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Printed Drug-Delivery Systems for Improved Patient Treatment

The use of various types of printing technologies offer potential solutions for personalized medicine and tailored dosage forms to meet the needs of individual treatments of the future. Many types of scenario for printed dosage form exist and the concepts include, on the simplest level, accurately deposited doses of drug substances. In addition, computer design allows endless opportunities to create suitable geometries with tailored functionality and different levels of complexity to control the release properties of one or multiple drug substances. It will take some time to convert these technological developments in printing to better treatments for patients, because challenges exist. However, printing technologies are developing fast and have the potential to allow the use of versatile materials to manufacture sophisticated drug-delivery systems and biofunctional constructs for personalized treatments.

3D-Printed Drugs for Children—Are We Ready Yet?

The first medicine manufactured by three-dimensional (3D) printing was recently approved by the Food and Drug Administration (FDA). The advantages of printing as a manufacturing route enabling more flexibility regarding the dose, and enlarging individual treatment options, have been demonstrated. There is a particular need for flexible drug delivery solutions when it comes to children. Printing as a new pharmaceutical manufacturing technology brings manufacturing closer to the patient and can easily be adjusted to the required dosing scheme, offering more flexibility for treatments. Printing of medicine may therefore become the manufacturing route of choice to provide tailored and potentially on-demand treatments for patients with individual needs. This paper intends to summarize and discuss the state of the art, the crucial aspects which should be taken into account, and the still-open questions, in order to make 3D printing a suitable manufacturing route for pediatric drugs.

Tailored approaches in drug development and diagnostics:from molecular design to biological model systems

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century.

Application of a handheld NIR spectrometer in prediction of drug content in inkjet printed orodispersible formulations containing prednisolone and levothyroxine

Quality control tools to assess the quality of printable orodispersible formulations are yet to be defined. Four different orodispersible dosage forms containing two poorly soluble drugs, levothyroxine and prednisolone, were produced on two different edible substrates by piezoelectric inkjet printing. Square shaped units of 4cm2 were printed in different resolutions to achieve an escalating drug dose by highly accurate and uniform displacement of droplets in picoliter range from the printhead onto the substrates. In addition, the stability of drug inks in a course of 24h as well as the mechanical properties and disintegration behavior of the printed units were examined. A compact handheld near-infrared (NIR) spectral device in the range of 1550-1950nm was used for quantitative estimation of the drug amount in printed formulations. The spectral data was treated with mean centering, Savitzky-Golay filtering and a third derivative approach. Principal component analysis (PCA) and orthogonal partial least squares (OPLS) regression were applied to build predictive models for quality control of the printed dosage forms. The accurate tuning of the dose in each formulation was confirmed by UV spectrophotometry for prednisolone (0.43-1.95mg with R2=0.999) and high performance liquid chromatography for levothyroxine (0.15-0.86mg with R2=0.997). It was verified that the models were capable of clustering and predicting the drug dose in the formulations with both Q2 and R2Y values between 0.94-0.99.

Novel biorenewable composite of wood polysaccharide and polylactic acid for three dimensional printing

Hemicelluloses, the second most abundant polysaccharide right after cellulose, are in practice still treated as a side-stream in biomass processing industries. In the present study, we report an approach to use a wood-derived and side-stream biopolymer, spruce wood hemicellulose (galactoglucomannan, GGM) to partially replace the synthetic PLA as feedstock material in 3D printing. A solvent blending approach was developed to ensure the even distribution of the formed binary biocomposites. The blends of hemicellulose and PLA with varied ratio up to 25% of hemicellulose were extruded into filaments by hot melt extrusion. 3D scaffold prototypes were successfully printed from the composite filaments by fused deposition modeling 3D printing. Combining with 3D printing technique, the biocompatible and biodegradable feature of spruce wood hemicellulose into the composite scaffolds would potentially boost this new composite material in various biomedical applications such as tissue engineering and drug-eluting scaffolds.

