AAPS PharmSciTech ( # 2018)

DOI: 10.1208/s12249-018-1105-1

Research Article
Theme: Printing and Additive Manufacturing
Guest Editors: Niklas Sandler and Jukka Rantanen

The Effect of Inkjet Printing over Polymeric Films as Potential Buccal Biologics
Delivery Systems

Miguel Montenegro-Nicolini,1,2 Patricio E. Reyes,2 Miguel O. Jara,1 Parameswara R. Vuddanda,3

Andrónico Neira-Carrillo,4,5 Nicole Butto,4,5 Sitaram Velaga,3 and Javier O. Morales1,3,4,6

Received 21 March 2018; accepted 8 June 2018

Abstract. The buccal mucosa appears as a promissory route for biologic drug
administration, and pharmaceutical films are flexible dosage forms that can be used in the
buccal mucosa as drug delivery systems for either a local or systemic effect. Recently, thin
films have been used as printing substrates to manufacture these dosage forms by inkjet
printing. As such, it is necessary to investigate the effects of printing biologics on films as
substrates in terms of their physical and mucoadhesive properties. Here, we explored solvent
casting as a conventional method with two biocompatible polymers, hydroxypropyl
methylcellulose, and chitosan, and we used electrospinning process as an electrospun film
fabrication of polycaprolactone fibers due to its potential to elicit mucoadhesion. Lysozyme
was used as biologic drug model and was formulated as a solution for printing by thermal
inkjet printing. Films were characterized before and after printing by mechanical and
mucoadhesive properties, surface, and ultrastructure morphology through scanning electron
microscopy and solid state properties by thermal analysis. Although minor differences were
detected in micrographs and thermograms in all polymeric films tested, neither mechanical
nor mucoadhesive properties were affected by these differences. Thus, biologic drug printing
on films was successful without affecting their mechanical or mucoadhesive properties. These
results open way to explore biologics loading on buccal films by inkjet printing, and future
efforts will include further in vitro and in vivo evaluations.
KEY WORDS: biologics; mucoadhesion; mechanical properties; inkjet printing; buccal films.

INTRODUCTION without prior treatment (1). The administration of biologics is

In the last decades, pharmaceutical drug development
has focused in biologics, which is reflected in the industry
efforts, representing an important advancement in therapeu-
tic treatments with success and expanding therapy to diseases
Guest Editors: Niklas Sandler and Jukka Rantanen
1
Department of Pharmaceutical Science and Technology, School of
Chemical and Pharmaceutical Sciences, University of Chile, Santos
Dumont 964, 4to piso, Oficina # 09, Independencia, 8380494,
Santiago, Chile.
2 the benefits of the intravenous route, some drawbacks include
Instituto de Salud Pública de Chile, 7780050, Santiago, Chile.
3 difficulties for initiating and maintaining an injectable treat-
Pharmaceutical Biomaterial Research Group, Department of
Health Sciences, Luleå University of Technology, 97187, Luleå,
Sweden.
4
Advanced Center for Chronic Diseases (ACCDiS), 8380494,
Santiago, Chile.
5
Faculty of Veterinary and Animal Sciences, University of Chile,
Santiago, Chile.
6
To whom correspondence should be addressed. (e–mail:
jomorales@ciq.uchile.cl)
difficult: unlike small molecules, biologics are usually not
bioavailable through the oral route, due to their higher
molecular weights (> 1000 Da) limiting membrane passage,
the enzymatic and acid sensibility, extensive exposure across
the gastrointestinal tract surface area, and the hepatic first
past effect (2). Biological drug products are commonly
administered intravenously to achieve complete bioavailabil-
ity and thus optimize drug use. This addresses the elevated
cost of treatment, provides protection from gastrointestinal
tract interaction, but increases the risk of adverse events due
to the full dose being available into the blood (3,4). Despite
ment in ambulatory patients, e.g., administration technique or
initial rejection to injectable treatment (5), the appearance of
adverse effects (6), and problems at the site of injection such
as pain, bruise, or itching. All these drawbacks limit the
compliance of prescribed injectable treatments (7).
Thus, alternative administration routes for biologics with
both high bioavailability and comfortability as the oral route

