Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5669_Библиотеки_им_академика_М_И_Перельмана
.pdf
Stereolithography (SLA) in Pharmaceuticals
Prashanth Ravi and Parimal Patel
Abstract
Commercial stereolithography (SLA) 3D printing has been around for over
three decades. However, only recently the technology has been employed in
pharmaceuticals to 3D print pills and devices for drug delivery, aided in part
by the miniaturization of this technology. Compared to other 3D printing
technologies based on powder or filament-based feedstock, SLA offers superior
surface finish, accuracy, and material versatility. This chapter covers the major
advancements in SLA 3D printing of pharmaceuticals and provides insight
into the origin of SLA 3D printing and the current subcategories within this
technology, the important governing process parameters, various applications
in pharmaceuticals from peer-reviewed literature, and challenges that must be
addressed to bring the technology closer to the clinic. Using SLA, rigid pills
loaded with drugs such as paracetamol, caffeine, naproxen, chloramphenicol,
prednisolone, aspirin, and berberine have been successfully 3D printed. In
addition, soft devices for drug release have also been 3D printed. However,
unexpected reactions have been reported in the literature which emphasize the
cautionary aspect of 3D printing pharmaceuticals using SLA and the need for
further meticulous research. Additionally, the regulatory hurdles including a
general lack of quality control processes need to be addressed to bring this
technology into the clinic. The throughput of SLA 3D printing for pharmaceuticals, like other 3D printing technologies, is substantially lower compared
3
P. R a vi ( )
Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
e-mail:
raviph@ucmail.uc.edu; prashanth.ravi@uc.edu
P. P a te l
Department of Mechanical & Aerospace Engineering, University of Texas at Arlington,
Arlington, TX, USA
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404- 2_3
97
98 P. Ravi and P. Patel
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
to conventional industrial fabrication processes. Further, post-processing steps
such as support structure removal and post-curing are needed to achieve the
desired end-use characteristics. However, a novel technique of volumetric 3D
printing of pharmaceuticals holds promise to address some of these limitations,
but the technology is still in the nascent stage and technical challenges such as
dimensional accuracy and material compatibility still need to be addressed. SLA
3D printing of pharmaceuticals is a new and active area of research with potential
to impact clinical practice in the future as critical roadblocks are addressed.
Keywords
3D printing · Pharmaceuticals · Drug delivery · Stereolithography · Medical
3D printing · Vat photopolymerization
3.1 Introduction
Additive Manufacturing (AM) or three-dimensional (3D) printing technologies
have transformed manufacturing across industries such as automotive, aerospace,
healthcare, consumer products, and construction since their invention in the 1980s
(Campbell et al.
primary methods of manufacturing wherein a large block of material was gradually
chipped away using different techniques to achieve the desired shape. In AM or
3D printing, this paradigm is totally upended by instead gradually adding material
layer-by-layer to form the intended object (Ravi et al.
user to fabricate complex objects including organic shapes such as those found in
anatomical models utilized in pre-surgical planning in a relatively short period of
time which would traditionally not be possible to manufacture or would require
complex and often expensive tooling (Ravi et al.
to note that there are varying degrees of post-processing needed subsequent to
the printing operation to achieve the desired part characteristics based on the
technology used. Within 3D printing, there are 7 distinct technologies as per
the ASTM: Material Extrusion (MEX), Vat Photopolymerization (VP), Material
Jetting (MJT), Binder Jetting (BJT), Powder Bed Fusion (PBF), Sheet Lamination
(SL), and Directed Energy Deposition (DED) (Alexander et al.
these technologies has its own governing physics, process parameters, and usable
material(s). Although the term “3D printing” has become mainstream because of its
conciseness and parallel to the “2D” or paper-based inkjet printing, it really does
not do justice in capturing the essence of the technology when compared to the term
“Additive Manufacturing.” This is because the set of 7 AM technologies can be
employed to actually fabricate physical parts having functional properties suited to
real-world applications. Collectively, the 7 AM technologies enable the manufacture
of complex objects using polymers, metals, composites, and ceramics. Although
polymeric 3D printing was where the technology arose, metal 3D printing is seeing
the highest growth recently in part due to the usage of the technology to manufacture
2012). Historically, subtractive manufacturing was one of the
2017). This empowers the
2022a). However, it is important
2021). Each of
3 Stereolithography (SLA) in Pharmaceuticals 99
high profile components such as the General Electric (GE) Aviation Leading Edge
Aviation Propulsion (LEAP) engine nozzles, and an entire space shuttle engine for
a National Aeronautics and Space Administration (NASA) project.
