Dissolution testing of oral film preparations: Experimental comparison of compendial and non-compendial methods.

In vitro dissolution testing is one of the most frequently used tests in pharmaceutical quality control, since evaluation of the drug release profile and estimation of the dosage form performance is enabled. However, for oral film preparations no standardized compendial dissolution method or specifications are available worldwide. Therefore, four different dissolution methods described in the literature, namely the basket method, the paddle and glass disc (PGD) method, the flow-through cell with adapted film sample holders produced via 3D printing (FTC + FH3D) and the "Punch and Filter" (PAF) method were chosen and their suitability to investigate oral films with different release properties was compared. For this purpose, oral films with immediate (ODFIR) and prolonged theophylline release (ODFPR) as well as double layer films (ODFDL) were produced and investigated. All produced ODFs disintegrated rapidly in 27-46 s and showed content uniformity with acceptance values between 7.3 and 11.3%. The FTC + FH3D and the PGD method showed increased discriminatory power and were suitable to investigate the integrity of the shielding layer of ODFDL as shown by linear prolonged release (mean dissolution time at 80% drug release (MDT80) of 366.8 and 217.1 min for FTC + FH3D and PGD method), which was not possible applying the basket and PAF method. These methods did not allow clear discrimination between ODFIR and ODFDL, since immediate release profiles with MDT80 values of 4.1 and 11.0 min for the basket method and 6.8 and 15.5 min for the PAF method were found for both, ODFIR and ODFDL respectively. The FTC + FH3D method provided high flexibility, which may be used to simulate gastrointestinal transit. The PAF method reflects physiological conditions of the oral cavity and enables mimicking the in vivo film application. These methods are particularly valuable for research and development purposes. Due to the simple and well standardized instrumental setup as well as high robustness, the basket and PGD method are particularly suitable for use in pharmaceutical quality control.

3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis-Personalized Dosing and Drug Release.

The aim of the present work was to produce 3D-printed oral dosage forms with a sufficient drug dose displaying various release profiles. Hot-melt extrusion was utilized to produce drug-loaded feedstock material that was subsequently 3D-printed into 6, 8, and 10 × 2.5 mm tablets with 15% and 90% infill levels. The prepared formulations contained 30% (w/w) isoniazid in combination with one or multiple pharmaceutical polymers possessing suitable properties for oral drug delivery. Thirteen formulations were successfully hot-melt extruded of which eight had properties suitable for fused deposition modeling 3D printing. Formulations containing HPC were found to be superior regarding printability in this study. Filaments with a breaking distance below 1.5 mm were observed to be too brittle to be fed into the printer. In addition, filaments with high moisture uptake at high relative humidity generally failed to be printable. Different release profiles for the 3D-printed tablets were obtained as a result of using different polymers in the printed formulations. For 8 mm tablets printed with 90% infill, 80% isoniazid release was observed between 40 and 852 min. Drug release characteristics could further be altered by changing the infill or the size of the printed tablets allowing personalization of the tablets. This study presents novel formulations containing isoniazid for prevention of latent tuberculosis and investigates 3D printing technology for personalized production of oral solid dosage forms enabling adjustable dose and drug release properties.

Prolonged release from orodispersible films by incorporation of diclofenac-loaded micropellets.

Prolonged drug release provided by multiple-unit dosage forms is highly beneficial to enhance the compliance and safety of the pharmacotherapy even for patients with swallowing deficiencies. To facilitate the intake for these patients, multiple-unit tablets and capsules have to be crushed or opened. An attempt to overcome these issues has been made by the introduction of orodispersible films (ODFs), which rapidly disintegrate within the oral cavity and facilitate the intake of oral solid dosage forms. The aim of this study was to develop a rapidly disintegrating ODF with prolonged release properties by incorporation of small-sized micropellets (MPs). MPs with a drug load of 70% were produced by wet extrusion and spheronization using Vivapur® MCG as pelletizing aid and diclofenac sodium (DS) as model drug. MPs were film-coated with an Eudragit® RS/RL coating and incorporated into the ODF-forming hypromellose solution. ODFs were produced by solvent casting technique. Disintegration times were determined using the PharmaTest® disintegration tester equipped with sample holders for ODFs. Dissolution studies were performed for MPs and ODFs. X-ray micro-computed tomography was used to visualize internal and external surface structures of MPs before and after release studies. MP-loaded ODFs show fast disintegration within 30 s, whereby film-coated MPs remain intact. Uncoated MPs are disintegrating thus revealing immediate DS release. In comparison, DS release was prolonged for film-coated MPs and corresponding ODFs. Incorporation of different amounts of MPs had no effect on the dissolution, but on mechanical properties of ODFs, which decrease with increasing amounts of MPs. The production of rapidly disintegrating ODFs with prolonged release properties for DS, representing a freely water-soluble drug, was feasible.