1530-9932/18/0000-0001/0 # 2018 American Association of Pharmaceutical Scientists


for small molecules are investigated. Ideal attributes of these
alternative routes include providing protection from enzy-
matic and acid degradation and avoidance of the hepatic first-
pass effect (8). Among these routes, the buccal epithelium is
easily accessible and provides a higher surface area and blood
irrigation than the sublingual epithelium in the oral cavity (9).
To exploit the buccal route, polymeric films have become an
attractive dosage form and can be used as platforms for
buccal delivery of biologics (10). Previously, it was evaluated
the permeation of insulin formulated as nanoparticles
through a human buccal model both in solution and films,
being more effective in drug loaded films (10). Tetanus toxoid
was also formulated in nanostructured carriers, for protection
enhancement, and then incorporated in films as dosage forms
to provide comparable immunization using traditional
methods (i.e., intramuscular and per oral routes vaccines) in
a mouse animal model (11). In another study, Chen et al.
developed polymeric films for biologics for sublingual admin-
istration and achieved a sustained glutathione retention,
uniform drug content, desirable release profiles, adequate
drug permeation, and efficient delivery using in vitro drug
release and ex vivo permeation studies (12). Furthermore,
films as dosage forms can be tailored for personalized dose
requirements, which is particularly relevant in pain control
for diseases like rheumatoid arthritis, juvenile rheumatoid
arthritis, and ankylosing spondylitis (13). Moreover, the films
are easily administered and thus highly convenient for
pediatric and geriatric patients, which can have difficulties in
swallowing associated to choking risk (14), can improve
patient compliance (15), and can elicit mucoadhesive proper-
ties and thus increase the interaction time with the mucosal
tissue, increasing the drug residence time in the buccal cavity
leading to increased absorption (16).
Drug loaded films for the buccal route have been recently
proposed to be develop through inkjet printing in a two-step
approach, i.e., film (printing substrate) manufacture and drug
loading by inkjet printing (17). Additionally, it has been described
for small molecules that the solvent casting process can result in
drug dispersion within the polymeric film, thus modifying the
mechanical properties of the free film; moreover, this alteration
was not detected when the drug was incorporated by inkjet
printing (18). Thus, recent research efforts have been directed to
adapt inkjet printing to biologics. Previously, we have demon-
strated that it is possible to dispense a biologic drug model
efficiently and maintaining its structure using a home thermal
inkjet printer with a polyethylene terephthalate as printing
substrate. In buccal film development, three main methods are
described: solvent casting, hot melt extrusion, and
electrospinning. Solvent casting is most widely used to produce
films and consists of solubilizing a film forming polymer in a
volatile solvent to generate a homogeneous solution or dispersion
casted on molds to produce films (19). In hot melt extrusion, the
film forming polymer, excipients, and drug are thermally
processed and passed through a die to render the dosage form
(20). Electrospinning is a more recent method applied in the
fabrication of buccal films and consists in the use of a high-voltage
dc current to a viscous polymer film former solution, generating
fibers that are collected on a ground metal screen (21). In this
work, we explore solvent casting as the most widely accepted
method due to its ease to implement, low temperatures required,
and homogeneity of the final film produced (22) and
Montenegro-Nicolini et al.
electrospinning for its potential to increase the surface area of
its internal structure and thus accommodate the drug loaded
within the fibrous scaffold (23). The fabrication of buccal films
can be addressed using different manufacturing processes, and
quality control has many approaches suggested in the literature,
but no standardized tests are yet available (24).
We selected hydroxypropyl methylcellulose (HPMC),
chitosan (CH), and polycaprolactone (PCL) as model film
forming polymers. HPMC is a non-ionic water-soluble
polymer with lower elastic modulus and higher percent
elongation compared to original cellulose molecule (25). CH
is a partially deacetylated polymer of N-acetyl glucosamine
(26) and has gained attention in the pharmaceutical field due
to well documented biocompatibility, non-toxicity, biodegrad-
ability, and film-forming ability (27). Moreover, CH has been
reported as being mucoadhesive and a permeation enhancer
in the buccal mucosa due to the cationic nature of the
polymer backbone and the increased retention at the mucosal
surface (28). PCL is a biodegradable polyester, which has
gained relevance in recent years due to its excellent
mechanical and structural properties, as well as being non-
immunogenic (29,30), and adaptable as fibers forming poly-
mer for electrospinning (31).
The effect of biologics printing process over polymeric
films as printing substrates has not been studied. In the
literature, Buanz et al. investigated the mechanical properties
and physical stability of films prepared by solvent casting and
ink jet printing using clonidine hydrochloride finding differ-
ences and superiority of the films prepared by printing in
terms of mechanical properties and stability (18). Here, we
investigated the effect of inject printing of biologics over
different polymeric film substrates on the mechanical and
mucoadhesive properties of the films.
MATERIALS AND METHODS
Materials
Lysozyme from chicken egg white, mucin from porcine
stomach, and CH 20–300-cps viscosity and 75–85% deacetylated,
PCL average molecular weight Mn: 80000 g mol−1 were
purchased from Sigma-Aldrich (St. Louis, USA). Glycerol 85%
analysis grade for solvent casting and ethyl acetate were
purchased from Merck KGaA (Darmstadt, Germany), and
acetone for electrospinning was purchased from Winkler (Santi-
ago, Chile) and used as received. Methocel K100 premium LV
(HPMC) was kindly donated by the Dow Chemical Company
(MI, USA). Tween 80 was purchased from J.T. Baker (NJ, USA).
Triethyl citrate was acquired from AK Scientific Inc. (CA, USA).
The water used in all experiments was ultrapure collected freshly
from a Merck Millipore water system (Darmstadt, Germany).
Methods
Inkjet Printer Preparation and Printing Process
The thermal inkjet printer system was modified to allow
printing of biologics. Hewlett Packard black cartridges
compatible with Hewlett Packard Deskjet 1000 (CA, USA)
were opened removing the lid while maintaining its structure
and functionality. Cartridges were emptied of ink and cleaned
The Effect of Inkjet Printing over Polymeric Films

