The Mechanism of Improvement of Film Solubility:

Design and Evaluation of Film Forming System with

Terbinafine as a Model Drug
Jing Zhang
Guangdong Pharmaceutical University
bohong lu
Guangdong Pharmaceutical University
Qiuyan Ma
Guangdong Pharmaceutical University
Shelke Om
Bright Future Pharmaceutical Laboratories Limited
William Wu
Bright Futrure Pharmaceutical Laboratories Limited
huaqing lin (  [email protected] )
Guangdong Pharmaceutical University https://orcid.org/0000-0003-2915-8672

Research Article

Keywords: Film Forming Systems, Rheology, Enthalpy Thermo Analysis, Film Solubility, Super Saturation
System

DOI: https://doi.org/10.21203/rs.3.rs-731064/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Purpose: Film forming system (FFS) combines the advantages of patch and gel, it is expected to replace
small doses of topical administration in the future. This work targets the design and evaluation of HPC-
acrylic FFS with different excipients in appearance, rheology and in vitro properties. Also, the reason of
improving the solubility of terbinafine film was illustrated by melting enthalpy thermo analysis.

Methods: In this work, we prepared 8 HPC-acrylic FFS samples with different excipients, and
characterized the film forming solutions and films in appearance, rheological properties, drug
crystallization and in vitro performance. Then used melting enthalpy thermo-analysis to explain the
mechanism of improvement of film solubility.

Results: According to appearance evaluation, the samples which had a small amount of plasticizer could
achieve an uniform surface morphology. The XRD and DSC demonstrated HPC could maintain drug
amorphous in films. Based on oscillation frequency sweep, short chain plasticizer tributyl citrate (TBC)
leading to strong entanglement and hydrogen bonding among the molecules. In vitro release test showed
FP1 had favorable release. And the melting enthalpy thermo-analysis explained why FP1 had favorable
release.

Conclusions: HPC acted as an effective crystallization inhibitor. TBC could lead stronger intermolecular
hydrogen bonds. The poloxamer had favorite miscibility with HPC-acrylic FFS. The combination of MCT
and poloxamer with HPC resulted in a high Terbinafine solubility.

1. Introduction
The study of film forming systems (FFS) allows the therapy to be adapted to the patient or application
requirements. The conventional topical preparations, such as ointment and cream, can be easily wiped
off by clothes, which leads to a poor treatment effect due to the improper dosing. The need of the
repeated application of the topical preparation generates a series of issues associated with the patient
compliance. Although the patches can be effectively retained on the skin, their disadvantages, such as
prevent skin from sweating, cause allergy, or obviously visual, that cannot be ignored in surface
application [1, 2]. FFS can provide an effective drug concentration, along with an invisible cosmetic
appearance, thus, prolonging the maintenance time on the skin. It reduces the dosing frequency and
improves the patient compliance [3]. FFS contain three main components - drug, film forming polymer
and volatile solvent. FFS can replace the small dosage topical preparation by combining the advantages
of gels and patches [4].

In order to achieve the rapid film formation after application, the volatile solvent system with a high
concentration is required. After evaporation of the volatile solvent, the drug concentration in the residual
film increases and even reaches the super-saturation state. The observed enhancement in the drug
saturation and thermodynamic activity can result in an improved driving force for the drug delivery across
the skin, which rises in a proportional manner as the drug saturation degree in the residual formulation
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after evaporation [5, 6]. Because of such a metastable state, the drug is thermodynamically unstable [7].
A few polymers are known to act as the crystallization inhibitors, preventing the crystallization and
enhancing the drug flux, even after the solvent has been completely evaporated. The examples of the
crystallization inhibitor polymers include polyvinyl pyrrolidone, polyethylene glycol and hydroxyl propyl
methyl cellulose [8].

