Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems.

Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.

Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients.

OBJECTIVE: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. SIGNIFICANCE: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. METHODS AND RESULTS: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. CONCLUSIONS: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.

Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across PermeapadⓇ membrane and in vivo absorption.

Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic PermeapadⓇ membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free PermeapadⓇ permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.

Supersaturated lipid-based drug delivery systems - exploring impact of lipid composition type and drug properties on supersaturability and physical stability.

Objective: The objective of this study was to systematically investigate the impact of lipid composition on the ability to design supersaturated lipid-based drug delivery systems (sLBDDS) using three model drugs with different physico-chemical properties.Significance: This study expands the list of investigated sLBDDS by using alternative vehicle compositions relative to current literature.Methods and results: Drug supersaturation was thermally-induced based on previously reported methods and was successfully achieved for celecoxib and cinnarizine. For the novel drug, JNJ-2A, a lower supersaturation potential was observed for the tested LBDDS. For celecoxib and cinnarizine, crystalline precipitate was observed for some sLBDDS upon storage at 25 °C/65%RH, particularly for medium chain sLBDDS (celecoxib) and long chain sLBDDS (cinnarizine). The greater risk of precipitation observed for celecoxib and cinnarizine, particularly at higher apparent degree of supersaturation (aDS) may be related to their higher crystallization tendency as determined by differential scanning calorimetry.Conclusions: The potential for supersaturation in LBDDS, and the risk of precipitation, was found to be highly drug dependent. The apparent degree of supersaturation was considered a major factor impacting the ability to maintain drug supersaturation upon storage.

Improvement of dissolution rate of indomethacin by inkjet printing.

The aim of this study was to prepare printable inks of the poorly water soluble drug indomethacin (IMC), fabricate printed systems with flexible doses and investigate the effect of ink excipients on the printability, dissolution rate and the solid state properties of the drug. A piezoelectric inkjet printer was used to print 1×1cm(2) squares onto a paper substrate and an impermeable transparency film. l-arginine (ARG) and polyvinylpyrrolidone (PVP) were used as additional formulation excipients. Accurately dosed samples were generated as a result of the ink and droplet formation optimization. Increased dissolution rate was obtained for all formulations. The formulation with IMC and ARG printed on transparency film resulted in a co-amorphous system. The solid state characteristics of the printed drug on porous paper substrates were not possible to determine due to strong interference from the spectra of the carrier substrate. Yet, the samples retained their yellow color after 6months of storage at room temperature and after drying at elevated temperature in a vacuum oven. This suggests that the samples remained either in a dissolved or an amorphous form. Based on the results from this study a formulation guidance for inkjet printing of poorly soluble drugs is also proposed.

Fabrication of drug-loaded edible carrier substrates from nanosuspensions by flexographic printing.

The main goal of the current work was to investigate the possible use of flexographic printing for the conversion of nanosuspensions into solid dosage forms. Aqueous nanosuspensions of indomethacin (IND) and itraconazole (ITR) with Poloxamer 407 as the stabilizer agent were prepared by wet ball-milling. The nanosuspensions were flexographically printed on three different substrates, including two commercially available edible substrates. The printed formulations were characterized with X-ray diffractometry (XRD) and scanning electron microscopy (SEM). In addition, dissolution studies for the printed IND and ITR formulations were conducted. The mean particle size of milled nanosuspensions of IND and ITR was 422.6 ± 7.7 nm and 698.1 ± 14.0 nm, respectively. The SEM imaging showed even distribution of nanosuspensions on the substrates after printing without any evident agglomeration. The printed formulations contained drug at least partially in crystalline form. The drug dissolution rate from the prepared formulations was improved compared to the pure drug. The drug release from the preparations on edible substrates was slightly slower due to the incorporation of the drug particles into the substrate matrix. In conclusion, the results indicated that flexographic printing can be considered as a promising fabrication method of solid nanoparticulate systems with enhanced dissolution behavior.

Hyperspectral imaging in quality control of inkjet printed personalised dosage forms.