using a hydro-alcoholic solution. Finally, three sonication
cycles in water of 3 min each were conducted. The procedure
was an adaptation of a previous investigation on rasagiline
and thermal inkjet printing (32).
One milliliter of ink solution was transferred into clean
cartridges. The lid was replaced and then the cartridge
inserted back into the printer. Polyethylene terephthalate
sheets were used as a support to adhere the polymeric films as
printing substrates. To configure the printing areas, Microsoft
Word was used while printing at best quality print, i.e., 600 ×
600 dots per inch (dpi) from the printer settings. For all
printing conditions 7-cm × 7-cm black templates were printed.
Ink Formulation
As model biologic drug, a previously optimized lysozyme
solution concentration of 10 mg/mL was prepared (17). To
simulate the ink original viscosity, ink formulations consisted
in said lysozyme solutions and glycerol in 7:3 v/v ratio. This
ratio has been previously identified to emulate the viscosity of
original inks (32), avoiding leakage from the cartridge.
Film Fabrication
Solvent Casting. Polymeric films formulated using
HPMC and CH were obtained by solvent casting. A 2% w/v
aqueous HPMC solution was prepared by dispersing the solid
HPMC in 2/3 parts of 70-°C water, and the rest was added as
iced cold water, while continuously stirring at 800 rpm for 1 h.
Glycerol as plasticizer was added (10, 20, and 30% w/w based
on the weight of HPMC) and mixed by magnetic stirring at
800 rpm for another hour. The resulting solution was stored at
4 °C overnight to remove air bubbles. A 2% w/v CH solution
was prepared in acetic acid 2% v/v under magnetic stirring at
800 rpm for 1 h. Tween 80 as hydrophilic surfactant and
triethyl citrate as plasticizer were added in a fixed proportion
of 0.5% w/v and 4% w/w based on CH weight and stirred for
another hour at 800 rpm. The resulting solution was stored at
room conditions for at least 12 h before using to remove air
bubbles.
HPMC and CH solutions were casted on non-adherent
polytetrafluoroethylene (PTFE) plates in different mass
amounts (i.e., 15, 25, and 35 g of material) to obtain different
film thickness. Casted films were dried for 24 h at room
temperature under a vertical laminar airflow chamber and
stored at room conditions.
To analyze the influence of the plasticizer and the film
thickness on film mechanical and mucoadhesive properties,
we formulated films as summarized in Table I.
Electrospinning. PCL films were obtained after
electrospinning and collecting PCL fibers in a rotary collector.
The electrospun PCL fibers were prepared according to a
previously reported procedure (33). Briefly and to optimize
the wet-spinning process, PCL solutions in the range of 11–
18% w/v concentration were prepared in an ethyl
acetate:acetone solvent mixture (3:1) v/v, which was put
under powerful magnetic stirring at 40 °C for 2 h. After
preliminary electrospinning testing, a 18% w/v was selected
(Table I) for further film manufacture due to exhibiting
optimal film uniformity (33). The PCL solution was then kept
at room temperature overnight without stirring to obtain a
homogenous solution.
The electrospinning process was carried out using an
eStretching LE-10 Fluidnatek instrument (Valencia, Spain) at
a 13–15-kV high voltage from the power supply. The PCL
solution was placed in a 10-mL syringe equipped with a Luer
Lock metallic needle, with an inner diameter of 14.9 mm, and
the solution feeding rate was automatically controlled at
1500–2000 μL/h with a syringe pump for 7 h. The electric field
was applied between the metallic needle of the syringe and an
electrical grounded rotating aluminum collector set to 1800–
2000 rpm at a distance from the needle tip of 15 cm (34,35).
The rotating collector was covered with aluminum foil in
order to obtain aligned fibers with a diameter of 0.5 to 4 μm
(36,37). The collected film was unwrapped carefully from the
aluminum foil and stored for future evaluations at room
conditions.
Film Characterization
Mechanical Properties. Mechanical testing was con-
ducted on a TA1 texture analyzer (Lloyd Instruments
Ltd., Bognor Regis, UK) equipped with a 50-N load cell
using Nexygen Plus 3 software as previously described
(38), according to ASTM standard method D882 (39).
Briefly, samples of HPMC, CH, and PCL films were cut in
strips of 6 cm × 1 cm and were held through their length
between clamps attached to the texture analyzer; thus, the