Many film forming agents which can form a stable film structure in the aqueous solution, but they may
not form a stable film in the alcohol system. Hydroxypropyl cellulose (HPC) possesses low toxicity and
optimal film-forming properties, and it swells in ethanol to form a gel-like solution. Furthermore, the pure
HPC films do not demonstrate an excellent water barrier due to the presence of a large number of
hydrophilic groups [9], which can cause the films to break and fall off during sweating. Owing to the
excellent compatibility of acrylates/octylacrylamide copolymer (ACOA) and HPC, the incorporation of
ACOA in the system as a hydrophobic film forming component can improve the water and wearing
resistance. It indicates that a favorable pharmaceutical blend film can be developed by combining these
polymers. Carbomer and poloxamer are usually used in hydrogels, but now they are introduced to non-
aqueous solution. However, neither carbomer nor poloxamer possesses an independent film-forming
capacity. So the HPC matrix as a vehicle to maintain a stable polymer system.

Usually, plasticizers are used to enhance the flexibility and adhesion of the films by reducing the glass
transition temperature (Tg) of the film forming polymer. plasticizers can improve the drug release
performance by enhancing the polymer free volume and mobility of the polymer chains [10-12].
Furthermore, it not only weakens the intermolecular forces among the polymer chains [13], but also leads
to the formation of the hydrogen bonds with polymer chains [14]. In this study, medium-chain
triglycerides (MCT) and tributyl citrate (TBC) were chosen as plasticizers owing to their satisfactory
safety.

Terbinafine is an antifungal materials and inhibits the ergosterol synthesis in cytoderm by inhibiting the
squalene epoxidase. Terbinafine displays a strong affinity with stratum corneum (SC), and Terbinafine
can form a reservoir in SC [15]. In this study, FFS was used for the treatment of superficial cutaneous
fungal infections (SCFIs). The penetration enhancer was not included in the formulation owing to the
high drug penetration in the skin would make it difficult to maintain a drug reservoir in SC [16]. In addition,
it was vital to prevent the side effects by avoiding the systemic circulation of the drug.

During the formation of a solid film, the dynamic nature of the solvent evaporation process makes it
challenging to fully understand the role of each component and their impact on the final product. The
rheological analysis is sensitive to the changes in the molecular structure, it can provide an
understanding of the impact of the excipients changes on the topical preparation. The viscoelasticity can
reflect the changes in the molecular interactions, thus, allowing the effective characterization of the film
[17]. Moreover, the skin sensation is an important in topical preparation. The polymer system can
influence the sensorial parameters by modifying the final texture [18]. In this way, the subjective feeling
can be expressed and compared with objective physical parameters.

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In the first part this work targets the design and evaluation of HPC-acrylic FFS in appearance, rheology, in
vitro properties. The second half is to demonstrate both the feasibility and the practicability of applying
melting enthalpy thermo-analysis in drug-film solubility determination. This method used to explain the
mechanism of improvement of film solubility. It is a functional tool but it has rarely used in mechanism
demonstration. This study provides new strategies for the development and evaluation of a new topical
preparation, which may facilitate to replace a part of defective traditional topical preparations.

2. Materials And Methods

2.1 Materials
Hydroxypropyl cellulose (HPC, molecular weight: 8.5×105 Da, 25 ℃ Brookfield viscosity of 2%
concentration in water: 4000~6500 mPa·s, fine particle size) purchased from Ashland Industries Europe
Gmbh (Nanjing, China). Acrylates/octylacrylamide copolymer (ACOA) used as hydrophobic film forming
polymers purchased from Nouryon Chemicals Co., Ltd (Boxing, China). Poloxamer 124 and Carbomer
980 used as co-film forming material. Poloxamer 124 was kindly provided by BASF SE (Guangzhou,
China). Carbomer 980 was purchased form Lubrizol Corporation (Guangzhou, China). Medium-chain
triglycerides (MCT) and tributyl citrate (TBC) used as plasticizers were purchased from IOI Oleo GmbH
(Hamburg, Germany) and Shanghai Aladdin Bio-Chem Technology Co., LTD (Shanghai, China),
respectively. Terbinafine hydrochloride(TH) purchased from Qilu Antibiotics Pharmaceutical Co., Ltd(Linyi,
China). 96% Ethanol was purchased from Hayman Group, Kimia, UK. The commercial product (Lamisil
once® Cutaneous solution) was purchased from GlaxoSmithKline PLC (Basel, Switzerland). All other
chemicals were used without any further purification.