The aim of the study was to investigate applicability of near infra-red (NIR) hyperspectral imaging technique in quality control of printed personalised dosage forms. Inkjet printing technology was utilized to fabricate escalating doses of an active pharmaceutical ingredient (API). A solution containing anhydrous theophylline as the model drug was developed as a printable formulation. Single units solid dosage forms (SDFs) were prepared by jetting the solution onto 1 cm × 1 cm areas on carrier substrate with multiple printing passes. It was found that the number of printing passes was in excellent correlation (R(2)=0.9994) with the amount of the dispensed drug (µg cm(-2)) based on the UV calibration plot. The API dose escalation was approximately 7.5 µg cm(-2) for each printing pass concluding that inkjet printing technology can optimally provide solutions to accurate deposition of active substances with a potential for personalized dosing. Principal component analysis (PCA) was carried out in order to visualize the trends in the hyperspectral data. Subsequently, a quantitative partial least squares (PLS) regression model was created. NIR hyperspectral imaging proved (R(2)=0.9767) to be a reliable, rapid and non-destructive method to optimize quality control of these planar printed dosage forms.

Inhibitory activity of the isoflavone biochanin A on intracellular bacteria of genus Chlamydia and initial development of a buccal formulation.

Given the established role of Chlamydia spp. as causative agents of both acute and chronic diseases, search for new antimicrobial agents against these intracellular bacteria is required to promote human health. Isoflavones are naturally occurring phytoestrogens, antioxidants and efflux pump inhibitors, but their therapeutic use is limited by poor water-solubility and intense first-pass metabolism. Here, we report on effects of isoflavones against C. pneumoniae and C. trachomatis and describe buccal permeability and initial formulation development for biochanin A. Biochanin A was the most potent Chlamydia growth inhibitor among the studied isoflavones, with an IC50 = 12 µM on C. pneumoniae inclusion counts and 6.5 µM on infectious progeny production, both determined by immunofluorescent staining of infected epithelial cell cultures. Encouraged by the permeation of biochanin A across porcine buccal mucosa without detectable metabolism, oromucosal film formulations were designed and prepared by a solvent casting method. The film formulations showed improved dissolution rate of biochanin A compared to powder or a physical mixture, presumably due to the solubilizing effect of hydrophilic additives and presence of biochanin A in amorphous state. In summary, biochanin A is a potent inhibitor of Chlamydia spp., and the in vitro dissolution results support the use of a buccal formulation to potentially improve its bioavailability in antichlamydial or other pharmaceutical applications.

Inkjet printing of Chitlac-nanosilver--a method to create functional coatings for non-metallic bone implants.

Biostable fiber-reinforced composites, based on bisphenol-A-dimethacrylate and triethyleneglycoldimethacrylate thermoset polymer matrix reinforced with E-glass fibers have been successfully used in cranial reconstructions and the material has been approved for clinical use. As a further refinement of these implants, antimicrobial, non-cytotoxic coatings on the composites were created by an immersion procedure driven by strong electrostatic interactions. Silver nanoparticles (nAg) were immobilized in lactose-modified chitosan (Chitlac) to prepare the bacteriostatic coatings. Herein, we report the use of inkjet technology (a drop-on-demand inkjet printer) to deposit functional Chitlac-nAg coatings on the thermoset substrates. Characterization methods included scanning electron microscopy, scanning white light interferometry and electro-thermal atomic absorption spectroscopy. Inkjet printing enabled the fast and flexible functionalization of the thermoset surfaces with controlled coating patterns. The coatings were not impaired by the printing process: the kinetics of silver release from the coatings created by inkjet printing and conventional immersion technique was similar. Further research is foreseen to optimize printing parameters and to tailor the characteristics of the coatings for specific clinical applications.

Towards fabrication of 3D printed medical devices to prevent biofilm formation.

The use of three-dimensional (3D) printing technologies is transforming the way that materials are turned into functional devices. We demonstrate in the current study the incorporation of anti-microbial nitrofurantoin in a polymer carrier material and subsequent 3D printing of a model structure, which resulted in an inhibition of biofilm colonization. The approach taken is very promising and can open up new avenues to manufacture functional medical devices in the future.