Table I. Composition of the Formulated Films by Solvent Casting or Electrospinning

Composition Film code

A1 A2 A3 A4 A5 A6 A7 A8 A9 B1 B2 B3 C

Hydroxypropyl methylcellulose K100% w/v 2 2 2 2 2 2 2 2 2 – – – –

Glycerol% w/v 10 20 30 10 20 30 10 20 30 – – – –
Chitosan% w/v – – – – – – – – – 3 3 3 –
Tween 80% w/v – – – – – – – – – 0.5 0.5 0.5 –
Triethyl citrate% w/v – – – – – – – – – 4 4 4 –
Polycaprolactone% w/v – – – – – – – – – – – – 18
Casted mass 15 15 15 25 25 25 35 35 35 15 20 25 –

effective testing area was 4 × 1 cm2. The upper clamp
(connected to the mobile arm of the texture analyzer)
stretched the film upwards at a rate of 0.5 mm/s until film
rupture. Before the mechanical test, the thickness of each
film was measured using an electronic micrometer IP54
Mitutoyo (Kawasaki, Japan), measure range 0–25 mm with
± 0.001-mm precision. Measurements were taken at five
random positions of each test film.
Stress was obtained from the force measurements
obtained from the instrument divided by the film cross-
sectional area, while strain was computed by dividing the
increase in length by the initial film length. From the
stress versus strain plot, the tensile strength (TS) and the
elongation at break (EB) are obtained from the peak
stress and the maximum strain, respectively, also repre-
sented by the following equations:
Peak stress
Tensile strength ðTSÞ ¼
Cross−sectional area of the sample
Increase in length at break
Elongation at breakðEBÞ ¼  100
Original film length
Additionally, the Young’s modulus or elastic modulus
(EM) was determined as the slope of the linear portion of the
stress versus strain plot, i.e., the initial elastic deformation
region. Since the rate of the mobile arm extension was
constant for all samples tested, direct comparison of the slope
in this region can be done. All these properties were
measured before and after the printing process.
Mucoadhesion. Mucoadhesion tests were conducted on
TA1 texture analyzer (Lloyd Instruments Ltd., Bognor Regis,
UK) equipped with a 50-N load cell and Nexygen Plus 3
software. Briefly, 1.5-cm × 1.5-cm samples of HPMC, CH, and
PCL films were held horizontally and 70 μL of model mucus, a
freshly made 2% w/v mucin solution, was placed on top of the
film (40). This amount was chosen to mimic the average saliva
thickness (41). A stainless-steel cylindrical probe (11-mm
diameter) was attached to the mobile arm of the texture
analyzer and brought in contact with the film and mucin
solution, exerted a force of 50 mN for 30 s, and was then
withdrawn at a rate of 0.5 mm/s. The peak detachment force
(DF) and work of adhesion (WoA) were obtained from the peak
and the area under the curve, respectively, in the force versus
distance profile using the base line as reference.
Scanning Electron Microscopy. A scanning transmission
electron microscope was used in its scanning electron
microscopy (SEM) mode (Inspect F50, FEI, Hillsboro,
OR, USA) to analyze the surface and cross section
morphology of the formulated films. Film samples were
obtained before and after printing by immersion in liquid
nitrogen. Through this fracture by freezing method, we
ensured clean-cut edges and avoided plastic deformation
(often resulting from mechanical cutting). Film pieces
were immobilized on aluminum stubs by means of
double-sided adhesive conductive carbon tape, before
sputter coating with a gold target to a thickness of 10–
Montenegro-Nicolini et al.
15 nm in a high vacuum evaporator. All samples were
analyzed using a 5-kV accelerating beam.
T h e r m a l A n a l y s i s b y D i f f e re n t i a l S c a n n i n g
Calorimeter. Thermograms of samples (blank and printed
films of CH, HPMC, and PCL) were recorded using a
differential scanning calorimeter (TA Instruments Q 1000,
New Castle, USA) equipped with refrigerated cooling system.
Each film sample ranging between 2 and 5 mg was cut into
small pieces and fixed into aluminum pans and non-
hermetically sealed. The sample pans were transferred to
the DSC furnace under a nitrogen purge of 50 mL/min. The
experimental conditions were as follows: temperature range
20 to 200 °C, heating rate 10 °C/min, modulation amplitude
0.747 °C, and period 60 s. The DSC was previously calibrated
for temperature and heat capacities using indium and
sapphire. Results were analyzed using the Universal analysis
software (TA instruments, New Castle, USA).
Statistical Analyses
All the data were collected from at least five parallel
experiments. Two-sample, two tailed Student’s t test with
equal variances was used to determine significant differences
among groups for normally distributed data; otherwise,
Wilcoxon rank-sum test was used. The normality of data sets
and equality of variances was established using Shapiro-Wilks
and Fisher’s F tests, respectively. Stata version 15 software
was used in data analysis. Statistical significance was accepted
at an alpha level of p ≤ 0.05.
RESULTS
Printing Process
The printing process was conducted after fixing the HPMC,
CH (fabricated by solvent casting technique), and PCL (fabri-
cated by electrospinning technique) films to an inert substrate.
Films were successfully printed without difficulties and after
drug loading; printed films were cut into samples for mechanical,
mucoadhesive, and microscopy analysis. No apparent differ-
ences were observed during and after printing films obtained by
solvent casting or electrospinning.
Mechanical Properties
The results for mechanical properties before printing are
presented in Table II. As expected, in HPMC films, it is possible
to observe high association between the plasticizer content and
an increase of the EB. At a constant mass of casted material (15,
25, and 35 g), the correlation r2 factor was over 0.95.
TS and EM showed a decreasing trend in the three different
groups (15, 25, and 35 g of casted mass). The best TS correlation
was found in the 35-g group (formulations A7, A8, and A9 with
r2 = 0.95 for A7, and 0.99 for A8 and A9). Furthermore, an
increase of plasticizer was correlated with a higher thickness in
two groups (15 and 25 g), but was not observed in the 35-g group.
For printing, we selected formulation A6 (25 g of casted material,
30% of glycerol plasticizer), because it exhibited the best EB
The Effect of Inkjet Printing over Polymeric Films