Pediatric Drug Development and Dosage Form Design

For many years, children have been described as Btherapeutic orphans^ to indicate that medicinal research, regulation, and formulation development has mainly focused on diseases in adults (1). The development of age-appropriate medicine for the heterogeneous pediatric population is a particular challenge. It starts with the right choice of drugs and their dose, but equally important is the route of administration. This theme issue of AAPS PharmSciTech provides an overview on (a) regulatory considerations for pediatric products, (b) appropriate dosage forms and drug formulations for children, and (c) test methods to assess critical attributes of such preparations. Despite the increasing awareness for age-appropriate formulations, available licensed pediatric drugs are still lagging behind those for adult patients. Van Riet-Nales et al. gives an overview on the European perspective regarding the development and design of pediatric drugs (2), and the key aspects of the recent European BGuideline on the Pharmaceutical Development of Medicines for Paediatric Use^ are discussed. Subsequent articles in this theme issue address the pharmaceutical formulation challenges associated with a Pediatric Investigation Plan (Europe) or Pediatric Study Plan (United States). Various initiatives have been set up to promote and facilitate the preparation of better and safe medicines for children (3,4). Recent studies revealed that even the youngest children are capable to take small-sized solid dosage forms. The results of the conducted clinical studies on the acceptability of mini-tablets in children are summarized and discussed in an overview article (5). Besides the mentioned small-sized tablets, orally disintegrating films appear as a promising dosage form to facilitate the drug administration in children, offering more flexible dosing and ease of administration (6). With a dosage form that additionally enables the drug to be released immediately in the oral cavity or to be absorbed via the buccal mucosa, higher requirements for palatability and understanding the necessity of appropriate excipients have to be considered (7). The continuous research in oromucosal drug delivery will potentially lead to more products and applications, such as vaccine delivery (8). New technologies to manufacture tailored and flexible dosage forms that comply with the specific needs of pediatric patients are entering the market, such as printing technologies. However, it is crucial to define, which quality attributes and control tools are required to ensure the performance and safety of these products (9,10). Taking into account that drug administration in children can be challenging for caregivers and often food is used to facilitate the process, it is worthwhile to investigate different dosing scenarios (11), but also suitable gastrointestinal digestion models (12). Mixing drugs into foodstuff is one approach to additionally mask the taste of pharmaceuticals and facilitate the swallowing procedure. However, multiple aspects such as the viscosity and pH value but also fat and sugar contents have to be considered and evaluated. To avoid cost-intensive human sensory panels, studies in this theme issue address animal models and electronic sensors to assess the taste of pediatric formulations (13,14). Pediatric drug development and the identification and characterization of appropriate dosage forms go hand in hand. Recent research progress shows the importance and the need for clinically relevant pediatric products and in addition advisably in-vitro methods to keep up with new technologies and demands. Pediatric formulation initiatives and the competent authorities are working on providing improved and detailed guidance for pediatric product development. The demand for more flexible and individual drug dosing will evolve in significant improvement of medicines for pediatric use in the near future. 1 Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, BioCity, Artillerigatan 6A, 20520, Turku, Finland. 2 Institute of Pharmaceutics and Biopharmaceutics, Heinrich-HeineUniversität Düsseldorf, Universitätsstraße 1, Geb. 26.22, 40225, Düsseldorf, Germany. 3 To whom correspondence should be addressed. (e-mail: maren.preis@abo.fi) AAPS PharmSciTech (# 2017) DOI: 10.1208/s12249-016-0705-x

Investigation of dissolved cellulose in development of buccal discs for oromucosal drug delivery