Novel Dissolution Method for Oral Film Preparations with Modified Release Properties.

Oromucosal film preparations have gained popularity in pharmaceutical research and development. Therefore, oral films have been integrated into the monograph "oromucosal preparations" of the European Pharmacopeia in 2012. Regulatory authorities explicitly demand dissolution studies for films, but neither refer to suitable methods nor established specifications. Test methods described in the literature are often limited to immediate release formulations or not applicable to investigate the drug release of films with prolonged release profiles considering the different stages of gastrointestinal transit. The aims of this study were to develop a dissolution test method, which is suitable to investigate the drug release of film preparations with immediate as well as modified release profiles and to explore the potential of the test setup considering some physiological characteristics. Therefore, a conventional flow-through cell was equipped with in-house built sample holders. Three-dimensional printing technology was used for prototyping one of the sample holders. Four different types of films were investigated, such as ODFs with immediate (ODFIR) and prolonged release (ODFPR) characteristics as well as a double-layer film (ODFDL), produced with a water-insoluble shielding layer. Anhydrous theophylline was used as a model drug for all film types. Introducing special fixtures for oral films to a conventional flow-through cell enables successful determination of the drug release behavior of oral film preparations with immediate as well as modified release properties. Investigating ODFDL, the application of film sample holders with backing plates such as film sample holder with backing plate (FHB) and 3D printed film sample holder (FH3D) showed prolonged release profiles with 14.6 ± 1.30% theophylline dissolved within 2 h for FHB compared to 92.9 ± 3.33% for the film sample holder without backing plate (FH). This indicates their suitability to examine the integrity of the shielding layer. The application of the backing plate further decreased the drug release of ODFPR < 315 to 61.0 ± 1.69% dissolved theophylline within 2 h using FHB compared to 82.3 ± 0.74% using FH, due to a reduced ODF surface exposed to the dissolution medium. The potential of the dissolution test setup to consider physiological conditions of the human gastrointestinal transit was investigated by applying different flow rates and media compositions to simulate conditions within the oral cavity, stomach, and intestine. For the application of a low flow rate of 1 ml/min, comparable to the salivary flow within the oral cavity, decreased theophylline release was observed, while similar release profiles were obtained for flow rates between 2 and 8 ml/min. Substantial impact on the theophylline release was exerted by varying the composition of the dissolution medium. Since the drug release from ODFPR is controlled by diffusion through a water-insoluble matrix, ion species and concentration strongly affect the release behavior. In the future, IVIVC studies have to be performed to explore, whether obtained data can be used to predict drug release behavior of ODFs during the human gastrointestinal transit.

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

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.

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

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 µm 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.

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.

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

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.

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.

Development of Oromucosal Dosage Forms by Combining Electrospinning and Inkjet Printing.

Printing technology has been shown to enable flexible fabrication of solid dosage forms for personalized drug therapy. Several methods can be applied for tailoring the properties of the printed pharmaceuticals. In this study, the use of electrospun fibrous substrates in the fabrication of inkjet-printed dosage forms was investigated. A single-drug formulation with lidocaine hydrochloride (LH) and a combination drug system containing LH and piroxicam (PRX) for oromucosal administration were prepared. The LH was deposited on the electrospun and cross-linked gelatin substrates by inkjet printing, whereas PRX was incorporated within the substrate fibers during electrospinning. The solid state analysis of the electrospun substrates showed that PRX was in an amorphous state within the fibers. Furthermore, the results indicated the entrapment and solidification of the dissolved LH within the fibrous gelatin matrix. The printed drug amount (2-3 mg) was in good correlation with the theoretical dose calculated based on the printing parameters. However, a noticeable degradation of the printed LH was detected after a few months. An immediate release (over 85% drug release after 8 min) of both drugs from the printed dosage forms was observed. In conclusion, the prepared electrospun gelatin scaffolds were shown to be suitable substrates for inkjet printing of oromucosal formulations. The combination of electrospinning and inkjet printing allowed the preparation of a dual drug system.

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.

Colorimetry as Quality Control Tool for Individual Inkjet-Printed Pediatric Formulations.