2.2 Preparation of film forming solution

TH was dissolved in 96% ethanol to achieve a clear solution, followed by the addition of ACOA. The film-
forming solutions were prepared by dispersing the HPC in the lipophilic plasticizers. The HPC dispersions
were added to the earlier formed solution of TH and ACOA in 96% ethanol at a concentration of 1.125%
(w/w) (equivalent to 1.0% (w/w) Terbinafine). The contents were stirred until a clear solution was
obtained, and the film forming solution was kept in dark overnight. In the formulations without MCT, HPC
was swollen in ethanol for more than 12 h until no insoluble white HPC particles were observed. It was
followed by the addition of 96% ethanol solution with TH and ACOA. The contents were stirred until a
clear solution was obtained. The compositions of the formulations are presented in Table 1.

Table 1 Composition of film forming system

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 Materials FMP1 FMP2 FMC1 FMC2 FC1 FC2 FP1 FP2

w/w [%]

TH 1.125 1.125 1.125 1.125 1.125 1.125 1.125 1.125

MCT 3.000 3.000 3.000 3.000 - - - -

ACOA 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

HPC 2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000

TBC 1.000 - 1.000 - 1.000 - 1.000 -

Polxamer 124 1.000 1.000 - - - - 1.000 1.000

Carbomer 980 - - 1.000 1.000 1.000 1.000 - -

96% Ethanol QS to 100%

Note: Naming rule: M = MCT, C = Carbomer, P = Poloxamer, 1 = With TBC, 2=Without TBC.

2.3 Chromatographic equipment and conditions

Quantitative analysis of Terbinafine was performed using Waters Alliance W2690/5 high-performance
liquid chromatography with Waters W2998 PDA detector and Shimadzu, Inertsil ODS-2 column (5 μm,
3.0×150 mm). The detection method of Terbianfine was based on the Chinese pharmacopoeia [19]. The
retention time of Terbinafine under these conditions was approximately 15 min. The HPLC procedure was
validated for linearity, precision and accuracy. The produced calibration curve A= 40115.8c-10716.7 was
linear over the concentration range 2~1000 μg·mL-1, with a coefficient of determination (r2) of 0.9999.
The intra-and inter-day precision (% RSD) for the three standards representing the high, medium and low
drug concentrations ranged from 0.22% to 0.66% and 0.86% to 1.59% respectively. The accuracy of the
three concentrations ranged between 98.76% and 98.98% (RSD=0.10%).

2.4 Scanning electron microscopy

The films were observed by using scanning electron microscope (Helios Nanolab 600i, FEI, USA). The
surface of the films was sputtered with a thin gold coating. The analysis was performed at an
accelerating voltage of 5 kV, and the images were acquired at magnifications of 5000×.

2.5 Rheological properties

2.5.1 Steady shear measurement

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The steady shear properties were evaluated using a rotational rheometer (MARS 40, Haake Ltd., Hamburg,
Germany) at 25 °C with a cone-plate geometry of 60 mm diameter. The cone angle and gap were set at 1°
and 1.00 mm, respectively. The shear rate was varied from 0.001 to 100 s-1 to evaluate the viscous
behavior of the sample, and the associated data was fitted to the following power law equation:

where τ is the shear stress (Pa), K is the consistency index (Pa s), is the shear rate (s−1), and n is the flow
index.

2.5.2 Dynamic viscoelasticity measurement

The dynamic rheological analysis was performed using the same conditions as the steady shear
analysis. The shear stress was varied from 0.01 to 2000 Pa at a frequency of 5.00 Hz to evaluate the
linear viscoelastic zone (LVR).