Abstract Mucoadhesive formulations have a wide scope of application for both systemic and local treatment of various diseases. In the case of recurrent aphthous stomatitis, to ensure effective therapy, the concentration of corticosteroids, and/or anesthetics at the mouth ulcer side should be maintained with minimal systemic absorption. Therefore, the aim of the study was to investigate cellulose-based formulations, in achieving suitable hardness, mucoadhesiveness, and sustained release of the active ingredients directed towards the mucosa for an extended period of time (∼4 h). This was examined by creating polymer reinforced cellulose composites which consisted of porous cellulose discs (CD) and different polymer components namely polyethylene glycol 6000 (PEG6000), polyethylene glycol 400 (PEG400), and ethyl cellulose. Empty CDs were formed by dropping dissolved cellulose into coagulation medium. The empty porous CDs were immersed into different drug loading solutions which were prepared by dissolving three different concentrations of triamcinolone acetonide and lidocaine hydrochloride in five different ratios of PEG 6000:PEG 400:ethanol (w:w:w %) solutions. All formulations were investigated regarding drug content, release, hardness, and mucoadhesive properties. The results indicate that the non-dispersing buccal discs had sufficient hardness, drug content and in vitro release properties, but further studies are needed to achieve proper mucoadhesiveness.

Prolonged drug release properties for orodispersible films by combining hot-melt extrusion and solvent casting methods

Graphical abstract Figure. No caption available. &NA; Orodispersible films (ODFs) are an advantageous dosage form to accomplish patient convenience and compliance in oral drug delivery. They provide a number of special application features, such as the ease of administration without water and suitability for patients with swallowing problems. However, this promising dosage form has been limited to immediate release formulations so far. The aim of this study was to develop a thin film produced by solvent casting, which is rapidly disintegrating when placed in the mouth, but which provides prolonged drug release characteristics by incorporating drug‐loaded matrix particles (MPs). MPs were produced by hot‐melt extrusion and subsequent milling, using theophylline anhydrous as model drug and Eudragit® RS as matrix‐forming agent enabling prolonged drug release. ODFs were manufactured using hypromellose as film former. Dissolution studies were performed to investigate the kinetics and the duration of drug release. Additionally, disintegration time was determined using the PharmaTest® disintegration tester equipped with a specific sample holder for ODFs. All produced ODFs containing theophylline‐loaded MPs show fast disintegration while the drug release was prolonged. The degree of release prolongation increases with increasing sizes of incorporated MPs. Matrix‐controlled release kinetics were found for ODFs containing MPs with at least 315 &mgr;m in size. In summary, the production of fast disintegrating ODFs with prolonged release properties was feasible. Furthermore, freely adjustable dissolution profiles could be realized for ODFs by incorporating MPs of various particle sizes.

Mesoporous silica nanoparticles facilitating the dissolution of poorly soluble drugs in orodispersible films

&NA; Orodispersible films (ODF) are immediately dissolving/disintegrating intraoral dosage forms, presented as substitutes of conventional tablets or capsules to ease problems associated with swallowing. Efforts have been made to be able to exploit ODFs as dosage forms for poorly soluble drugs. In the last two decades, mesoporous silica nanoparticles (MSNs) have been extensively used in drug delivery applications to overcome solubility problems of drugs. The tunable features of MSNs make them suitable candidates as drug carriers and solubility enhancers. In this study, the feasibility of MSNs as a carrier of poorly soluble drugs, using prednisolone as a model drug, in ODFs was investigated. Our results revealed that the increased amount of MSNs in ODFs leads to shortening of the disintegration time of the films. Drug content investigations showed that low dose ODFs with prednisolone incorporation efficiencies higher than 80% could be produced. Furthermore, the prednisolone release profile from ODFs can be tuned with the incorporation of MSNs as drug carrier (MSNpred). The MSNpred incorporated ODFs yield with immediate release of drug from the ODF, whereby 90% of the prednisolone content could be released in the first minutes. By modifying the MSNpred design with copolymer surface coating, prednisolone (cop‐MSNpred) release can be modulated into a two‐step sustained release profile. To sum up, the MSNs platform does not only provide careful low dose incorporation into ODF with high efficiency, but it also aids in tuning the drug release profiles from ODFs. Graphical abstract Figure. No caption available.