Table II. Thickness, Mechanical, and Mucoadhesion Properties of the Manufactured Films Before Printing

Film code Thickness μm Elongation Tensile strength Elastic modulus Detachment Work of
at break % N/mm2 N/mm2% force adhesion
mN mN/mm

A1 31 (0.4) 21.602 (4.130) 54.982 (3.373) 12.263 (1.166) 13 (2) 52 (10)

A2 32 (1.1) 26.734 (6.256) 47.190 (2.981) 9.529 (1.066) 19 (1) 66 (13)
A3 34 (3.3) 35.810 (2.126) 48.861 (3.652) 8.281 (0.573) 25 (2) 126 (32)
A4 54 (0.8) 23.943 (5.550) 51.595 (5.638) 9.871 (0.789) 15 (2) 43 (4)
A5 58 (1.5) 35.750 (4.039) 49.324 (5.645) 8.208 (1.283) 21 (3) 57 (5)
A6 62 (2.1) 45.509 (3.772) 43.894 (2.441) 7.135 (0.604) 30 (3) 67 (8)
A7 84 (1.3) 23.635 (4.583) 51.460 (3.417) 9.669 (0.908) 24 (2) 52 (6)
A8 84 (1.3) 34.031 (6.820) 42.914 (8.051) 8.051 (0.599) 30 (3) 62 (5)
A9 83 (1.1) 38.691 (4.830) 36.786 (2.976) 6.592 (0.287) 41 (3) 71 (3)
B1 55 (1.3) 13.355 (15.820) 49.749 (2.954) 10.271 (0.900) 16 (3) 67 (1)
B2 78 (7.9) 31.495 (11.235) 51.866 (6.133) 7.481 (0.282) 17 (5) 54 (5)
B3 110 (5.7) 7.716 (4.580) 42.339 (2.535) 5.686 (0.322) 37 (9) 35 (2)
C 89 (7.0) 59.323 (9.569) 0.433 (0.076) 0.043 (0.006) 12 (1) 27 (2)