2.5.3 Oscillation frequency sweep

The oscillation frequency sweep was performed by using the same conditions. The shear stress in LVR
was set as 10 Pa, and the frequency ranged from 0.10 to 20 Hz. The changed in the storage and the loss
moduli were subsequently recorded.

2.6 Differential scanning calorimetry

The thermal properties of the films were measured by using a differential scanning calorimeter (TA Q100-
DSC, TA instruments, UK) under nitrogen atmosphere. The film samples (5 mg) were placed in the
aluminum pans, followed by sealing of the pans. The samples were heated in the temperature range 25
°C to 300 °C using a heating rate of 10 °C/min.

2.7 X-ray diffraction

The crystal structure of the pure TH powder, physical mixture of TH and HPC, TH and HPC films and
blend films were characterized by using an X-ray diffractometer (SmartLab 9 kW, Rigaku, Japan)
equipped with Cu Kα radiation (λ = 0.1542 nm). The samples were scanned in the 2θ range from 1.5° to
20° using a scanning rate of 2° min-1.

2.8 In vitro release test

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The experiments were conducted using Vertical Diffusion Cell (RermeGear V6-Ca-01, USA) with a Nylon
membrane (JINTENG ® TJMF25 Nylon membrane, 0.45 μm) at a constant stirring speed at 600 rpm. The
receptor medium based on methyl alcohol and water (30:70) was added, and the water bath temperature
was set to 32±1℃. Subsequently, 300 mg FFS was added on the membrane soaked prior for 30 min in
the medium for equilibration. A period of 180 min was provided to achieve the film formation. The cells
were occluded with Parafilm® throughout the analysis to prevent the evaporation of the medium. 1 mL
receptor cells samples were withdrawn after 1, 2, 4, 6 and 8 h and replenished with the same amount of
the medium.

2.9 Statistical analysis

The samples were tested at least in triplicate, and the results were presented as mean±standard
deviation. The statistical analyses were performed using the Origin 2018 95C software (OriginLab
Corporation, Northampton, MA, USA). Two-way ANOVA (p < 0.05) was used to compare the statistical
differences in the obtained values.

3. Results And Discussion

3.1 Appearance of FFS and films
Supplemental Fig. 1 demonstrates the appearance of the different FFS. The poloxamer FFS was
observed to be a transparent and uniform gel-like solution, whereas the carbomer FFS was an off-white
gel-like solution. For 0.5 g film forming solution applied on the forearm skin, the formed thin and invisible
film dried within 3 min.

3.2 Scanning electron microscopy

Some formulations couldn’t get integrated films in drying process. Like FMC1 and FMC2, the separated
two-phase structure generated cracks on the film surface, and the FC1 films exhibited cracks and did not
form an integrated structure (Supplemental Fig. 2). This phenomenon could be interpreted as the
carbomer-HPC FFS had a poor miscibility with the lipophilic plasticizer.

As shown in Fig. 1, the surface of the original HPC-ACOA blend film demonstrated a few cracks, which
indicated that the original blend film was not ideal as a drug carrier. Similarly, FC2 and FP2 also displayed
cracks and a certain extent of breakage, while FP1 presented a smooth morphology with uniform texture.
It revealed that a small amount of plasticizer was necessary to achieve the uniform surface morphology.

When the MCT was gradually added to poloxamer FFS, The the SEM images of FMP1 and FMP2 revealed
the soft MCT inclusions surrounded by the rigid polymer framework. The inclusions also led to the
formation of inter-connected holes. Such drug-carrying films may be beneficial for buccal mucosa and

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oral delivery. As the saliva and gastric juice enter the holes, it can promote the polymer framework
swelling and drug dissolution. It is feasible to control the rate of drug release by controlling the number of
holes, which has a positive correlation with the plasticizer content.

