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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5669_Библиотеки_им_академика_М_И_Перельмана
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1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 17
Hsu et al. (2013)
different release rate of low soluble API
Wickström et al. (2015)
ASD produces stable formulation with
proper excipients
ASD produces stable formulation by
incorporating foreign substrate
ASD using nanosuspension ink Cheow et al. (2015)
Clark et al. (2020)
ODF-stable drug loaded dispersion in layers Elbl et al. (2020)
ASD-stable formulation with proper polymer Cho et al. (2020)
ASD-with different geometry shows
Jacob et al. (2016a)
IR high-dose orodispersible. Micronized
crystalline API wet-gran’d ahead of BJ3DP
Sorbitol
Benzydamine HCl (II) Maltodextrin
HEC
Kollidon VA
Olanzapine (II) PEO
Poloxamer 188
photocurable N-vinyl-2-pyrrolidone
BJ3DP Carvedilol (II) Irgacure 2959
poly(ethylene glycol) diacrylate
PVP
Indomethacin (II) L-arginine
HPMC
Naproxen (II) Polyvinylpyrrolidone, chitosan,
cellulose
Ciprofloxacin (IV) Dextran sulfate (complexing agent)
polyethylene glycol
binders
Oxcarbazepine (II) Povidone and HPC among potential
18 K. Sen et al.
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1.3.2.3 SSE
The typical formulation for SSE contains i. matrix former, ii. plasticizer, and iii.
disintegrant. For low solubility APIs, SSE has shown feasibility for immediate
release dosage forms and orally disintegrating films (ODF). For IR dosage forms,
matrix formers such as Kollicoat IR, PVP, HPMC, HPC, PEG (Aita et al.
Conceição et al.
lactose monohydrate and HPC (Cho et al.
2019;Lietal.2019) have been used. For ODF, Kollidon VA64,
2020;Elbletal. 2020; Sjöholm and San-
2019;
dler 2019; Yan et al. 2020a) have been used as adjuvant to load APIs onto the films.
In addition, SSE has been explored with S-SMEDDS, API nanocrystal suspension
printing, and floating core-shell system (CSS). SSE provides an innovative approach
to incorporate lipid-based excipients such as Gelucire
Kolliphor
®
P 188 for S-SMEDDS formulation (Vithani et al. 2019). Due to SSE’s
®
44/14, Gelucire ® 48/16, and
versatility, the ink medium can be selected from an emulsion-based system (e.g.,
solid lipid emulsion gel such as glyceride, triglyceride, etc.) to print thermolabile
drug (Johannesson et al.
ink medium to print nanocrystals using SSE (Lopez-Vidal et al.
2021) to a suspension-based system (e.g., PEG1500/PPG
2022)).
1.3.2.4 Inkjet Printing and BJ3DP
Inkjet printing process has also been applied successfully to increase solubility
or improve delivery of BCS II/IV APIs. The jetting of ink onto a preformed
substrate used in the printing has enabled fabrication of ASD-based dosage forms
for increased effective solubility. The stability of the amorphized drug in the
matrix can be achieved by incorporating a proper polymer matrix former in the
ink composition (such as Irgacure 2959, poly (ethylene glycol) diacrylate (Clark
et al.
2020) or l-arginine, PVP, and HPMC) (Hsu et al. 2013; Wickström et al.
2015). Moreover, amorphous API can also be stabilized in the ink prior to the
printing with complexing agent such as dextran sulphate (Cheow et al.
2021). For powder-based systems, BJ3DP has also made rapidly disintegrating
et al.
2015; Chou
tablets using granules containing a micronized crystalline API from BCS Class II.
(Jacob et al.
2016a). In this example, the micronized API particles aid dissolution
rate and the granules aid powder flow for BJ3DP.
1.3.3 Modulating Release Kinetics of Dosage Forms
AM technologies are among the newest tools in a multipronged pursuit: steady
blood levels within a drug’s therapeutic window, ideally while reducing dosing
frequency in a dosage form that is easy for a patient to take reliably. The oral
route remains the most facile, with a goal of obtaining release patterns more
tailored than those of conventional immediate release (IR) tablets and capsules. For
certain therapeutic regimes, transdermal and implantable routes are also considered.
