug release profiles and piperine solubility studies of the extrudates were evaluated. A non-everted intestinal sac was employed for the most promising formulation, 10% w/w piperine/Soluplus(®) , and pure piperine to study the permeability characteristics. KEY FINDINGS: Dissolution studies demonstrated enhancement in piperine per cent release of 10% and 20% w/w piperine/Soluplus(®) extrudates up to 95% and 74%, respectively. The solubility of 10% and 20% piperine/Soluplus(®) increased more than 160- and 45-fold in water, respectively. Furthermore, permeability studies demonstrated the enhancement in piperine absorption of 10% w/w piperine/Soluplus(®) extrudates up to 158.9 µg/5 ml compared with pure piperine at 1.3 µg/5 ml within 20 min. CONCLUSION: These results demonstrated that increasing the bioavailability of piperine may be achieved as demonstrated by findings in this study.

Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets.

The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus(®) as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box-Behnken design for response surface methodology was developed using three factors, processing temperature ( °C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs. The influence of these factors on pellet sphericity and mechanical characteristics was assessed and evaluated for each experimental run. Pellets with optimal sphericity and mechanical properties were chosen for further characterization. This included differential scanning calorimetry, drug release, hardness friability index (HFI), flowability, bulk density, tapped density, Carr's index, and fourier transform infrared radiation (FTIR) spectroscopy. TGA data showed no drug degradation upon heating to 190 °C. Hot melt extrusion processing conditions were found to have a significant effect on the pellet shape and hardness profile. Pellets with maximum sphericity and hardness exhibited no crystalline peak after extrusion. The rate of drug release was affected mainly by pellet size, where smaller pellets released the drug faster. All optimized formulations were found to be of superior hardness and not friable. The flow properties of optimized pellets were excellent with high bulk and tapped density.

Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions.

The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus® (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters. The solubility of FEL within SOL was determined to be in the range of 6.2-9.9% (w/w). Various techniques were applied to characterize the solid-state properties of the amorphous SDs. These included Fourier Transform Infrared Spectrometry spectroscopy and Raman spectroscopy to detect the formation of hydrogen bonding between the drug and the polymer. Scanning electron microscopy was performed to study the morphology of the SDs. Among all the hot-melt extrudates, FEL was found to be molecularly dispersed within the polymer matrix for the extrudates containing 10% drug, while few small crystals were detected in the 30 and 50% extrudates. In conclusion, solubility of FEL was enhanced while a homogeneous SD was achieved for 10% drug loading.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.

Influence of Molecular Weight of Carriers and Processing Parameters on the Extrudability, Drug Release, and Stability of Fenofibrate Formulations Processed by Hot-Melt Extrusion.

The objective of this study was to investigate the extrudability, drug release, and stability of fenofibrate (FF) formulations utilizing various hot-melt extrusion processing parameters and polyvinylpyrrolidone (PVP) polymers of various molecular weights. The different PVP grades selected for this study were Kollidon® 12 PF (K12), Kollidon® 30 (K30), and Kollidon® 90 F (K90). FF was extruded with these polymers at three drug loadings (15%, 25%, and 35% w/w). Additionally, for FF combined with each of the successfully extruded PVP grades (K12 and K30), the effects of two levels of processing parameters for screw design, screw speed, and barrel temperature were assessed. It was found that the FF with (K90) was not extrudable up to 35% drug loading. With low drug loading, the polymer viscosity significantly influenced the release of FF. The crystallinity remaining was vital in the highest drug-loaded formulation dissolution profile, and the glass transition temperature of the polymer significantly affected its stability. Modifying the screw configuration resulted in more than 95% post-extrusion drug content of the FF-K30 formulations. In contrast to FF-K30 formulations, FF release and stability with K12 were significantly influenced by the extrusion temperature and screw speed.

Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF.

