Polysorbate 80 is one of the most commonly used surfactants in the formulation of biotherapeutics, particularly those administered intravenously. It comprises a mixture of fatty acids but is not a precisely defined chemical entity. Hence, there are a range of different grades available in the market, all meeting compendial specifications. Polysorbate 80 is known to undergo auto degradation producing protein-damaging by-products, and to contain residual impurities that can have an impact on the stability and integrity of the active ingredients in the formulation. Given the variety of chemical compositions that polysorbate 80 can comprise, the degradation pathway and extent could vary depending on the grade used in the formulation. This study compared the physical and chemical properties of four commercially available polysorbate 80 grades with different degrees of purity and oleic acid content and investigated their degradation profiles. This study did not find any significant differences between the properties or degradation profiles of the four grades investigated. Further studies are underway to understand the formation of other reactive impurities and their impact on the model protein formulations.
Welcome to the 15th volume of the Journal of Excipients and Food Chemicals (JEFC) 2024. It is my pleasure to introduce myself as the new Editor for this publication. To quote the ubiquitous Taylor Swift on X (2015); “This is a new year. A new beginning. And things will change”. For The Journal of Excipients and Food Chemicals (JEFC), this means a new perspective that stems from my thirty-plus year career in the pharmaceutical industry, working on new product development and drug delivery.
The objective of the work presented here was to assess the feasibility of using glucosamine HCl as a solid-dispersion (SD) carrier to enhance the biopharmaceutical properties of a BCS class III/IV drug, acyclovir (ACV). The solid-dispersions of acyclovir and glucosamine HCl were prepared by an ethanol-based solvent evaporation method. The prepared formulations characterized by photomicroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectrophotometry (FTIR), powder x-ray diffractometry (PXRD) and drug content analysis. The functional characterization of ACV-SD was performed by aqueous solubility evaluation, dissolution studies, fasted versus fed state dissolution comparison, ex vivo permeability, and stability studies. Photomicroscopy and SEM analysis showed different surface morphologies for pure ACV, glucosamine HCl and ACV-SD. The physical-chemical characterization studies supported the formation of ACV-SD. A 12-fold enhancement in the aqueous solubility of ACV was observed in the prepared solid dispersions, compared to pure ACV. Results from in vitro dissolution demonstrated a significant increase in the rate and extent of ACV dissolution from the prepared ACV-SD formulations, compared to pure ACV. The rate and extent of ACV permeability across everted rat intestinal membrane were also found to be significantly increased in the ACV-SD formulations. Under fed conditions, the rate and extent of the in vitro dissolution of ACV from the formulation was appreciably greater compared to fasted conditions. Overall, the results from the study suggest the feasibility of utilizing glucosamine HCl as a solid dispersion carrier/excipient for enhancement of biopharmaceutical properties of acyclovir, and similar drugs with low solubility/permeability characteristics.
The developments in pharmaceutical excipient science and technology since 1995 have been reviewed. The field of excipients science and technology has changed and continues to change. Some good progress has been made in such areas as harmonization of excipient pharmacopeial monographs, and the application of new analytical methods to better characterize excipients
Recent advances in the encapsulation of bioactive compounds that are found in some important Brazilian fruits are discussedin this paper. Bacuri, Tucumã, Ticazo, Taperebá, Pineapple, and Jabuticaba are examples of typical fruits from the Brazilian Cerrado region, where bioactive compounds known for their sensory attributes such as color, flavor, and aroma, in addition to, their high nutritional values grow increasingly. However, many of the bioactive compounds in the fruits degrade naturally quickly, with functional loss due to several factors. Thus, in the food industry, the immediate need for the development of systems to protect and release the bioactive compounds present in the various fruits is evident. Microencapsulation and nanoencapsulation of bioactive fruit compounds are technologies that prevent degradation and possible functional loss of the bioactive compounds. Different techniques used in encapsulating will be presented, as well as, encapsulation materials and the principal results achieved by various studies of micro and nanoencapsulation.