Modulated or modified release (MR) encompasses many descriptors, including
both fast (IR, accelerated, or intermediate) and slow release (sustained, delayed,
tailored, continuous, pulsatile, progressive), alone or in combination (Fig.
1.3).
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 19
Fig. 1.3 Represents the basic
release profiles of different
released dosage form
Plasma Conc
Zero order release
Sustained release
Conventional release
Time
Building upon the composition-based approaches of prior MR techniques, AM
offers increased control of structure and material placement, further refining the
forms of MR that can be achieved. These capabilities differ based on the specific
form of AM.
State of the Art
To date there is extensive research applying AM for MR. Although no MR products
have been approved yet using AM, FDM-type AM appears to be at the most
advanced stage of development for MR use. In particular, Investigational New Drug
(IND) applications have been cleared by FDA in 2021 and 2022 for candidates T19,
T20, and T21 using Triastek’s MED 3D (Melt Extrusion Deposition) technology.
T19 is modular chronotherapeutic drug delivery system for rheumatoid arthritis that
controls drug release based on the shape and internal geometric pattern of the tablet.
It is administered at night and targets peak blood levels of drug in the morning
when pain and joint stiffness are most acute. Triastek expects to file a New Drug
Application (NDA) for T19 by 2023. Triastek candidate T20 is a new once-daily
formulation of a drug for cardiovascular and clotting disorders that is presently given
twice daily in other marketed forms (Everett 2021;Trieste 2022). T21 is intended for
colonic
drug delivery in the treatment of ulcerative colitis while reducing systemic
side effects. In 2022, Triastek announced a partnership with Eli Lilly for targeting
drug release in specific regions of the intestine to improve bioavailability (Triastek
Inc 2022).
T
able 1.3 summarizes the key published examples for using AM to pursue dosage
forms
exhibiting MR kinetics. (Triastek candidates T19, T20, and T21 are not listed,
as the identity of the APIs and formulation details are undisclosed as of this writing).
1.3.3.1 SLA
Few studies have explored SLA for modulating release kinetics due to the limited
availability of suitable raw materials. Thus far sustained release dosage forms
(Krkobabi´cetal. 2019; Wang et al. 2016) have been fabricated. In both cases, the
modified
drug release has been achieved by optimizing the formulation composition
20 K. Sen et al.
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´
cetal.(2019)
Fina et al. (2018a)
Goyanes et al. (2015a,
(2017)
2015b)
Awad et al. (2019)
Extended-release profile Wang et al. (2016)
Polyethylene glycol diacrylate (PEGDA)
diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide
(Photo initiator)
Paracetamol
Sustained release Krkobabi
diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide
(Photo initiator)
Acetaminophen Polyethylene glycol diacrylate (PEGDA)
release/Tailored release
Hydrochlorothiazide PVAl, mannitol, PLA CR-zero order Gioumouxouzis et al.