The ability of 3D printing to manufacture complex shapes and customize both
internal and external geometries translates well into medicine. Within healthcare,
3D printing is transforming medicine via the fabrication of patient-specific anatomic
models, anatomic guides, implants with optimized internal architecture, and other
devices (Mitsouras et al.
2015). The ability to personalize devices improves patient
outcomes compared to using one size fits all devices. Traditional pharmaceutical
manufacturing is generally time consuming, labor intensive, costly, rigid, and cumbersome, although once setup it can be used to manufacture huge volumes of tablets
and other drug-loaded excipients. Three-dimensional printing technology offers
the potential to address several of the shortcomings in traditional pharmaceutical
manufacturing, although it is challenging to achieve high volume production using
the current throughout of 3D printing technologies. In the last decade, researchers
have begun exploring the fabrication of drug-loaded excipients using 3D printing
technologies primarily owing to the ability to personalize dosages, customize
external shapes as well as internal geometries, tailor the constituent materials, and
reduce operational costs, among other characteristics. However, to date there is only
1 United States (US) Food & Drug Administration (FDA) approved 3D printed drug
that was developed by Aprecia Pharmaceuticals and cleared in 2015 (Ravi
2020),
although startup companies such as FabRx are making promising progress using
their Printlets
™
technology for fabricating oral dosage forms. One of the reasons
for this is the lack of tight quality control processes in 3D printed pharmaceuticals
compared to traditional manufacturing. The part-to-part variability in properties
can be relatively quite high when fabricated using 3D printing compared to when
fabricated using traditional manufacturing. Large well-controlled studies are needed
to ascertain whether the part-to-part variability within the pharmaceutical domain is
acceptable considering the advantages offered by 3D printing technologies.
Since 2016, researchers have increasingly begun studying VP (stereolithography
—SLA) 3D printing for pharmaceutical research. The SLA/VP 3D printing technology is widely different in terms of the feedstock material, process parameters,
and end-use properties compared to conventional tablet manufacturing using power
compression. This chapter will cover the major advancements in SLA/VP 3D
printing of pharmaceuticals. A historical context of the development of SLA
3D printing over nearly 50 years will be provided in the beginning which will
include the major subcategories within SLA/VP 3D printing along with certain
benefits offered by this technology. This will be followed by a discussion of the
important process parameters and considerations governing this technology. Next,
a comprehensive summary of the major research works in the field over the last 6–
7 years will be discussed and summarized in tabular form. Recent works with high
future potential will be highlighted. This will be followed by a discussion of the
roadblocks preventing rapid progress and clinical translation of this technology with
some final concluding remarks. The overarching goal of this chapter is to provide an
overview of the state of SLA/VP 3D printing research in the pharmaceutical domain.
100 P. Ravi and P. Patel
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
3.2 History and Principles of Stereolithography (SLA) 3D
Printing
The idea of 3D printing evolved from the early 1970s when Pierre A. L. Ciraud
described a method of application of layers of powdered material and their
subsequent solidification through action of a high energy beam (Jamróz et al.
Over the nearly 40 years of existence of 3D printing, several different technologies
were developed, but they are primarily based on liquid solidification, powder
solidification, and extrusion. The first significant work linked to modern SLA 3D
printing emerged during the early 1970s when Dr. Hideo Kodama invented the
modern layered approach foundational to 3D printing. In the late 1970s, Swainson
presented a system for constructing 3D objects by two intersecting radiation beams
(Huang et al.
2020). Commercial SLA or vat photopolymerization (VP) 3D printing
is a liquid photopolymer-based technology invented in the 1980s (Hull
inventor Charles Hull was working with a company that used ultraviolet (UV) light
to apply thin layers of plastic veneers on furniture, paper products, and tabletops.
He then developed the idea of placing multiple layers of this material, one on top
of each other, to build three-dimensional (3D) objects in almost any conceivable
shape (Martinez et al.
2018a). In SLA 3D printing, a light source, typically a laser,
is used to fabricate the 3D model layer-by-layer from a photopolymer reservoir.
Traditionally, SLA 3D printing was confined to laser-based top-down industrial
systems that were used for prototyping large components. However, progress across
multiple technologies resulted in the miniaturization of SLA 3D printing to the
desktop environment. The last decade has seen the rapid rise of bottom-up or
inverted SLA 3D printing systems (Fig.
3.1), a key transformation enabling the
2018).
1986). The
Fig. 3.1 Major types of inverted stereolithography 3D printing technology adapted with permission from (Pagac et al.
liquid resin, (3) building platform, (4) UV laser source, (5) XY scanning mirror, (6) laser beam,
(7) resin tank, (8) window, and (9) layer-by-layer elevation. Center: components of a typical DLP
machine (only different components labeled): (4) light source, (5) digital projector, (6) light beams.