3.3 Rheological properties

3.3.1 Steady shear measurement

As shown in Fig. 2a and 2b, viscosity decreased rapidly on increasing the shear rate. The high shear rates
simulates the activity of applying samples on the skin. Based on the power law fitting, the parameters n
and K are presented in Supplemental Table 1. All film forming solutions exhibited a high correlation
coefficient (R2 >0.98). The film forming solutions with n < 1 revealed a shear thinning behavior
representing the non-Newtonian pseudo-plastic fluids. It represents an ideal property of topical semisolid
systems, as the low viscosity system is more conducive to achieve the uniform paint and subsequent
application.

3.3.2 Dynamic viscoelasticity measurement

The storage (G') and loss (G'') moduli of the sample are presented in Fig. 3a and 3b. As the stress was
increased, the storage and loss moduli curves ran nearly parallel to each other. This was followed by a
rapid decline in G', generating a crossover point with G''. The crossover point indicated the irreversible
damage in the internal structure of FFS. The parallel range is also termed as the linear viscoelastic range
(LVR).

In practice, G' values in LVR represent the stiffness of the sample or gel strength. The poloxamer FFS
exhibited a reduction in the G' values after the incorporation of MCT in the formulations (Fig. 3a). FMP1
and FMP2 demonstrated lower G' values as compared to FP1 and FP2 (Supplemental Table 1). Another
lipophilic plasticizer TBC was also evaluated in this work. As shown in Fig. 3a, an increment in the
amount of the lipophilic plasticizer (both MCT and TBC) was inversely proportional to the stiffness and
strength of FFS (P<0.05).

However, the inverse relation was not evident in the carbomer FFS. As observed in Fig. 3b and
Supplemental Table 1, the G' values and lipophilic plasticizer did not exhibit any significant relation.
Except for FC1 demonstrating the highest G' values (P<0.05), other changes in the carbomer formulation
did not significantly impact the G' values (P>0.05).

The yield stress values (Supplemental Table 1) of the samples between 10 and 100 Pa indicated that a
minimal force could initiate the flow (1-10 mN force over 1 cm2 area), which confirmed the easy
application of the developed formulations on the skin [20].

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3.3.3 Oscillation frequency sweep
Oscillation frequency sweep was used to determine the system response to the impact or gradual loading
forces. Fig. 4a and 4b demonstrate the changes in G' and G'' as a function of frequency. G'' was higher
than G' at low frequency values, which indicating the viscous characteristic of the system. At high
frequency values, G' was higher than G'', revealing the elastic characteristic.

A large number of literature studies [17, 21, 22] have explained the observed changes: at low frequency
values, the polymer molecular chains have sufficient time to relax and disentangle, thus, rendering the
viscous fluid characteristic. However, on enhancing the frequency (the high frequency acting more like a
strike on the system), the short periodic oscillation does not provide sufficient time to the entangled
molecular chains to relax. These entanglements, thus, play the role of the three-dimensional (3D) network
of the temporary junction. Although the entanglement of the polymer chains can be regarded as the
temporary 3D structure at high frequency, G' and G'' show frequency dependency, suggesting that HPC in
FFS is present as a polymer solution rather than a network structure [17, 23].

Classified curves by MCT, then respectively compared the samples with or without TBC. Both G' and G''
were observed to increase for the system with TBC, and the crossover point moved towards the low
frequency values, representing a strong entanglement and hydrogen bonding among the molecules. This
confirmed that the short chain plasticizer TBC was more likely to be inserted in the incompletely swollen
polymer chains, so that exposed carboxyl groups on the stretched chains to form a large number of
strong intermolecular hydrogen bonds

3.4 Differential scanning calorimetry

As shown in Fig. 5a, the TH drug powder demonstrated two characteristic endothermic peaks in the DSC
pattern: one of the peaks was attributed to TH, while the other peak was related to its homeopathic
isomers. However, these characteristic heat-absorption peaks were observed to disappear in the physical
mixture. The observed phenomenon is due to the reason that a drug was physically mixed with an
amorphous polymer it can dissolved in, the amorphous polymer initially absorbs the heat to form a
glassy structure. On further heating to the drug melting temperature, the drug dissolves in the glassy
polymer, resulting in the reduced melting enthalpy. This phenomenon can be used to determine the drug
solubility in polymers [6]. The disappearance of peaks was also observed in the films indicating the
crystal transformation in FFS. Overall, the crystal transformation to the amorphous structure is conducive
for the drug entry in SC.