Printing technologies were recently introduced to the pharmaceutical field for manufacturing of drug delivery systems. Printing allows on demand manufacturing of flexible pharmaceutical doses in a personalized manner, which is critical for a successful and safe treatment of patient populations with specific needs, such as children and the elderly, and patients facing multimorbidity. Printing of pharmaceuticals as technique generates new demands on the quality control procedures. For example, rapid quality control is needed as the printing can be done on demand and at the point of care. This study evaluated the potential use of a handheld colorimetry device for quality control of printed doses of vitamin Bs on edible rice and sugar substrates. The structural features of the substrates with and without ink were also compared. A multicomponent ink formulation with vitamin B1, B2, B3, and B6 was developed. Doses (4 cm2) were prepared by applying 1-10 layers of yellow ink onto the white substrates using thermal inkjet technology. The colorimetric method was seen to be viable in detecting doses up to the 5th and 6th printed layers until color saturation of the yellow color parameter (b*) was observed on the substrates. Liquid chromatography mass spectrometry was used as a reference method for the colorimetry measurements plotted against the number of printed layers. It was concluded that colorimetry could be used as a quality control tool for detection of different doses. However, optimization of the color addition needs to be done to avoid color saturation within the planned dose interval.

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.

Application of a colorimetric technique in quality control for printed pediatric orodispersible drug delivery systems containing propranolol hydrochloride.

The feasibility of a colorimetric technique was investigated in CIELAB color space as an analytical quality control method for content uniformity of printed orodispersible pediatric delivery systems. Inkjet printing was utilized to fabricate orodispersibe film formulations containing propranolol hydrochloride in a colored ink base using three different edible substrates. A thin sweetener coating layer of saccharin was successfully included in the final dosage forms for palatability purposes using a casting knife. Optical microscopy, scanning electron microscopy and scanning white light interferometry analyses were conducted to study the effect of printing on the surface morphology and topography of the substrates. Differential scanning calorimetry and attenuated total reflectance infrared spectroscopy were used to study the solid state properties and possible interactions between the drug and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur. to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride.

Oromucosal film preparations: points to consider for patient centricity and manufacturing processes.

INTRODUCTION: According to the European Pharmacopoeia, oromucosal films comprise mucoadhesive buccal films and orodispersible films. Both oral dosage forms receive considerable interest in the recent years as commercially available pharmaceutical products and as small scale personalized extemporaneous preparations. AREAS COVERED: In this review, technological issues such as viscosity of the casting liquid, mechanical properties of the film, upscaling and the stability of the casting solution and produced films will be discussed. Furthermore, patient-related problems like appearance, mucosal irritation, taste, drug load, safety and biopharmaceutics are described. Current knowledge and directions for solutions are summarized. EXPERT OPINION: The viscosity of the casting solution is a key factor for producing suitable films. This parameter is amongst others dependent on the polymer and active pharmaceutical ingredient, and the further excipients that are used. For optimal patient compliance, an acceptable taste and palatability are desirable. Safe and inert excipients should be used and appropriate packaging should be provided to produced films. Absorption through the oral mucosa will vary for each active compound, formulation and patient, which gives rise to pharmacokinetic questions. Finally, the European Pharmacopoeia needs to specify methods, requirement and definitions for oromucosal film preparations based on bio-relevant data.

In-vitro and in-vivo evaluation of taste-masked cetirizine hydrochloride formulated in oral lyophilisates.

The use of solid oral dosage forms is typically favored with regard to stability and ease of administration. The aim of this study was to investigate whether cyclodextrins (CD) or ion exchange resins (IER) could be used to taste-mask cetirizine HCl when formulated in a freeze-dried oral formulation. The oral lyophilisates were produced using the Zydis(®) technology that offer the opportunity to produce the dosage form directly in the aluminum laminate blister packs. This study confirmed that a pre-formed resinate of cetirizine HCl and various cyclodextrins can be successfully incorporated into the Zydis(®) oral lyophilisate. A chemically stable product with acceptable release profile was obtained in the case of cyclodextrin. This study has also demonstrated that the Insent(®) taste sensing system is a useful technique for predicting the taste-masking potential of Zydis(®) formulations. The electronic taste sensing system (e-tongue) data can be used to provide guidance on the selection of taste-masked formulations. Principal component analysis (PCA) of sensor data by plotting the PCA scores revealed the effects of used taste-masking techniques on the e-tongue sensors, indicating the successful taste improvement. The PCA plot of the taste sensor data revealed larger distances between the non-taste-masked sample and the CD- and IER-loaded samples, and the shift toward the drug-free formulations and excipient signals indicates a modification of the product taste. The human taste trial confirms the acceptability of the selected promising formulations. The taste evaluation results showed that an effectively taste-masked formulation has been achieved using ß-cyclodextrin and cherry/sucralose flavor system with over 80% of volunteers finding the tablet to be acceptable.