Results represent mean (SD), n = 5

45.509% and the TS and EM were 43.894 N/mm2 and 7.135 N/
mm2%, respectively.
In CH films, the influence of casted material over thickness
was correlated with an r2 of 0.99. Additionally, EM was
correlated with film thickness positively (r2 = 0.98), but EB and
TS did not show correlation. We selected formulation B2 due to
its EB of 31.495% and similar TS and EM to the HPMC selected
film of 51.866N/mm2 and 7.481 N/mm2%, respectively.
For developing the PCL film formulation, a preliminary
process optimization consisted of testing various PCL con-
centrations (11–18% w/v) and electrospinning conditions to
achieve the formation of fibers instead of beads (observed by
simple microscopy) and a homogeneous film with a minimum
thickness for simple detachment from the collector after 7 h
of electrospinning. After process optimization, the EB was
the highest among the selected formulations 59.323% (PCL >
HPMC > CH), the TS was the lowest of three materials
0.433 N/mm2 (CH > HPMC > PCL), and PCL films had the
lowest EM at 0.043 N/mm2% (CH > HPMC > PCL).
Films of selected formulations were produced and
printed to compare their mechanical properties after printing
(Fig. 1). No statistical differences were detected between the
film samples before and after the printing process (p < 0.05).
Mucoadhesion Properties
The results for DF and WoA are summarized in Table II.
HPMC and CH films show an increasing trend for DF and WoA
with plasticizer increase (10, 20, and 30%) in three different
groups (15, 25, and 35 g). The formulation A6 has DF and WoA
over the median value, i.e., 30 mN and 67 mN/mm, respectively.
Formulation B2 (CH film) exhibited a DF of 17 mN and WoA of
54 mN/mm. The PCL film had 12 mN and 27 mN/mm of DF and
WoA, respectively. As such, DF and WoA had the following
order among selected film formulations: HPMC > CH > PCL.
Films of selected formulations were manufactured and then
printed to compare DF and WoA as shown in Fig. 2. No
statistical differences were detected between the film samples
with and without printing process (p < 0.05), showing that the
printing process does not have an impact on the mucoadhesive
properties analyzed here.
Scanning Electron Microscopy
The SEM was developed to take images from the
microstructural surface and cross-sections of HPMC (Fig. 3),
CH (Fig. 4), and PCL films (Fig. 5) comparing the biologic
printing effect on them. All the analyzed HPMC and CH films
samples showed only minor differences, with a continuous
structure exempt of cracks or pores. The HPMC films present
a rough morphology especially at cross-sections before printing,
which could be attributed to the humectation produced by the
printing process. As CH tends to hydrate more slowly than
HPMC (42), these differences are less pronounced in CH films.
No differences between the PCL films before and after
printing in surface and cross-section cuts were detected.
Thermal Analysis by Differential Scanning Calorimeter
Figure 6 presents the differential scanning calorimetry
(DSC) thermograms of the analyzed HPMC, CH, and PCL
films before and after printing. HPMC films show a melting
temperature reported between 157 and 180 °C (43) in different
formulations; for CH, the melting temperature was estimated in
203 °C (44), and for PCL, the melting temperature is near 60 °C
(45). For PCL before and after printing, the observed melting
temperature is similar to the reported value (45). The ink
incorporates water to the printing process of polymeric films and
this especially affects hydrophilic materials such as HPMC and
CH, and it is difficult to observe the characteristic melting point,
especially in the printed samples. For HPMC and CH, it has
been described that moisture presence and plasticizers can
modify the glass transition temperature (43,44). Additionally, no
apparent differences were detected between blank and printed
samples for all the polymers especially in HPMC and CH films.
PCL films exhibit minor differences between the blank and
printed samples probable related with and incomplete ink
lysozyme inclusion into the film, staying at the surface.
 Montenegro-Nicolini et al.

Fig. 1. Mechanical properties including a elongation at break, b tensile strength, and c elastic modulus of selected substrates of HPMC, CH,
and PCL before and after printing. Non-statistical differences were detected (p > 0.05)

DISCUSSION plasticizer is required to provide the essential flexibility of the

Solvent Casting and Electrospinning Processes Were Useful
for Film Manufacturing and Evidenced No Changes in
Mechanical and Mucoadhesion Properties Before and After
Printing
The solvent casting method was used to prepare HPMC
films using glycerol as plasticizer (42). For CH, the same
casting method was used, adding as plasticizer a combination
of triethyl citrate and tween 80 (46,47). The importance of the
film (48), making it possible to undergo mechanical stress by
manipulation or even the printing process. The plasticizer
mechanism of action occurs by the reduction in the glass
transition temperature of the films, thereby reducing its TS
(49). To evaluate the influence of the plasticizer in HPMC
films, three plasticizer levels were studied (10, 20, and 30% w/
w). Furthermore, three different mass levels were used to
provide increasing film thickness. The solvent evaporation
process occurs more rapidly when the level of plasticizer was
higher and results in a more resistant film. This is related with