3.5 X-ray diffraction

XRD analysis was performed to verify the crystal structure of TH in the physical mixture. As shown in Fig.
5b, the pure TH powder and physical mixture exhibited sharp diffraction peaks, especially at 2θ = 5.98°.

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This indicated that the crystal structure still existed in the mixture at room temperature. The characteristic
peaks were observed to disappear or broaden in the films. It suggested that the transformation of the
Terbinafine crystal occurred in the films due to the hydrogen bonding interactions, which was consistent
with the findings from DSC. Combining the DSC and XRD results also revealed that HPC maintained TH
in the amorphous form during the solvent volatilization. HPC act as an ideal crystallization inhibitor.

3.6 In-Vitro release test

As shown in Fig. 6, the formulations exhibited a significantly higher extent of release than the commercial
product(P<0.05), indicating the formation of a higher drug reservoir formed in SC. The high lipophilicity of
TH makes it difficult to pass through the hydrophilic dermis in the absence of a penetration enhancer,
thus, a high concentration of the drug reservoir does not enhance the risk of the side effects. Two
features can be clearly noted from Fig. 6. Firstly, TBC occupied a content of 10.9%~16% in the dried films,
however, it did not significantly influence the released amount (P>0.05). Secondly, a high amount of MCT
(3 times higher than TBC) added in the carbomer-films (FMC1 and FMC2) significantly enhanced the drug
release rate than FC1 and FC2 (P<0.05), which was consistent with the plasticizer effect mentioned
earlier. In contrast, poloxamer improved the initial release and release rate, however, the presence of MCT
in the poloxamer-film reduced the extent of release. A probable reason is that the solubility of Terbinafine
may be enhanced due to the combination of MCT and poloxamer. This corresponds to a decrease in the
drug saturation and thermodynamic activity, thus, reducing the drug delivery. The release curves were
fitted with the first-order, zero-order and Higuchi functions respectively. As per Supplemental Table 2, the
formulations mainly followed the first-order release behavior.

3.7 Thermo-analysis of release behavior

It is important to analyze the observed decrease in the drug release on adding MCT in the poloxamer FFS.
In order to explore if the observed decrease in the drug release was related to the improvement in the drug
solubility, the TH+HPC+P physical mixtures were prepared using different mixing ratios. DSC analysis
was performed to ascertain the solubility of TH in HPC. The solubility was re-measured after adding MCT.
The principle is that the drug dissolves in the glassy polymer during melting, a reduction in the melting
enthalpy can be observed. This reduction should linearly related to the drug fraction. In case the weight
fraction of the drug exceeds the maximum solubility level within the polymer, a fraction of the drug is no
longer dissolved in the polymer, and the linear relationship with the melting enthalpy may change.

As shown in Fig. 7a, the glass transition temperature of HPC was ~55 ℃, and the glass transition curve
was noted to flatten after adding MCT (Fig. 7b). This could be attributed to the molecular interactions in
the HPC-poloxamer-MCT system.

As shown in Fig. 7a and 7b, compared to the TH+HPC+P mixture, the reduction in the TH melting peak
was deeper in the mixture with MCT. Especially for the 40:60 mixtures, the TH+HPC+P+MCT mixture

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exhibited a small TH melting peak, while the melting peak was obvious in the TH+HPC+P system. This
indicated that TH had a superior solubility in the HPC+P+MCT mixture.

