Application of 3D printing in early phase development of pharmaceutical solid dosage forms.

Three-dimensional printing (3DP) is an emerging technology, offering the possibility for the development of dose-customized, effective, and safe solid oral dosage forms (SODFs). Although 3DP has great potential, it does come with certain limitations, and the traditional drug manufacturing platforms remain the industry standard. The consensus appears to be that 3DP technology is expected to benefit personalized medicine the most, but that it is unlikely to replace conventional manufacturing for mass production. The 3DP method, on the other hand, could prove well-suited for producing small batches as an adaptive manufacturing technique for enabling adaptive clinical trial design for early clinical studies. The purpose of this review is to discuss recent advancements in 3DP technologies for SODFs and to focus on the applications for SODFs in the early clinical development stages, including a discussion of current regulatory challenges and quality controls.

Powder filling of electrospun material in vials: A proof-of-concept study.

The present paper reports the powder filling of milled electrospun materials in vials, which contained voriconazole and sulfobutylether-ß-cyclodextrin. High-speed electrospinning was used for the production of the fibrous sample, which was divided into 6 parts. Each portion was milled using different milling methods and sizes of sieves to investigate whether the milling influences the powder and filling properties. Bulk and tapped density tests, laser diffraction and angle of repose measurements were applied to characterize the milled powders, while a vibratory feeder was used for the feeding experiments. The correlation between the material property descriptors and the feeding responses was investigated by multivariate data analysis. Based on the results, three samples were chosen for the vial filling, which was accomplished with 3400 mg electrospun material containing 200 mg voriconazole, representative of the commercial product. The feed rate was set to fit the 240 g/h production rate of the electrospinning and the relative standard deviation of three repeated vial filling was determined to see the accuracy of the process. This research shows that by applying a suitable milling method it is possible to process electrospun fibers to a powder, which can be filled into vials and used as reconstitution dosage forms.

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy.

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.

Monoclonal antibody formulation manufactured by high-speed electrospinning.

Solid formulations of monoclonal antibodies present several advantages, such as improved stability and increased shelf-life as well as simpler storage and transportation. In this study, we present a gentle drying technology for monoclonal antibodies, applying the water soluble 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as matrix, to prepare a solid reconstitution dosage form. High-speed electrospinning of an aqueous infliximab-containing HP-ß-CD solution was carried out at 25 °C resulting in fibers with an average diameter of 2.5 µm. The mAb-loaded electrospun fibers were successful to preserve the stability of infliximab in solid form. The results of size exclusion chromatography and gel electrophoresis indicated no significant increase in aggregate formation during the electrospinning process compared to the initial matrix solution. The binding activity of infliximab was preserved during electrospinning compared to the reference liquid formulation. Due to the enhanced surface area, excellent reconstitution capability, i.e. clear solution within 2 min without any vigorous mixing, could be achieved in a small-scale reconstitution test. The results of this work demonstrate that high-speed electrospinning is a very promising technique to manufacture the solid formulation of monoclonal antibodies for applications such as fast reconstitutable powders.

Electrospun Solid Formulation of Anaerobic Gut Microbiome Bacteria.

A model anaerobic bacterium strain from the gut microbiome (Clostridium butyricum) producing anti-inflammatory molecules was incorporated into polymer-free fibers of a water-soluble cyclodextrin matrix (HP-ß-CD) using a promising scaled-up nanotechnology, high-speed electrospinning. A long-term stability study was also carried out on the bacteria in the fibers. Effect of storage conditions (temperature, presence of oxygen) and growth conditions on the bacterial viability in the fibers was investigated. The viability of the sporulated anaerobic bacteria in the fibers was maintained during 12 months of room temperature storage in the presence of oxygen. Direct compression was used to prepare tablets from the produced bacteria-containing fibers after milling (using an oscillating mill) and mixing with tableting excipients, making easy oral administration of the bacteria possible. No significant decrease was observed in bacterial viability following the processing of the fibers (milling and tableting).

Continuous drying of a protein-type drug using scaled-up fiber formation with HP-ß-CD matrix resulting in a directly compressible powder for tableting.