Fast , intermediates, and
Two pulse DR Maroni et al. (2017)
Fast and sustained
two compartment capsular device
Hydrochlorothiazide PVP,SSG, TEC,TCP, Channeled tablet Accelerated release Sadia et al. (2018)
Theophylline PVP, Eudragit enteric shell core Delay release Okwuosa et al. (2017)
Amlodipine PVAl, SSG, HPMC infill patterns, and wall thickness Tailored DR Obeid et al. (2021)
Acetaminophen PLA, PVAl, HPMC, KIR
Curcumin PVAl single/double/triple reservoir Progressive DR Russi and Gaudio (2021)
Rifampicin and isoniazid Compartmental dosage unit CR Genina et al. (2017)
sustained release
release
Eudragit RL
ethyl cellulose
Paracetamol Polyethylene oxide
Fast and immediate Hamed et al. (2021)
Eudragit L
Ethyl cellulose
Lopinavir Kollicoat IR
Lactose monohydrate, talc
Technology API Polymer Release type Reference
SLA 4-aminosalicylic acid
Tab le 1 .3 Use of AM for modulating release from dosage forms
FDM Budesonide, paracetamol PVAl MR-sustained
SLS Paracetamol/Ibuprofen Kollicoat IR
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 21
(continued)
Kulinowski et al. (2021)
kinetics by changing the
hatch spacing in infill
pattern
Gueche et al. (2021)
kinetics by changing
porosity
Algahtani et al. (2020)
Modified sustained
release profile by
printing a shell with rate
controlling polymer and
optimizing the gap in
between the shell inner
D-mannitol
Cuietal.(2019)
wall and API tablet
inside
kinetics were achieved
by changing grid pattern
and printing orientation
along with conc of
Tagami et al. (2022)
HPMC
Controlled drug release
Cuietal.(2020)
of ophthalmic patches
Immediate release by
Mannitol
Xylitol
controlling the lattice cell
size in the printing
pattern
Croscarmellose sod
Paracetamol Powdered charcoal Modulating release
Paracetamol Kollidon VA64 Modulating release
SSE Propranolol HCl Cellulose acetate
Glipizide HPMC Modulating drug release
Levofloxacin HPMC
Levetiracetam HPC
22 K. Sen et al.
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Infanger et al. (2019)
SSL-SFP IR
SL-FP CR
Ink (ethanol, water)
Delayed Release Katstra et al. (2000)
PH301 (Additive)
Eudragit E-100
Ink (ethanol)
Rowe et al. (2000)
Dual pulsatile release
Yu e t a l . ( 2009)
and IR, ER)
Eudragit RL-PO
Ink (Acetone)
changing shape,
dimensions, and conc of
release retardant
polymers.)
Wang et al. (2006)
Rowe et al. (2002)
Tunable near-zero order
Encapsulating potent
active, core-shell
PVP K-25
Lin et al. (2001)
12 week+ continuous
release, pH independent,
HPMC
release from rod-shaped
human pilot PK
PLGA
TEC
Monkhouse et al. (1997)
Conceptual implant
implant, rabbit PK study
PLGA
releasing 4 pulses of
5-FU and continuous
release of diclofenac
P(FAD:SA)
IR Sen et al. (2020))
MCC
PVPK30
5-Fluorouracil
Pseudoephedrine HCl PVAc/PVP K-30
maleate
Diclofenac sodium MCC
Chlorpheniramine
Technology API Polymer Release type Reference
BJ3DP Caffeine HPC
Tab le 1 .3 (continued)
Acetaminophen Ethyl cellulose Modulating release (by
9-Nitrocamptothecin HPMC
Ethinyl estradiol PCL
Diclofenac
Amitriptyline HCl Lactose MH
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 23
such as by tuning the ratio of photocrosslinkable polymer and hydrophilic excipient
to control the dissolution rate of the drug.
1.3.3.2 FDM
Developing controlled release or modified release formulations using FDM has
been of interest for the past decade, leveraging FDM’s ability to process malleable
thermoplastic polymer at high temperature and its ability to create complex,
compartmentalized architectures. Thus, FDM can modulate release kinetics by
optimizing formulation composition and also by optimizing the dosage form
architecture.
Compositionally, FDM uses a main thermoplastic polymer (such as polyvinyl
alcohol, PVAl), a plasticizer, and an optional disintegrant (for IR or fast release).
PVAl has been widely used as a main polymer for CR/MR dosage forms based on
its suitable water solubility properties and its extrudability properties (Goyanes et
al.
2015a). In some cases, PVAl has worked alone, but in other cases, a plasticizer
such as mannitol, sorbitol, or HPMC has been added to aid extrusion (Ðuranovi´cet
al.
2021; Gioumouxouzis et al. 2017; Wei et al. 2020). In addition to CR, various IR
dosage forms have also been produced from PVAl by FDM that include plasticizer
and disintegrant/pore former (Ðuranovi´cetal.
2021; Wei et al. 2020).
For architecture-based release control, FDM can use infill patterns (Sadia et
al.
2018), infill density (Obeid et al. 2021), shape of the tablets (Goyanes et al.