Cinnarizine (CN) is an antihistaminic drug that is commonly used for the treatment of chronic conditions for the reduction of cerebral blood flow such as vertigo. However, CN is poorly water soluble with erratic absorption and low bioavailability. Chitosan is a biodegradable natural polymer with approved skin permeation enhancement properties; therefore, the formulation of CN-loaded chitosan nanoparticles could enhance the skin permeability of CN. In this work, for the first time, CN-loaded chitosan nanoparticles were prepared (using the nanoprecipitation method) and characterized. Additionally, the described nanoparticles were subjected to in vitro release and ex vivo permeation studies. Dynamic light scattering (DLS) characterization showed that the method was successful in the production of small (down to 12.4 nm), positive, and relatively homogenous or monodispersed nanoparticles. The highest entrapment efficiency (EE) of CN in the chitosan nanoparticles was 62±2.7%. Further, the release study showed that chitosan nanoparticles can effectively reduce the burst release and create a sustained release pattern of CN. The ex vivo permeation study, using rat skin as a model, showed that chitosan nanoparticles improved the CN permeability three times compared to the control. In conclusion, chitosan used as a nanocarrier enhances drug penetration in to the skin which may lead to the formulation of a transdermal formulation of CN
The objective of this study was to evaluate the viscosity, zeta potential and soluble and total solids of the emulsion and microparticles of oregano essential oil (Origanum vulgare) using gum arabic as a coating agent and to analyze the morphology of the microparticles produced by the spray drying method. The rheological analysis showed a viscosity for emulsion of 36.23 ± 0.59 mPas and for microparticles of 20.13 ± 0.15 mPa.s. The zeta potential of the emulsion was - 6.67 ± 0.32 mV and of the oregano oil microparticles -16.47 ± 0.70 mV. Soluble solids showed Brix° of 8.44 ± 0.13 and 0.98 ± 0.36 and total solids 8.95 ± 0.42 and 1.03 ± 0.02 % for emulsion and microparticles, respectively. The morphology of the microparticles presented irregular spherical shapes and agglomeration.
The adoption of cocrystals into oral pharmaceutical formulations is expected to propel this, as yet, moribund field into clinical and monetary prominence. The increase in resources and research that will inevitably follow is expected to address long standing problems in crystal engineering. Ab initio predictions of heterosynthon structure, identification of molecular descriptors to enable bioavailability enhancing coformer selection and a priori prediction of the cocrystal lattice have thus far been insoluble. Solutions to the prediction of supersaturation levels and polymorphic transition of the cocrystal formulated API in GI fluids, and solvation barrier and solubilization free energies, remain empirical. Properties such as on-demand/environment, formulation enabled, proton transfer between API and coformer and the development of neural networks or AI, trained on empirical data to predict ideal API-coformer pairs without the need to explicitly understand mechanisms, remain obscure, and hence un-researched. It is ironic that failure mechanisms that result in the delayed appearance of a less- soluble polymorph in pharmaceutical formulations (disappearing polymorphs) could (and should) be gainfully utilized to facilitate the delayed appearance in vivo of less-soluble polymorph(s) in cocrystal formulations. The bioavailability increase afforded by cocrystal formulations has the potential to enable greater patient compliance due to favorable posology, introduce more efficacious drugs into the therapeutic armamentarium, enable line- extensions and expand intellectual property portfolios, reduce the cost-of-goods; and hence of medicines, and add one more valuable tool in the repertoire of the pharmaceutical formulation scientist.
Metronidazole topical formulations such as gels, creams, and lotions are used in the treatment of bacterial vaginosis and inflammation lesions of rosacea. Metronidazole precipitating from a Carbopol-based gel resulted in the formation of unique, highly branched, curvilinear microstructures. In contrast, metronidazole precipitated as linear, acicular crystals from drug solutions. The reason for the change in crystal habit was investigated by preparing different custom-made solutions and gels. Custom-made solutions were prepared using different solvent systems. Custom-made gels were prepared using different concentration of pH modifier, carbopol and other excipients. Characterization studies were carried out on the recrystallized metronidazole using bright-field microscopy, polarized microscopy, scanning electron microscopy (SEM), Differential Scanning Calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and Powder X-Ray Diffractometry (PXRD). The results indicated that the change in crystal habit was likely due to the interactions between the nitro-imidazole moiety of metronidazole and the polymer without a change in the polymorphic form.
Since the ingredients of soft drinks are generally hidden and protected by law, unknown substances may affect cell proliferation and the function of the gastrointestinal epithelial cells. Concerns have been expressed regarding the toxicity of caramel coloring used in soft drinks. The present study examined the potential toxicity of 2-acetyl-4(5)-tetrahydroxy butylimidazole (THI), a byproduct of caramel coloring III, and its effects on three types of gastrointestinal cells (HGC-27, IEC-6, and Caco-2 cells). The inhibition of cell proliferation was stronger by Caramel III containing THI than by Caramel I or IV without THI. However, the inhibition of cell proliferation was not observed under THI exposure conditions, suggesting that THI does not act as a failure factor. On the other hand, since THI increased trans-epithelial electrical resistance (TEER), an indicator of epithelial physical barrier function, it may exert enhancing effects on tight junctions, a representative physical barrier. No cytotoxicity against gastrointestinal epithelial cells was observed, even under THI exposure conditions at concentrations that were markedly higher than those obtained from the ingestion of beverages. Conversely, TEER was elevated by the exposure to high THI concentrations, and was suggested to enhance epithelial cell barrier function. Since THI appears to act on absorption-regulating factors, further studies are needed, including methods for the application of THI.