Right: components of a typical CLIP machine (only different components labeled): (8) oxygenpermeable window, (9) dead zone, and (10) continuous elevation
2021). Left: components of a typical SLA machine: (1) printed part, (2)
3 Stereolithography (SLA) in Pharmaceuticals 101
Fig. 3.2 Scheme of masked LCD-based VP 3D printing. Reproduced with permission from (O¨zóg
et al.
2022)
miniaturization of the bulky and industrial SLA technology, aided in large part by
the expiration of early key patents. This miniaturization is a key trait that makes this
technology suitable for pharmaceutical 3D printing, since the pills/tablets/excipients
3D printed are relatively smaller compared to the large bulky components 3D
printed for automotive, aerospace, or other prototyping applications. Some of these
systems now incorporate digital light projection (DLP) sources or masked liquid
crystal displays (LCD) backlit with light emitting diode (LED) arrays, which allow
superior throughput compared to traditional laser-based scanning systems (Fig.
3.2).
This superior throughout is achieved by exposing the entire layer at once in contrast
to a raster-by-raster scan of the layer using a laser beam.
Continuous liquid interface production (CLIP) was invented in 2015 and
improves the post-layer fabrication peel operation in inverted SLA 3D printing
(Tumbleston et al.
2015). A dead zone of liquid resin is created between the
cured resin and oxygen-permeable membrane by exploiting the oxygen-based
inhibition of free radical photopolymerization. Nexa3D invented the lubricant
sublayer technology to substantially reduce the post-layer peel separation forces
by incorporating a thin layer of lubricant (silicone oil) between the cured resin and
bottom membrane (Zitelli et al.
2022). The post-layer peel separation (Fig. 3.3)is
one of the fundamental limitations of inverted VP 3D printing technology limiting
throughput of this powerful technology. It can consume up to 75% of the total print
time, particularly with improvement in the intensity and efficiency of the LED array
102 P. Ravi and P. Patel
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Fig. 3.3 (Left) Schematic of the post-layer peel separation process in inverted VP 3D printing.
The current layer (green) adheres to the elastic membrane (red) at the bottom of the vat (resin
container, walls in orange) after exposure to curing light radiation (not shown). The build platform
(gray) is then gradually lifted up (gray arrow) to tense the elastic membrane (red) and separate
the cured layer from the vat. After separation, the elastic membrane returns to normal position to
allow resin (purple dashes) to flow back into the newly created void for fabricating the next layer.
The process then repeats continuously until the part is 3D printed. (Right) The membrane tensional
force (F
vat walls is H, the vertical lift distance is L, the peel angle is θ and F
normal forces, respectively. Reproduced with permission from (Ravi et al.
) acts to detach the cured layer. The horizontal distance from the edge of the part to the
M
and FN are the shear and
S
2021a)
light sources and the recent transition to the monochromatic LCD masks that allow
substantially higher transmission of light compared to the traditional color LCD
screens. Digital light processing (DLP) and two photon polymerization (2PP) are
also VP based 3D printing technologies (Xu et al.
2021a). DLP technology was
invented by Texas Instruments (TI) and works by projecting an entire layer using
an array of dynamic mirrors, whereas 2PP works by the sequential energizing of a
resin voxel using two energetic photon pulses.
The inverted SLA 3D printing technology necessitates the use of support
scaffolding to anchor any floating model elements to the rest of the model and to deal
with the peel separation forces (Awad et al. 2018). The printed model is in a green
state that requires rinsing in a solvent to wash away uncured resin followed by post
printing UV curing to fully set the crosslinking reactions that ultimately determine
the mechanical properties of the final 3D printed object. The support scaffolding
must be manually separated from the model in a meticulous manner to not damage
any delicate features. Further, the post-processing must be factored into the picture
before actually printing the model to ensure optimal orientation, support placement,
and no suction cups. The liquid photopolymeric nature of materials affords superior
versatility because the base photopolymer can be combined with a multitude of
materials. For instance, resins can be created for diverse applications such as dental
crowns, engineering prototypes, anatomic models, surgical guides, jewelry castings,
flexible components, etc. and fabricated on the same desktop inverted SLA 3D
printing system by having a modular system for swapping out the vat, build plate,
and material cartridge. Furthermore, the accuracy and surface finish are among the
3 Stereolithography (SLA) in Pharmaceuticals 103
best of any 3D printing technology available while the cost is substantially lower
or on par compared to other 3D printing technologies (Awad et al.
been demonstrated to produce models with less than 10-micron accuracy, whereas
DLP can fabricate models with 30–100 micron accuracy (Martinez et al.