2015b), and internal compartments in the tablets (Genina et al. 2017; Russi and
Gaudio
2021). Reducing infill pattern and infill density, adding disintegrant, and
optimizing use levels can accelerate release and provide the ability to tailor release
rate. Changing the overall shape of the tablet, a general capability of AM techniques,
can be used to modify the release rate based on surface area to volume ratio. In
addition, FDM can form one or more internal compartments for modified release
(accelerated, progressive, two pulse dosage form (Maroni et al.
2017)).
1.3.3.3 SLS
Similar to FDM, SLS can modulate release using composition and dosage form
architecture.
Compositionally, the MR research has focused on thermoplastic polymers
recognized for pH- and time-dependent solubility (Awad et al.
2019; Fina et al.
2018a; Hamed et al. 2021). Kollidon IR and PEO have been used for immediate
release components, whereas polymers such as ethyl cellulose have been applied to
sustained release. The concentration of thermoplastic polymer is used to modulate
release rates. When copovidone or powdered charcoal is used as a matrix former, a
separate laser absorbent is not required (Gueche et al.
2021; Kulinowski et al. 2021).
For architecture-based release control, the SLS infill pattern can be used to
alter the extent of laser-based local binding. Specific patterns can be screened in
combination with different polymers to elucidate release properties (Fina et al.
2018a). Hatch spacing can be used to alter the resulting local pore structure as part
of modulating release rate (Kulinowski et al.
2021).
24 K. Sen et al.
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1.3.3.4 SSE
Like other AM, SSE can use a combination of compositional control (rate controlling polymers) and architectural control (e.g., infill pattern or design) to achieve MR.
Polymers such as HPC, HPMC, and cellulose acetate have been explored with SSE
to achieve release rates ranging from immediate to sustained release. Changing the
infill pattern, lattice cell size, and printing orientation of a rate controlling polymer
have also successfully tailored the drug release in an SSE dosage form (Cui et
al.
2020; Cui et al. 2019). In addition , encapsulating a BCS I drug inside a rate
controlling polymer chamber has provided sustained release in certain instances
(Algahtani et al.
2020). Beyond oral dosage forms, ophthalmic patches designed by
SSE for clinical trial setting have shown drug release primarily dependent upon the
water uptake of the incorporated polymer (Tagami et al.
2022).
1.3.3.5 BJ3DP
BJ3DP has also shown CR and MR capability by integrating rate controlling
polymer in the formulation and compartments into the dosage design. For example,
the release rate of acetaminophen was modulated by changing the tablet shape
(doughnut) and the concentration of rate controlling polymer. Here, acetaminophen
was embedded in HPMC matrix and coated with ethyl cellulose to create a constant
rate of surface erosion during dissolution (Yu et al.
2009). Also, diclofenac sodium
embedded in rate controlling polymer was used to demonstrate four specific type of
release patterns: instant release followed by continuous release; continuous release
from subdividing (breakaway) units; enteric dual pulsatory (two pulse release in
gastric pH); and dual pulsatory (two pulse release on two different pH -acidic and
gastric) (Rowe et al.
2000). Caffeine tablets were made using BJ3DP with different
grades of HPC to produce immediate release and extended-release dosage form
(Infanger et al.
2019). Near-zero order release of pseudoephedrine hydrochloride
was demonstrated from BJ3DP tablets having modular core/shell (reservoir-like)
structure tunable by changing the ratio of Kollidon SR and HPMC, supported
by pilot biostudy results (Wang et al.
designs for 12-week continuous release of ethinyl estradiol (Lin et al.
2006). For implantable systems, conceptual
2001)
and for combined continuous and pulsatile release (diclofenac and 5-fluorouracil,
respectively) (Monkhouse et al.
1997) have been demonstrated using degradable
polyesters.
1.3.4 Combining Medications into a Single Dosage Unit (“Polypill”)
A polypill can be defined as a dosage form containing two or more active ingredients. Although the term “polypill” has a specific lineage related to cardiovascular
disease (Gioumouxouzis et al. 2017; Wald and Law 2003), in broader usage it
can refer to any multidrug dosage form used to treat disease. In practice, that
means one pill replaces several. This approach reduces pill count and simplifies
dosing schedule, with associated benefits to patient adherence. When manufactured
centrally, the dose levels of each drug are preset, and such fixed-dose combination
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 25
Fig. 1.4 Examples of “Polypill” design using AM (Khaled et al.