Printing technologies in fabrication of drug delivery systems.

INTRODUCTION: There has been increased activity in the field recently regarding the development and research on various printing techniques in fabrication of dosage forms and drug delivery systems. These technologies may offer benefits and flexibility in manufacturing, potentially paving the way for personalized dosing and tailor-made dosage forms. AREAS COVERED: In this review, the most recent observations and advancements in fabrication of drug delivery systems by utilizing printing technologies are summarized. A general overview of 2D printing techniques is presented including a review of the most recent literature where printing techniques are used in fabrication of drug delivery systems. The future perspectives and possible impacts on formulation strategies, flexible dosing and personalized medication of using printing techniques for fabrication of drug delivery systems are discussed. EXPERT OPINION: It is evident that there is an urgent need to meet the challenges of rapidly growing trend of personalization of medicines through development of flexible drug-manufacturing approaches. In this context, various printing technologies, such as inkjet and flexography, can play an important role. Challenges on different levels exist and include: i) technological development of printers and production lines; ii) printable formulations and carrier substrates; iii) quality control and characterization; and iv) regulatory perspectives.

Tailored beads made of dissolved cellulose--investigation of their drug release properties.

In the frame of this work, we have investigated drug entrapping and release abilities of new type of porous cellulose beads (CBs) as a spherical matrix system for drug delivery. For that purpose, CBs prepared with three different methods were used as drug carriers and three compounds, anhydrous theophylline (Thp), riboflavin 5'-phosphate sodium (RSP) and lidocaine hydrochloride monohydrate (LiHCl) were used as model drug substances. The loading procedure was carried out by immersing swollen empty beads into the solutions of different concentrations of model drugs. The morphology of empty and loaded beads was examined using a field emission scanning electron microscopy (FE-SEM). Near-infrared (NIR) imaging was performed to identify the drug distributions on and within the loaded CBs. The drug amount incorporated into CBs was examined spectrophotometrically and in vitro drug release studies were performed to determine the drug release rates. The results of FE-SEM and chemical NIR imaging analyses revealed that incorporated drug were distributed on the surface and but also within the internal structure of the CBs. Physical properties of CBs and solubility of model drugs had effect on loading efficacy. Also, the drug release rates were controlled by solubility of model drugs (diffusion controlled release). In conclusion, CBs from dissolved cellulose show promise in achieving controlled drug delivery.

Evaluation of drug interactions with nanofibrillar cellulose.

Nanofibrillar cellulose (NFC) (also referred to as cellulose nanofibers, nanocellulose, microfibrillated, or nanofibrillated cellulose) has recently gotten wide attention in various research areas and it has also been studied as excipient in formulation of the pharmaceutical dosage forms. Here, we have evaluated the interactions between NFC and the model drugs of different structural characteristics (size, charge, etc.). The series of permeation studies were utilized to evaluate the ability of the drugs in solution to diffuse through the thin, porous, dry NFC films. An incubation method was used to determine capacity of binding of chosen model drugs to NFC as well as isothermal titration calorimetry (ITC) to study thermodynamics of the binding process. A genetically engineered fusion protein carrying double cellulose binding domain was used as a positive control since its affinity and capacity of binding for NFC have already been reported. The permeation studies revealed the size dependent diffusion rate of the model drugs through the NFC films. The results of both binding and ITC studies showed that the studied drugs bind to the NFC material and indicated the pH dependence of the binding and electrostatic forces as the main mechanism.

Nanofibrillar cellulose films for controlled drug delivery.

