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1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 27
(continued)
Goh et al. (2021)
Dietary Supplement
design
4-in-1 oral polypill with multiple
Proprietary craft blend 2 compartments with core-shell
patient
Khaled et al. (2015a)
hypertension of diabetic
release profiles
Multicompartment dosage
design
Captopril-zero order
PEG 6000
HPMC-SR
Mannitol
Khaled et al. (2015b)
order release
st
Rest—1
Multicompartment dosage
MCC
SSG
Cellulose acetate
Siyawamwaya et al. (2019)
CVD
design
5 in 1 dose with two
independently controlled and
(Change in design to make
IR release by mixing SSG
and mannitol and introducing
anti-HIV
3 in 1 loaded together and in
separate layers
well-defined release profiles
Hydroxyethyl cellulose
Ethoxylate
holes)
Cellulose acetate Phthalate
Vit B1,B3,B6-IR
SSE Caffeine-ER
Captopril-osmotic pump
nifedipine, glipizide-SR
Aspirin,
hydrochlorothiazide-IR
Pravastatin
Efavirenz
Atenolol
Ramipril-ER
Tenofovir Disoproxil
Fumarate
Emtricitabine
28 K. Sen et al.
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Hypertension
Acosta-Vélez et al. (2018)
Preform tablet composed of two
attachable compartments
hydrophobic PEG
Anti-epileptic
Hong et al. (2021)
Multicompartment structure
dispersible tablet
Powder Mix
MCC
Mannitol
PVP
Sucralose
Ink
IPA
PVP
Glycerin
Yo o e t a l . ( 2002)
Cough/cold
2 in 1 rapidly disintegrating
tablet having reinforced top and
bottom regions (drug free). Both
Powder Mix
Lactose
PVP K-25
drugs deposited in central
region.
Ink#1
PVP K-17
Ink#2
both drugs
PVP K-17
Lisinopril, Spironolactone Hydrophilic hyaluronic acid,
Technology API Polymer Design Reference and Therapy
BJ3DP
Tab le 1 .4 (continued)
(Combined
Levetiracetam (powder)
Pyridoxine HCl (ink)
material jet-
ting/standalone)
Chlorpheniramine maleate
and Pseudoephedrine HCl
(in same ink)
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 29
drugs (Keikhosravi et al. 2020); by changing the architecture of the dosage form
to extend multiple drug release in the GI tract with two drug release kinetics
(mini-floating polypill) (Windolf et al.
based on physicochemical properties, e.g., successfully printing two crystalline
and two amorphous drugs in a single dose (Pereira et al.
formulation-based technique is the incorporation of water as a plasticizer to reduce
the operating temperature and enabling FDM of amorphous and thermally sensitive
drug. Otherwise, polypills have the same compositional requirements as for other
solid oral dosage forms by FDM. Most often, PVA, Eudragit, and PEG have been
used as thermoplastic polymer for FDM polypills.
2022); by engineering drug release behavior
2019). An example
1.3.4.3 SLS
Fabrication of polypill using SLS has not been properly explored yet. A couple
of studies used two drugs loaded into one dosage unit. SLS polypills have been
fabricated by directly incorporating the customary ingredients into the powder blend
for SLS (APIs, thermoplastic polymer, and laser adsorbents such as Candurin). Two
drugs polypill exhibiting two release behaviors was achieved by loading drug in two
thermoplastic polymers enabling IR and SR property (Awad et al.
et al.
2020).
2019; Trenfield
1.3.4.4 SSE
Compared to the other AM, SSE has been investigated extensively for polypill
fabrication. A two compartmental core-shell design has been developed to deliver
dietary supplements (caffeine and four grades of Vitamin B) which exhibits different
release properties (Goh et al.
been developed to load antihypertensive and CVD drugs with IR and SR behaviors
(Khaled et al. 2015a, 2015b). Apart from multicompartment designs, multiple drugs
have been printed onto the same dosage form in separate layers using SSE as
well (Siyawamwaya et al.
corresponding commercial dosage form for HIV treatment. Although compartments
have been used for SSE polypills, excipients have maintained a critical function to
provide personalized release properties of the drug such as HPMC, cellulose acetate
phthalate for SR and PEG 6000 for IR.