2015a; Pereira et al. 2019)
(FDC) products are widely made today by traditional means, predominantly for
two-drug and three-drug regimens.
In this context, AM is most often seen as enabling much greater flexibility
for polypill manufacture, including the number and levels of drugs that can be
incorporated. This section will focus on polypill composition and design using AM.
Flexible manufacturing aspects of AM are already separately addressed in Sect.
1.3.1.
State of the Art
Although various research groups have shown the possibility of using AM to
fabricate polypills (Keikhosravi et al.
2020), this specific application has yet to
achieve a regulatory approval. An initial preclinical study explored the behavior
of two anti-tuberculosis drugs in a polypill showing promising results (Khaled et al.
2015a; Pereira et al. 2019) (Fig. 1.4). Additionally, a pilot study was conducted
to understand the preferences of patients regarding aesthetics, practicality, and
acceptability of dosage form designs (Fastø et al.
2019). The future aspect of
polypharmacy has been discussed predominantly for the clinical setting or at the
point of care (Trenfield et al.
2021) (Table 1.4).
1.3.4.1 SLA
SLA has not yet been explored extensively for polypill work. However, a recent
study showed the potential feasibility of polypill fabrication using SLA to incorporate six APIs (paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, and
aspirin) into one single dosage form (Robles et al.
2019). Another study illustrated
the importance of avoiding photopolymer drug degradation in fabricating a polypill
with four API (irbesartan, atenolol, hydrochlorothiazide, and amlodipine) (Xu et al.
2020). The SLA polypill has been optimized thus far by dosage form design (APIs
stacked on top of each other).
1.3.4.2 FDM
The contribution of FDM in polypill prototyping is extensive, including strategies
based on dosage form design and on formula composition. Dosage form design
has been used in the following ways: by building a multicompartment chamber
separated by divider to physically inhibit interaction between two incompatible
26 K. Sen et al.
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Robles et al. (2019)
Antipyretic
Cylinder shape and ring shaped
polypill
Polyethylene glycol
diacrylate (PEGDA)
diphenyl(2,4,6-
trimethylbenzoyl)phosphine
oxide (Photo initiator)
Hypertension
Cylindrical Xu et al. (2020)
PEG300
Polyethylene glycol
diacrylate (PEGDA)
diphenyl(2,4,6-
trimethylbenzoyl)phosphine
oxide (Photo initiator)
CVD
Keikhosravi et al. (2020)
Two compartment polypill
(Two API separated removing
incompatibility issues and
6000(with api)
thermal sensitivity problem by
Pereira et al. (2019)
integrating with melt casting)
PVA 4 in 1 polypill where water was
CVD
used as plasticizer to reduce
printing temp (two drug
crystalline and two amorphous)
Parkinson’s
Windolf et al. (2022)
3 in 1 polypill with customize
release to treat Parkinson’s
disease ( gastric floating
PVA-IR
Ethylene-vinyl acetate
copolymer-ER
Hypertension
Awad et al. (2019)
capabilities)
2 in 1 dose Trenfield et al. (2020)
2 in 1 dose Miniprintlets with
Candurin
Kollicoat IR-IR
Antipyretic
control release
Ethyl Cellulose -SR
naproxen, chloramphenicol,
prednisolone, and aspirin
Technology API Polymer Design Reference and Therapy
SLA Paracetamol, caffeine,
Tab le 1 .4 Examples of AM use to create “Polypills”
Irbesartan, atenolol,
hydrochlorothiazide, and
amlodipine
FDM Aspirin and simvastatin Eudragit L100-55 and PEG
Lisinopril dihydrate,
indapamide, rosuvastatin
calcium and amlodipine
besylate
Pramipexole-IR
levodopa, benserazide-ER
SLS Amlodipine and lisinopril Polyethylene oxide
Ibuprofen-IR
Paracetamol-SR
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