Fig. 8 present the melting enthalpy variation observed in each mixture. For the TH+HPC+P mixture (Fig.
8), the changes of melting enthalpy could be divided into two linear stages of drug loading. The first
stage occurred for the drug loading between 40 to 70%, while the second was noted from 70 to 90%. The
solubility obtained by the linear regression analysis was 71.81% w/w. Similarly, the TH solubility in the
HPC+P+MCT mixture was 80.90% w/w.

These findings qualitatively and quantitatively verified that the addition of poloxamer and MCT to HPC
resulted in an enhanced TH solubility. These also explained the reduction in the drug release on
incorporating MCT to the poloxamer FFS: the enhanced solubility led to a reduction in the super-
saturation driving force.

4. Conclusion
This work provide strategies for the design and development of new topical preparations that can replace
a part of defective traditional topical preparations, and explains the influence of excipients on drug-film
solubility. The different excipients effect in appearance, rheology, in vitro properties in HPC-acrylate blend
FFS has been demonstrated. HPC acted as an effective crystallization inhibitor to maintain drug
amorphous in films. the poloxamer had favorite miscibility with HPC-acrylic FFS. But carbomer FFS was
noted to be immiscible with the plasticizer, and its appearance and release behavior were unsatisfactory.
FP1 was confirmed to be the potential formulation because of uniform film appearance as well as high
drug release and satisfactory rheological performance. The drug-film solubility could be effectively
characterized by thermos-analysis. The combination of MCT and poloxamer with HPC resulted in a high
Terbinafine solubility All the formulations exhibited their easy application and uniform paint-forming
ability.

Declarations
Research involving humans and animals participants

No animal or human studies were carried out by the authors for this article.

Competing interests

The authors declare no competing interests regarding the publication of this paper.

Author information

Affiliations

Department of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510000, China

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Jing Zhang, Bohong Lu, Qiuyan Ma, Huaqing Lin

Bright Future Pharmaceutical Laboratories Limited, Yuen Long, New Territories, Hong Kong

Om Shelke, Tao Wu

Contributions

All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence to Huaqing Lin

Acknowledgements

Jing Zhang and Bohong Lu are co-first authors, they contribute equally to the article. This work was
supported by the Science and Technology Project of Guangdong Province [grant numbers 20182010047],
Innovation and Entrepreneurship Team special Fund project of Guangdong Province [ grand numbers
2014ZT05Y018] and Biomedical Innovation Institution of Hong Kong & Guangdong Pharmaceutical
University. The authors would like to acknowledge the Bright Future Pharmaceutical Laboratories Limited
(Hong Kong, China) for financial and technical support.

Funding

This work was supported by the Science and Technology Project of Guangdong Province [grant numbers
20182010047], Innovation and Entrepreneurship Team special Fund project of Guangdong Province
[grand numbers 2014ZT05Y018] and Biomedical Innovation Institution of Hong Kong & Guangdong
Pharmaceutical University.

Data availability

All data generated or analyzed during this study are included in this published article (and its
supplementary information files).

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Figures

Figure 1

SEM images of different films

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Figure 2

Viscosity behavior curve at 25℃.

Figure 3

Changes of storage (G') and loss (G'') modulus under increasing shear stress at 25℃.

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Figure 4

Changes of G' and G'' under frequency sweep at 25℃. The colored vertical lines indicate the crossover
point of the corresponding curve.

Figure 5

a) DSC profiles of Terbinafine and films. b) XRD profiles of Terbinafine and films.

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Figure 6

The drug release profiles of Terbinafine film forming system

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Figure 7

Representative DSC curves showing the TH melting transition for HPC+P physical mixtures (a) and
HPC+P+MCT physical mixtures (b) in varying proportions.

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Figure 8

The melting enthalpy curve for HPC+P physical mixtures and HPC+P+MCT physical mixtures in varying
proportions.

Supplementary Files
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SupplementaryMaterials.docx
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