The goals of this work were to evaluate if high-speed electrospinning can be used as a gentle and continuous drying technology to produce protein-containing cyclodextrin-based fibers from an aqueous solution and to convert the produced protein-cyclodextrin fibers into a directly compressible powder. A 400 mL/h feeding rate was used during the electrospinning experiments, corresponding to a ~270 g/h production rate of the dried material. The produced fibers were collected in a cyclone. The fibers were found grindable without secondary drying, and the ground powder was mixed with tableting excipients and was successfully tableted by direct compression. The model protein-type drug (ß-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and after 6 months of storage at room temperature in the tablets. The obtained results demonstrate that high speed electrospinning can be a gentle alternative to traditional drying methods used for protein-type drugs, and that tablet formulation is achievable from the electrospun material prepared this way.

Scale-up of electrospinning technology: Applications in the pharmaceutical industry.

Recently, electrospinning (ES) of fibers has been shown to be an attractive strategy for drug delivery. One of the main features of ES is that a wide variety of drugs can be loaded into the fibers to improve their bioavailability, to enhance dissolution, or to achieve controlled release. Besides, ES is a continuous technology with low energy consumption, which can make it a very economic production alternative to the widely used freeze drying and spray drying. However, the low production rate of laboratory-scaled ES has limited the industrial application of the technology so far. This article covers the various ES technologies developed for scaled-up fiber production with an emphasis on pharmaceutically relevant examples. The methods used for increasing the productivity are complied, which is followed by a review of specific examples from literature where these technologies are utilized to produce oral drug delivery systems. The different technologies are compared in terms of their basic principles, advantages, and limitations. Finally, the different downstream processing options to prepare tablets or capsules containing the electrospun drug are covered as well. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Scaled-Up Production and Tableting of Grindable Electrospun Fibers Containing a Protein-Type Drug.

The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, ß-galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% ß-galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and ß-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonly used during the preparation of pharmaceutical tablets and was successfully compressed into tablets. ß-galactosidase remained stable during each of the processing steps (electrospinning, grinding, and tableting) and after one year of storage at room temperature in the tablets. The obtained results demonstrate that high-speed electrospinning is a viable alternative to traditional biopharmaceutical drying methods, especially for heat sensitive molecules, and tablet formulation is achievable from the electrospun material prepared this way.

Continuous alternative to freeze drying: Manufacturing of cyclodextrin-based reconstitution powder from aqueous solution using scaled-up electrospinning.

The aims of this study were to evaluate electrospinning as a continuous alternative to freeze drying in the production of a reconstitution injection dosage form, and to prove that aqueous electrospinning can be realized with a high production rate at room temperature. High-speed electrospinning with a novel continuous cyclone collection was used to manufacture a formulation of the poorly water-soluble antifungal voriconazole (VOR) with sulfobutylether-ß-cyclodextrin (SBE-ß-CD). The freeze-dried, marketed product of this drug substance, Vfend® also contains SBE-ß-CD as excipient. SBE-ß-CD acted as a 'quasi-polymer', and it could be electrospun despite its low molecular mass (2163 Da). According to X-ray diffraction and differential scanning calorimetry, no traces of crystalline VOR were detectable in the fibers. Furthermore, Raman mapping and energy dispersive spectroscopy measurements showed a uniform distribution of amorphous VOR in the fibers. Reconstitution tests carried out with ground fibrous powder showed complete dissolution resulting in a clear solution after 30 s (similarly to Vfend®). The high productivity rate (~240 g/h) achieved using high-speed electrospinning makes this scaled-up, continuous and flexible manufacturing process capable of fulfilling the technological and capacity requirements of the pharmaceutical industry. This work shows that aqueous high-speed electrospinning, being a continuous and high-throughput process, is an economically viable production alternative to freeze drying.

Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals.

In chronic intestinal diseases like inflammatory bowel disease, parenteral administration of biopharmaceuticals is associated with numerous disadvantages including immune reactions, infections, low patient compliance, and toxicity caused by high systemic bioavailability. One alternative that can potentially overcome these limitations is oral administration of biopharmaceuticals, where the local delivery will reduce the systemic exposure and furthermore the manufacturing costs will be lower. However, the development of oral dosage forms that deliver the biologically active form to the intestines is one of the greatest challenges for pharmaceutical technologists due to the sensitive nature of biopharmaceuticals. The present article discusses the various drug delivery technologies used to produce orally administered solid dosage forms of biopharmaceuticals with an emphasis on colon-targeted delivery. Solid oral dosage compositions containing different types of colon-targeting biopharmaceuticals are compiled followed by a review of currently applied and emerging drying technologies for biopharmaceuticals. The different drying technologies are compared in terms of their advantages, limitations, costs and their effect on product stability.