The accuracy is particularly important when fabricating drug-loaded tablets or other
excipients that are relatively smaller in size to ensure correct drug dose delivery.
2018). SLA has
2018a).
3.3 Stereolithography (SLA)/Vat Photopolymerization (VP)
Materials
VP resins are developed using multiple components: liquid monomers, reactive
diluents, flexibilizers, and stabilizers. When a photoinitiator undergoes impact by
a UV light photon, it transforms into a reactive species and interacts with the
liquid monomers to commence the radical chain polymerization reaction. The
photoinitiator plays a key role in utilizing the electromagnetic energy of a particular
wavelength of light and converting it into chemical energy. This reaction generates
free radicals which propagate through the monomers and oligomers to create a
polymer network. Many resins have been developed for VP but generally these
are primarily composed of methacrylates or acrylic esters because they exhibit
fast reaction rates, tunable mechanical properties, and stability. Although it is
worthwhile to note that the resins can be highly brittle and prone to shrinkage
during the radical chain polymerization reactions. When it comes to medical devices
and the pharmaceutical industry, these resins must be biocompatible and digestible,
hence the resin material is a critical parameter. Poly (ethylene glycol) diacrylate
(PEGDA) monomer has been a regular choice to formulate resins by researchers
and industry resin manufacturers due to its biocompatibility and degradability
(Robles-Martinez et al.
are toxic to living organisms, hence it is crucial to keep the concentration to a
minimal level, typically not more than 1 wt% in the overall formulations. Typical
photoinitiators used are 2,4,6-trimethylbenzoyldiphenyl phosphine oxide (TPO) and
bis-acylphosphine oxide (BAPO). Furthermore, the resin’s transparency impacts the
scattering and attenuation of photons and its curing ability during printing. A clear
acrylate resin, for instance, can allow more photons to penetrate deeper potentially
leading to better cure compared to opaque resins. Certain dyes are added to the resin
to make them opaque and impart color, and this can in turn increase light scattering
and negatively impact the photon penetration into the resin therefore lowering the
overall curing. Each subcategory of SLA 3D printing: SLA, DLP, 2PP, and CLIP,
process these resins in slightly differing ways to create the actual 3D printed parts.
It is evident that current choices for pharmaceutical resins are limited compared
to the plethora of material choices available for conventional tablet manufacturing,
and this challenge is one of the important barriers in the future that will determine
success of the technology and penetration into the clinical space.
2019; Martinez et al. 2018b). Generally, the photoinitiators
104 P. Ravi and P. Patel
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
3.4 Stereolithography (SLA)/Vat Photopolymerization (VP)
Process Parameters
The printing process and process parameters can define the final mechanical
properties and geometrical accuracies of printed parts. The laser/light power, LCD
mask gray scale, resin temperature, laser scanning speed, and layer height are some
important process parameters governing the quality and characteristics of the printed
parts. While SLA can print up to 30 μm layers giving a high accuracy and smooth
surface finish, it is relatively slow due to its laser scanning process. DLP printers can
print 50–100 μm and print parts faster than SLA, while CLIP printers are 100 times
faster than any other VP technologies potentially rendering them the best candidate
for mass production. However, CLIP is known to struggle when 3D printing large
solid models that generate huge amounts of polymerization related heat and require
large volumes of resin to flow into the center for maintaining continuous fabrication.
2PP produces the highest resolution parts with as small as 100 nm features (Serbin
et al.
2004), although the throughout is substantially lower. Other than speed
and accuracy, each layer must peel from the transparent vat membrane, and this
determines success or failure of parts printed using DLP, SLA, and masked SLA.
The peel rate, governed by the lifting speed of the build plate, is positively correlated
with the peel forces generated. In general, the lower the peel force the better the print
quality and success rate. This is primarily why the optimal part orientation in SLA
3D printing reduces the largest as well as average cross-sectional area across layers.
Polydimethylsiloxane (PDMS) and acrylic sheets, such as those manufacture from
fluorinated ethylene polypropylene (FEP) and perfluoroalkoxy (PFA), are widely
used as the transparent membrane at the bottom of the vat since they allow easy peel
from the surface. However, drawbacks of these surfaces are that they permit passive
oxygen diffusion, restricting the interfacial polymer cure, and are consumables
that need frequent replacement which drive up the recurring cost of using this
technology. The CLIP technology developed in 2015 promises to overcome the
issue with an oxygen-permeable window at the print surface thereby integrating
a persistent liquid interface allowing it to print continuously instead of in a layerby-layer fashion, but the results are excellent primarily when printing highly porous
geometries and these results are not reproducible using large solid geometries. Last
but not the least, one of the post-processing steps in VP printing involves rinsing
the 3D printed parts using isopropyl alcohol (IPA) and post-curing with UV light to
fully set the mechanical properties. Most commercial printer manufacturers provide
washing and curing stations with meticulous instructions for use based on the type
of resin being used to streamline the workflow from the digital model to the final
physical 3D print.