2021). A multicompartment dosage platform has
2019), exhibiting higher drug release compared to the
1.3.4.5 BJ3DP
The application of BJ3DP in polypill production has not been properly explored. A
multicompartment structure of levetiracetam-pyridoxine hydrochloride (LEV-PN)
dispersible tablet has been developed wherein the pyridoxine hydrochloride has
been added to the ink and deposited into the middle nest layer of the tablet (Wang
et al.
2021). In some of the earliest BJ3DP work, a two-drug orodispersible tablet
of chlorpheniramine maleate and pseudoephedrine hydrochloride was demonstrated
(Yoo et al.
2002).
30 K. Sen et al.
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1.3.5 Orodispersible Dosage Forms
Orodispersibles can be defined as dosage forms that disintegrate rapidly when
placed in the oral cavity. These dosage forms provide ease of administration,
faster drug release, and the potential for quicker onset of action for certain
drugs. Orodispersibles can be either orally disintegrating tablets (ODTs) or orally
disintegrating films (ODFs) having low total mass and disintegrating without liquid
(FDA Guidance for Industry
2008), or they can be larger units specifically designed
to disintegrate in the mouth in response to added liquid. Orodispersibles made
by AM are mainly prototyped as ODT and ODF. The quick disintegration in
orodispersibles has been achieved primarily by higher specific surface area of
loosely bound particles and dissolution of water-soluble excipients or water-soluble
drug substances within the dosage form’s structure.
1.3.5.1 State of the Art
Orodispersible dosage forms are the most mature area of AM use for pharmaceuticals thus far. The first drug approval incorporating AM was in 2015 for Spritam
(levetiracetam), an orodispersible dosage form made using a proprietary scaled form
of binder jetting in a centralized plant by Aprecia Pharmaceuticals. Spritam is an
example from a category of formulations referred to as ZipDose technology, which
can incorporate chosen drugs at high doses (e.g., 1000 mg) and high total mass while
retaining fast-disintegrating properties when administered directly in the mouth with
a sip of liquid. Aprecia already offers development and manufacturing services for
partners using this technology. Aprecia has also recently introduced ZipCup
™
(ZFill) technology, which entails orodispersible shells that can be filled with diverse
dry payloads similar to capsules, but can still disintegrate in the mouth with a sip of
liquid.
Apart from binder jetting, a recent clinical example of orodispersibles is warfarin
film fabricated using SSE and inkjet technology. The film was precast using SSE,
and the drug was loaded using inkjet printing. The ODF was administered to patients
using naso-gastric tube at a hospital ward at HUS Pharmacy in Finland (Öblom et
al.
2019) as an on-demand patient specific dose (Table 1.5).
1.3.5.2 FDM
Among orodispersibles, FDM work has mainly focused on orodispersible films
(ODFs) which are more practical to fabricate than ODTs due to the characteristics of
the FDM process. These studies mainly use three ingredients: film former, support
materials, and API. PEO and PVA have been used as the main film forming agents in
ODF fabrication. In some cases, a backing substrate for the film such as poloxamer
(Jamróz et al.
film to aid handling by the user (Eleftheriadis et al.
2017) or ethyl cellulose has been used to modify the properties of the
2019).
1.3.5.3 SLS
SLS has been investigated significantly for fabrication of ODTs, including orodispersible Printlets
™
from FabRx. An ODT formulation using SLS requires API,
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 31
(continued)
(Awad et al. 2020)
Tab le 1 .5 Examples of AM use to create orodispersible dosage forms
ASD ODF (Cho et al. 2020)
Olanzapine PEO-film former
Technology API Key Excipients Dosage form Reference
FDM Aripiprazole PVA-film former ODF (Jamróz et al. 2017)
Kollidone VA64-ASD
former
Poloxamer 407,
Mucoadhesive film (Eleftheriadis et al. 2019)
Poloxamer 188-solubility
enhancer
Ethylcellulose-film base
Chitosan PVA-film base
ODT (Fina et al. 2018a)
SLS Paracetamol Kollidon VA64-
HPMC-
Candurin
ODT (Allahham et al. 2020)
Kollidone VA64-Binder
Mannitol
Ondansetron Cyclodextrin-drug loader
ODT(Brailied for visually
impaired patient)
Candurin
Candurin
Paracetamol Kollidon VA64
ODF (Yan et al. 2020b)
Maltitol
SSE Levocetirizine HCl HPMC-film former
Vet ODF (Sjöholm et al. 2020)