Oral delivery of olanzapine suffers from low oral bioavailability and there has been reports of metabolic side effects. This study aimed to prepare a nanoemulsion of olanzapine and incorporate it into an in situ gel for nasal delivery. Such nasal delivery of olanzapine could provide prolonged contact time with the nasal mucosa and a potential enhanced action with lower side effects. Several formulations of nanoemulsions were prepared and characterized through the measurements of conductivity, transmittance, pH, viscosity, hydrodynamic diameter, polydispersity index, Zeta potential, entrapment efficiency, and release profiles. In addition, a pharmacodynamics study was conducted through animal studies. The selected formulation showed excellent nanoemulsion with a size in the nanometre range, a good polydispersity index with acceptable stability as indicated by the thermodynamic stability test. The cumulative percentage of olanzapine released from the nanoemulsion showed a good release profile. Pharmacodynamics study on rats using Paw test demonstrated a very clear enhancement in the anti psychotic efficacy of olanzapine in the following order: Nanoemulsion-based in situ gel (with HPMC) > nanoemulsion based in situ gel > nanoemulsion > solution. Interestingly, olanzapine from the nanoemulsion-based in situ gel showed comparable antipsychotic efficacy to haloperidol, when given intraperitoneally. Nanoemulsion based nasal in situ gel is a promising drug delivery system for olanzapine for achieving a targeted delivery. However, further investigations on olanzapine accumulation in the brain after such delivery are recommended.
The aim of this work was to improve the solubility of various anti-HIV APIs extruding them with polyvinyl alcohol to allow a reduction in patient drug burden. There are no previously known cases of successful use of this polymer to improve the solubility of APIs using a convenient industrial technology. Anti-HIV API solid dispersion samples were obtained using hot melt extrusion with polyvinyl alcohol, and were studied with solubility testing, as well as various methods of confirming amorphousness (differential scanning calorimetry, X-ray powder diffraction). This study confirmed the presence of amorphousness and a significant increase in the solubility of the API in various dissolution media. According to the obtained data, the best samples were selected and utilized in tablet formulations, which successfully passed in vitro dissolution testing. The results of in vitro dissolution testing showed the improvement of dissolution kinetics for all APIs. These results howed the usefulness of hot melt extrusion with polyvinyl alcohol in a ratio of at least 1-3 or 1-5 for the studied APIs and improved the dissolution kinetics of the proposed tablet formulations compared to the controls.
Excipients are critically important in converting active pharmaceutical ingredients (API) into drug products that have optimal stability, bioavailability, manufacturability, duration of action, and therapeutic benefits. They will play even greater roles in the future to enable drug targeting, delivery of biotech products and vaccines, gene therapy, continuous manufacturing, 3D printing, and so forth. This commentary describes the author’s experience in teaching a graduate course on excipients at St. John’s University to train students on optimal selection and appropriate use of excipients in formulating dosage forms and development of drug delivery systems. The course is offered in 15 two-hour sessions over a semester, and the course materials are divided into 13 modules on chemistry of different classes of polymeric and non-polymeric excipients and their application in dosage form development, including the use as solubilizing agents, lyophilizing agents, cryoprotectants, buffers, biodegradable materials, and carriers for amorphous solid dispersions and 3D printing. The development of co- processed excipients, the need for new excipients, and the regulatory aspects of excipients are also covered. The course includes presentations by guest speakers from the industry, and the students also watch virtual presentations from experts that are publicly available from the internet. It is a popular course at St. John’s University taken by all graduate students in the pharmaceutics program. It is recommended that such courses are introduced in other pharmacy schools and academic institutions. The course may be adapted to meet specific needs of different academic programs. Professional associations, such as AAPS and CRS, industry groups like IPEC, and the pharmaceutical industry may be able to help in introducing such courses by providing lecture materials and guest lecturers.
The physicochemical, material and compressional properties of the Irvingia gabonensis (O’Rorke) Bail polymer were evaluated and compared with xanthan gum and hydroxy propyl methylcellulose (HPMC). The Irvingia polymer was extracted using established methods and processed using two methods of drying, that is, oven-drying and freeze-drying. The compression mechanisms were evaluated using the Heckel and Kawakita equations. The mechanical strength of the tablets was evaluated using crushing strength and friability. The results showed that the Irvingia kernel polymer was slightly acidic, free of heavy metals, with irregularly shaped particles that exhibited some degree of crystallinity. The Irvingia kernel polymer was directly compressible and formed intact non-disintegrating tablets similar to the standard polymers. The Heckel and Kawakita equations indicated that the Irvingia polymer deformed plastically with fast onset and a high amount of plastic deformation compared to xanthan gum and HPMC. The freeze-dried Irvingia gum showed significantly (p<0.05) higher crushing strength and lower friability than the oven-dried polymer. The results indicated that the drying method had a significant impact on the compression characteristics as well as the properties of the polymer tablets. Thus, the Irvingia polymer could be more suitable for the formulation of tablets using direct compression.