Fig. 2. Mucoadhesion properties including a detachment force and b work of adhesion of selected substrates of HPMC, CH, and PCL before
and after printing. Non-statistical differences were detected (p > 0.05)
The Effect of Inkjet Printing over Polymeric Films

Fig. 3. HPMC film surface and cross section images with and without printing process.
Formulation A6 (HPMC 2%,glycerol 20%): a surface no print, b surface print, c cross
section no print, d cross section print (scale bars 10 μm)

the property of plasticizers to reduce the intermolecular modulate the drug dissolution and permeation of the drug
forces between the polymer chains, increasing the free (51). The increase of plasticizer in HPMC films was corre-
volume (50). The porosity of the film could be useful to lated with an increase of EB and a decrease of EM and TS,

Fig. 4. CH film surface and cross section images with and without printing process.
Formulation B2 (CH 3%, tween 80 0.5%, triethyl citrate 4%): a surface no print, b surface
print (scale bars 10 μm), c cross section no print, d cross section print (scale bars 40 μm)
 Montenegro-Nicolini et al.

Fig. 5. PCL film surface and cross section images with and without printing process.
Formulation C (PCL18% in ethyl acetate): a surface before printing, b surface after
printing, c cross section before printing, d cross section after printing (scale bars 40 μm)

which is in agreement with previous research (49,52,53). film for homogeneity and thickness variability (54). The
For electrospun PCL film formation, a preliminary collector speed was set at 400 rpm, because lower rates
investigation of variables was conducted to optimize the resulted in variable film thickness, and higher speeds