Sucralose
Pregelatinized Starch
Prednisolone PEO, HPC-Viscosity
modifier
32 K. Sen et al.
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(Aprecia Pharmaceuticals
2021)
2022)
(Jacob et al. 2016a)
(Jacob et al. 2016b)
Pediatrics ODT (Eduardo and Ana 2021)
Hydrochlorothiazide PVP K30
Technology API Key Excipients Dosage form Reference
Tab le 1 .5 (continued)
Tablet for Oral Susp (can be
taken in mouth w/ sip of liquid)
ODT (Kozakiewicz-Latała et al.
Croscarmellose sodium
Lactose MH
MCC
PVP
Microcrystalline Cellulose
HPMC
PVP (Powder bed)
Quinapril hydrochloride,
clotrimazole
BJ3DP SPRITAM (Levetiracetam) Mannitol
ODT (Basit and Gaisford 2018)
Levetiracetam Mannitol
ODF (Wang et al. 2021)
PVP VA64
Microcrystalline cellulose
HPMC
Propylene Glycol
PEG 400 ODF (Thabet et al. 2018)
Triiodothyronine (T3) &
Thyroxine (T4)
Hydrochlorothiazide
ODT (Lee et al. 2003)
Tablet for Oral Susp. (can be
taken in mouth w/ sip of liquid)
Maltitol
Mannitol
HPC
Enalapril maleate
Captopril Mannitol
Oxcarbazepine MCC
Tablet for Oral Susp. (can be
taken in mouth w/ sip of liquid)
PVP
MCC
HPC
PVP
Topiramate Mannitol
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 33
thermoplastic polymer, and a laser adsorbent (such as Candurin). The ratio of API
and thermoplastic polymer is used to modify the disintegration properties of ODTs
generated by SLS. In some cases, Kollidon VA64 (Fina et al.
have been used as matrix formers for ODTs. In one study, mannitol (Allahham et al.
2020)was added to act as a pore former.
2018a) and HPMC
1.3.5.4 SSE
SSE has been used to develop both ODTs and ODFs. The thickness of ODF has been
limited to a range of 0.6 to 1 mm, whereas ODTs of 1.4–1.6 mm in thickness have
been demonstrated. Orodispersible formulations made by SSE typically contain
API, binder (ODT) or film former (ODF), and disintegrant. Some studies with SSE
used a water-soluble film former to load API and fabricate ODFs (Sjöholm et al.
2020). In other studies, pregelatinized starch and croscarmellose sodium have been
added to attain quick disintegration (Eduardo and Ana
Binder/film formers such as HPMC, PVP K30, and PEO have been used in the
previous studies.
2021; Yan et al. 2020b).
1.3.5.5 BJ3DP
BJ3DP has been used for making orodispersibles since the late 1990s (Yoo et al.
2002). To this day, the precision and accuracy of the jetting process remain attractive
for depositing low-dose drugs using a liquid carrier. For ODTs, the drugs can be
incorporated via the jetted liquid, via the dry powder that is spread, or both. Much
higher dosing is possible for drugs incorporated using the powder route. Drugs can
also be jetted onto ODTs after they are formed. Conversely, for ODFs inkjet printing
has been used to deposit drugs onto preformed films made either by AM or by
conventional techniques.
For ODTs, BJ3DP uses hydrophilic excipients such as lactose, mannitol, and
microcrystalline cellulose as part of the powder blend (Kozakiewicz-Latała et al.
2022; Basit and Gaisford 2018). To aid tablet binding, BJ3DP also uses water-
soluble binding agents such HPMC and PVP as part of the powder blend, the jetted
liquid, or both.