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug. Hot-melt extrusion (HME) processing was used to prepare solid dispersions utilizing blends of polymers. Drug loading showed a significant effect on the dissolution rate of CBZ in all of the tested ratios of Soluplus® and HPMCAS-HF. CBZ was completely miscible in the polymeric blends of Soluplus® and HPMCAS-HF up to 40% drug loading. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and dissolution studies. DSC and XRD data confirmed the formation of amorphous solid dispersions of CBZ in the polymeric blends of Soluplus® and HPMCAS-HF. Drug loading and release of CBZ was increased with Soluplus® (when used as the primary matrix polymer) when formulations contained Soluplus® with 7-21% (w/w) HPMCAS-HF. In addition, this blend of polymers was found to be physically and chemically stable at 40°C, 75% RH over 12 months without any dissolution rate changes.

Investigation of phase diagrams and physical stability of drug-polymer solid dispersions.

Solid dispersion technology has been widely explored to improve the solubility and bioavailability of poorly water-soluble compounds. One of the critical drawbacks associated with this technology is the lack of physical stability, i.e. the solid dispersion would undergo recrystallization or phase separation thus limiting a product's shelf life. In the current study, the melting point depression method was utilized to construct a complete phase diagram for felodipine (FEL)-Soluplus® (SOL) and ketoconazole (KTZ)-Soluplus® (SOL) binary systems, respectively, based on the Flory-Huggins theory. The miscibility or solubility of the two compounds in SOL was also determined. The Flory-Huggins interaction parameter χ values of both systems were calculated as positive at room temperature (25 °C), indicating either compound was miscible with SOL. In addition, the glass transition temperatures of both solid dispersion systems were theoretically predicted using three empirical equations and compared with the practical values. Furthermore, the FEL-SOL solid dispersions were subjected to accelerated stability studies for up to 3 months.

The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus®-based solid dispersions.

The dissolution enhancement advantages inherent to amorphous solid dispersions systems are often not fully realized once they are formulated into a solid dosage form. The objective of this study was to investigate the ability of inorganic salts to improve the dissolution rate of carbamazepine (CBZ) from tablets containing a high loading of a Soluplus®-based solid dispersion. Cloud point and viscometric studies were conducted on Soluplus® solutions to understand the effect of temperature, salt type and salt concentration on the aqueous solubility and gelling tendencies of Soluplus®, properties that can significantly impact dissolution performance. Studies indicated that Soluplus® exhibited a cloud point that was strongly dependent on the salt type and salt concentration present in the dissolving medium. The presence of kosmotropic salts dehydrated the polymer, effectively lowering the cloud point and facilitating formation of a thermoreversible hydrogel. The ability of ions to impact the cloud point and gel strength generally followed the rank order of the Hofmeister series. Solid dispersions of CBZ and Soluplus® were prepared by KinetiSol® Dispersing, characterized to confirm an amorphous composition was formed and incorporated into tablets at very high levels (70% w/w). Dissolution studies demonstrated the utility of including salts in tablets to improve dissolution properties. Tablets that did not contain a salt or those that included a chaotropic salt hydrated at the tablet surface and did not allow for sufficient moisture ingress into the tablet. Conversely, the inclusion of kosmotropic salts allowed for rapid hydration of the entire tablet and the formation of a gel structure with strength dependent on the type of salt utilized. Studies also showed that, in addition to allowing tablet hydration, potassium bicarbonate and potassium carbonate provided effervescence which effectively destroyed the gel network and allowed for rapid dissolution of CBZ. Subsequent dissolution studies in 0.1 N HCl showed that potassium bicarbonate was an effective tablet disintegrant at levels as low as 1% and provided for tablets that rapidly disintegrated over a wide range of applied compression forces, presumably due to synergy between the ability to form a weak hydrogel structure and carbon dioxide liberation. Similar dissolution performance was measured in pH 4.5 acetate buffer, despite reduced polymer solubility caused by kosmotropic salts in solution, demonstrating robustness. With the use of inorganic salts such as potassium bicarbonate, it may be possible to substantially improve disintegration and dissolution characteristics of tablets containing Soluplus®.