3 Stereolithography (SLA) in Pharmaceuticals 105
3.5 SLA in Pharmaceuticals
The dental and medical fields have widely adopted 3D printing to create patientspecific objects and even organs (Ravi et al.
In the pharmaceutical domain, SLA 3D printing can offer the ability to rapidly
fabricate dimensionally accurate drug-loaded excipients that are internally solid,
cost-effective, and externally smooth (Deshmane et al.
printing with other innovative technologies into pharmaceuticals is predicted to give
rise to a new digital pharmacy (Fig.
3.4). By incorporating non-invasive diagnostics
or drug monitoring techniques, electronic prescriptions, and artificial intelligence
(AI) technologies, 3D printing could provide a digital and decentralized platform for
the fabrication of customized medicines in response to monitored output (SeoaneViaño et al.
2021). The entire process could be largely automated with minimal
to no supervision once validated via extensive real-world testing across multiple
sites. One of the principal benefits common to 3D printing technology is the ability
to personalize medicine (Mathew et al.
to tailor the release profile and dosing of a 3D printed tablet simply by changing
the geometries using computer-aided design (CAD) and the ability to incorporate
drugs into injectable devices or mesh implants opens a wide range of possibilities.
For instance, despite the numerous standard dosages available for drugs such as
2021a, 2022b; Trenfield et al. 2019).
2021).Theintegrationof3D
2020; Elkasabgy et al. 2020). The ability
Fig. 3.4 The virtuous cycle of personalized medicine in the future. With AI serving as the focal
point, real-time monitoring can be used to customized dosages during the course of treatment
using an in-house pharmaceutical 3D printer. Reproduced with permission from (Seoane-Viaño et
al.
2021)
106 P. Ravi and P. Patel
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
levothyroxine, patients may still need to manually split pills on a daily/weekly
basis to achieve the targeted dosing. This could potentially be addressed by 3D
printing a personalized dosage of the medication for each patient. The fabrication
of multidrug-loaded dosage forms to reduce pill burden and improve patient
adherence becomes a possibility using the power of 3D printing technologies.
Further, 3D printing enables the on-demand fabrication of drug products which is
otherwise infeasible and expensive with conventional manufacturing (Seoane-Viaño
et al.
2021). During supply chain shortages caused by the first COVID-19 surge,
3D printing was highly effective in providing much needed personal protective
equipment (PPE) and ventilator parts to the healthcare community (Tino et al.
Ravi et al.
2021b). The pharmaceutical SLA 3D printing domain is relatively new
2020;
compared to fused deposition modeling (FDM), and there is a huge scope for further
development (Brambilla et al.
Pateletal.
2018). Although 3D printing confers several advantages, it currently
2021; Ravi and Shiakolas 2021; Patel et al. 2022;
cannot compete with industrial mass production and is limited to the production
of small batches of medicine due to the low throughput compared to traditional
mass manufacturing techniques (Trenfield et al.
2018). However, 3D printing allows
the fabrication of complex geometries that are impossible to manufacture using
conventional methods (Patel 2018). The future of 3D printing will require the
integration of real-time quality control processes to ensure product safety and
efficacy, both of which are key aspects in determining the initial foray of 3D printed
drugs into the clinic (Trenfield et al.
2019).
One of the first studies to report SLA 3D printing of oral modified-release
dosage forms was reported by Wang et al. (
2016). Poly(ethylene glycol) diacrylate
(PEGDA) monomer with diphenyl phosphine oxide (DPPO) photoinitiator was
combined with 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen)
as model drugs on a Formlabs Form 1+ 3D printer. The geometry fabricated was
a torus (Fig.
3.5) with 11 mm diameter, 4 mm height, and a central hole of 3 mm
Fig. 3.5 Torus-shaped
drug-loaded tablets with
11 mm diameter and 4 mm
height 3D printed using a
Form1+ 3D printer. Tablets
are loaded with (a)
paracetamol and (b)4-ASA
and contain varying ratios of
PEGDA/PEG300.
Reproduced with permission
from (Wang et al.
2016)
Соседние файлы в папке Библиотека им академика М.И. Перельмана