For ODFs, inkjet printing requires a preformed film which can be made from
water-soluble polymers such as PEG or HPMC (with glycerol) (Alomari et al.
Thabet et al.
(Thabet et al.
to aid solubilization of the drug (Alomari et al.
2018). Ink formation can either be by direct mixing of drug with water
2018) or with an appropriate solvent system (e.g., ethanol:DMSO:PG)
2018).
2018;
1.3.6 Other AM Uses of Note
Localized Drug Delivery
AM can facilitate localized drug delivery by making novel systems (Chakka and
Salem
2019) such as drug-eluting implants (Liaskoni et al. 2021; Stewart et al.
2020), BIOCAGE implants (Son et al. 2017), bladder devices (Xu et al. 2021), and
drug-eluting contact lenses (Mohamdeen et al.
2022). AM has improved the design
34 K. Sen et al.
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of devices such as mucoadhesive reservoirs that attain longer delivery time (Vaut et
al.
2020). SLA and FDM are the categories of AM explored predominantly in this
area.
Anticounterfeiting
AM has also been investigated to aid anticounterfeiting techniques. Using the
exceptional capability of inkjet printing, unique QR codes can be printed on tablet
surfaces using “smart inks” to track individual tablets (Trenfield et al.
2020). Internal
3D patterns or codes made using chemical markers have also been demonstrated
with BJ3DP (Shariff et al.
2020).
Masking API Taste
AM has also been applied to taste-masking of drugs in dosage forms. Taste-masking
is often necessary in order to achieve sufficient palatability of an oral formulation,
especially for pediatric populations, and most often to cover bitter sensations (Wang
et al.
2020). The forms of AM evaluated thus far are HME integrated FDM for
donut-shaped tablets (Wang et al.
2020), Starmix dosage form (Scoutaris et al.
2018), fruit chews (Tabriz et al. 2021) for pediatric patients, and BJ3DP for instant
dissolving tablets [172] and large-format orally disintegrating tablets including use
of coated API (Jacob et al.
2016b; Wang et al. 2021).
Bioprinting-Organ on a Chip
3D bioprinting is a specialized area of AM gaining popularity in the medical field.
It fabricates tissues and organs using “bioinks” formulated to deposit living cells
and biomaterials (e.g., collagen, cellulose, and agarose) that help mimic the cell’s
normal environment while creating scaffolds for the cells to grow into the tissue or
organ (Jamróz et al.
2018; Kassem et al. 2022). Apart from its main uses in tissue
and organ replacement, certain 3D bioprinting processes are relevant to early-stage
drug discovery and development such as organ on a chip (OoC) for toxicological
screening. OoC is a platform in which one or more organs can be mimicked based
on the inclusion of microfluidic channels and engineered tissue. By emulating
the microenvironment and tissue-specific functions, OoC can approximate the
physiological response to drug exposure. This approach has the long-term potential
to reduce or replace early animal studies over time (e.g., heart (Zhang et al.
liver (Bhise et al.
2016), etc.).
2016),
1.4 Conclusions
With its growing body of work, Additive Manufacturing (AM) has exposed the
pharmaceutical industry to new possibilities for drug development. In one sense,
AM promises an eventual revolution in formulation design by addressing longstanding needs such as improved bioavailability of low solubility compounds,
modulated release kinetics, polypills, and orodispersible forms. In another sense,
it has shown the immense potential of personalization to change the way medicine
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 35
is deployed to impact patients’ lives. Although the vast majority of AM use cited
in this chapter has been carried out in an academic or laboratory setting, both
BJ3DP and FDM-type AM have already obtained early regulatory traction in a
centralized manufacturing format, encompassing one 505(b)(2) approval and three
IND clearances, collectively. In addition, both FDM and SSE have begun clinical
usage in smaller decentralized formats, including the compounding pharmacy
context. Accordingly, following the existing examples of regulated pharmaceutical
use, AM holds tremendous potential for greater practical deployment to benefit
progressively more patients in the near future.
Acknowledgments The authors wish to thank Jaedeok Yoo (FoundationLayers, LLC) for contributing key concepts and review comments to Fig. 1.2.
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