Nanofibrillar cellulose (NFC) (also referred to as cellulose nanofibers, nanocellulose, microfibrillated, or nanofibrillated cellulose) has gotten recent and wide attention in various research areas. Here, we report the application of nanofibrillar cellulose as a matrix-former material for long-lasting (up to three months) sustained drug delivery. Film-like matrix systems with drug loadings between 20% and 40% were produced by a filtration method. This simple production method had an entrapment efficacy>90% and offers a possibility for the film thickness adjustment as well as applicability in the incorporation of heat sensitive compounds. The films had excellent mechanical properties suitable for easy handling and shape tailoring of the drug release systems. They were characterized in terms of the internal morphology, and the physical state of the encapsulated drug. The drug release was assessed by dissolution tests, and suitable mathematical models were used to explain the releasing kinetics. The drug release was sustained for a three month period with very close to zero-order kinetics. It is assumed that the nanofibrillar cellulose film sustains the drug release by forming a tight fiber network around the incorporated drug entities. The results indicate that the nanofibrillar cellulose is a highly promising new material for sustained release drug delivery applications.

Spray-dried nanofibrillar cellulose microparticles for sustained drug release.

Nanofibrillar cellulose (also referred to as cellulose nanofibers, nanocellulose, microfibrillated or nanofibrillated cellulose) has gained a lot of attention in recent years in different research areas including biomedical applications. In this study we have evaluated the applicability of nanofibrillar cellulose (NFC) as a material for the formation of matrix systems for sustained drug delivery. For that purpose, drug loaded NFC microparticles were produced by a spray drying method. The microparticles were characterized in terms of size and morphology, total drug loading, and physical state of the encapsulated drug. Drug release from the microparticles was assessed by dissolution tests, and suitable mathematical models were used to explain the drug releasing kinetics. The particles had spherical shapes with diameters of around 5 µm; the encapsulated drug was mainly in amorphous form. The controlled drug release was achieved. The drug releasing curves were fitted to a mathematical model describing the drug releasing kinetics from a spherical matrix. Different drugs had different release kinetics, which was a consequence of several factors, including different solubilities of the drugs in the chosen medium and different affinities of the drugs to the NFC. It can be concluded that NFC microparticles can sustain drug release by forming a tight fiber network and thus limit drug diffusion from the system.

Spray-dried cellulose nanofibers as novel tablet excipient.

The purpose of this study was to evaluate the potential of cellulose nanofibers (also referred as microfibrillated cellulose, nanocellulose, nanofibrillated, or nanofibrillar cellulose) as novel tabletting material. For this purpose, physical and mechanical properties of spray-dried cellulose nanofibers (CNF) were examined, and results were compared to those of two commercial grades of microcrystalline cellulose (MCC), Avicel PH101 and Avicel PH102, which are the most commonly and widely used direct compression excipients. Chemically, MCC and CNF are almost identical, but their physical characteristics, like mechanical properties and surface-to-volume ratio, differ remarkably. The novel material was characterized with respect to bulk and tapped as well as true density, moisture content, and flow properties. Tablets made of CNF powder and its mixtures with MCC with or without paracetamol as model compound were produced by direct compression and after wet granulation. The tensile strength of the tablets made in a series of applied pressures was determined, and yield pressure values were calculated from the measurements. With CNF, both wet granulation and direct compression were successful. During tablet compression, CNF particles were less prone to permanent deformation and had less pronounced ductile characteristics. Disintegration and dissolution studies showed slightly faster drug release from direct compression tablets with CNF, while wet granulated systems did not have any significant difference.

Electrospraying, spray drying and related techniques for production and formulation of drug nanoparticles.

IMPORTANCE OF THE FIELD: Spray drying and electrospraying are two widely used liquid atomization-based techniques for production and formulation of drug nanoparticles. The importance of spray drying in particular has increased lately in the production of nanostructured microparticles. The value of the particles is that they maintain the properties of individual nanoparticles but they are micrometer sized. AREAS COVERED IN THIS REVIEW: In this review the most important liquid atomization techniques, spray drying and electrospraying, are presented in detail, and a short introduction is presented for other methods, including the aerosol flow reactor method and spray congealing. WHAT THE READER WILL GAIN: A description of the possible tailoring processes depending on the technique and process parameters. Different product properties can be achieved; for example, nanosuspensions or dry powder formulations may be produced. TAKE HOME MESSAGE: The most important advantage of these techniques as compared with many other particle formation techniques is that the production of dried powders is possible without any extra drying step.