Fig. 6. DSC thermograms of HPMC films blank and printed (a), CH films blank and printed (b), and PCL films blank and printed (c)
The Effect of Inkjet Printing over Polymeric Films
decreased collection efficiency because fibers were
deflected away from the collecting drum by air flow from
the rotation (55).
The PCL film had the highest EB above HPMC and CH
films, which results from the microstructure conformation.
The electrospinning of PCL polymer generates multiple
fibers, which together form a film and generate a more
flexible material compared with individual fibers (56). A
similar behavior of PCL is reflected in the lowest TS and EM.
The WoA and DF were higher in HMPC films followed
by CH and PCL films, which is correlated with the use of
HPMC and the ability to increase the mucoadhesive proper-
ties, attributable to the formation of physical (including
hydrogen) bonds with the mucus components, and the large
number of hydroxyl groups that are responsible for adhesion
(57,58). Films made of CH perform a mechanism of
interaction based on the interface between the adhesive,
represented by the film, and the adherent, represented by the
mucosa, where an electrostatic bond between the two
materials is possible. At the mucosal pH, mucin develops a
negative charge, while CH exhibits a positive charge (59).
PCL films develop a mechanism of adhesion thanks to the
multiple nano-/microscale electrospun fiber interaction, which
contrasts with the non-adhesive behavior of non-woven PCL
(60,61). This result is aligned with previous literature (61),
where electrospun PCL films were developed and exhibited
mucoadhesive properties. This evidenced the potential of the
electrospinning and the resulting micro-/nanostructure into
modifying the material properties.
Comparing the three polymeric films, HPMC films
show the highest mucoadhesive properties explained by
the formation of bonds with mucus components (58) and
the ability, under moderate stresses, to remain in contact
with the mucosal surface due to the slower rate of
hydration, preventing it from being over-hydrated at
shorter time intervals (62).
The mechanical and mucoadhesion properties were
maintained after the printing process in the three selected
films (Figs. 1 and 2). The printing process implies the ejection
of a volume of ink enough to be absorbed by the film a few
seconds after printing, without a trace (63). Previously, TS,
maximum load, and EB were measured before and after
printing using flexographic printing in films produced by
solvent casting (HPMC, glycerol and crospovidone
orodispersible films) obtaining values of 15.72 MPa for TS,
5.50 N for maximum load, and 2.92% for EB after printing
rasagiline mesylate (64). The use of flexographic printing
could be difficult for biologics due to its need for drug
solubilization in a high ratio of organic solvent with the
inherent risk of precipitation and activity loss (65).
Successful Inkjet Printing Process Using Lysozyme Solution
in Polymeric Substrates
In our earlier investigation, we demonstrated that it is
possible to adapt a home thermal inkjet printing system to
dispense biologics solutions, resulting in a proportional
response in content over surface areas as well as maintaining
the enzyme activity with potential for buccal delivery (17). In
this work, we formulated lysozyme solutions to evaluate the
effect of printing over polymeric films as dosage forms in their
mechanical /mucoadhes ion properties and surface
morphology.
The printing of biologics happened with no difficulties,
after mixing the lysozyme solution with glycerol in a
proportion 70:30 v/v (66,67). It was observed that the
aqueous:glycerol mixtures result in a specific viscosity of
2.5 cP, which is included in the nominal value of viscosities of
the commercial inks (range 1.5–3 cP) (68). Also, the
aqueous:glycerol mixture has been found to provide stability
and activity preservation to fibroblast growth factor in
aqueous solution, which was attributed to glycerol being
highly hydrophilic and thus avoids the interaction with
hydrophobic residues (68).
For printing, we selected the black cartridge because
drop size is controlled at 13.5 pL (69) as opposed to the tri-
color cartridge that has a variable drop size ranging from 2.3
to 8.5 pL (70). The deposited solution of lysozyme is plainly
observed immediately after printing, at the surface of the
films within the limits defined by user configuration. A good
adhesion between the protein solution and the film former
polymers HPMC, CH, and PCL was evidenced due to drying
and tight contact among cartridge and film (66). The
lysozyme concentration of 10 mg/mL and printed area of
49 cm2 have already been investigated in our previous work
(17) obtaining 217.1 ± 4.3 μg/mL over the printed material.
We believe that these results could guide further research in
the use of proteins and peptides with similar structure to
lysozyme, such as insulin already described in solvent casting
films (10). Furthermore, it is important to highlight that just
one printing routine was conducted over the polymeric films
due to the high risk of dissolving the hydrophilic HPMC and
CH films (71). The drying method between multiple prints
would be crucial in attempting to increase drug loading
through successive printing routines over the same surface.
Microscopy Results and DSC Thermograms Reflect Minor
Differences
Sample morphology before printing appears rough, and
after the printing process, the sample looks smoother at
surface and cross section images (Figs. 3 and 4, respectively).
The images of PCL films look similar before and after the
printing process both at the surface and cross sections with a
woven-like morphology usual in the electrospinning film
formation (Fig. 5). Previously, the interaction of an aqueous
ink with three substrates was studied, finding that hydrophilic
fast dissolving substrate performs craters resulting from the
local and transient dissolution of the substrate (72). In a
hydrophobic, non-porous substrate, printed spots solidify in
the form of solid protuberances shaped as spherical caps.
Finally, the third substrate was a hydrophilic porous film, for
which most of the ink was absorbed within the film (72).
The obtained thermograms of the three different films
polymers (HPMC, CH, and PCL) before and after printing
for HPMC and CH show no differences when compared using
the same polymer. PCL films show differences and could be
related to the humectation and drying process after printing,
considering that PCL is a hydrophobic polymer (72) and the
drying process is more difficult compared with HPMC and
CH. Despite the above, the meting events of the HPMC and
CH are not detected, and this could be attributable to the

moisture added by the ink, the presence of plasticizer, and the
hydrophilic behavior of these polymers (43,44).
CONCLUSION
In this study, biologic printing on films demonstrated no
statistical differences in terms of mechanical, mucoadhesive,
and structural properties. This has been described using films
manufactured by solvent casting (HPMC and CH) and
electrospinning (PCL). The results of mechanical properties
showed that PCL exhibited better EB and EM in comparison
with HPMC and CH, which is possibly related to the
alignment process that electrospun fibers go through during
mechanical deformation. On the other hand, CH exhibited
the best TE of the selected formulations. Nonetheless, HPMC
films were adequately printed to develop drug loaded films.
In terms of mucoadhesion properties, the highest DF and
WoA were found in HPMC films, followed by CH and PCL.
This reflects that nitrogen and hydrogen bond formation with
mucin was more important than electrostatic CH interaction
or mechanical interaction of PCL films.
This work contributes to the development and formula-
tion of buccal films containing biologic drugs. Future steps
will be oriented into evaluate the in vitro and in vivo
performance tests generating an alternative route for biologic
drug administration.
FUNDING INFORMATION
M. Montenegro-Nicolini acknowledges the funding sup-
port from CONICYT 21150995. J.O. Morales thanks the
financial support from FONDECYT 1181689 and FONDAP
15130011. Andrónico Neira-Carrillo thanks the financial
support from FONDECYT 1171520.
COMPLIANCE WITH ETHICAL STANDARDS
Conflict of Interest The authors report no conflict of interest. The
authors alone are responsible for the content and writing of this
article.
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