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Review

Multilayered Polyelectrolyte Structures Deposited on Corona-Charged Substrate Blends as Potential Drug Delivery Systems

by
Asya Viraneva
*,
Maria Marudova
,
Aleksandar Grigorov
,
Sofia Milenkova
and
Temenuzhka Yovcheva
Department of Physics, Faculty of Physics and Technology, University of Plovdiv “Paisii Hilendarski”, 24 Tzar Assen Str., 4000 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Coatings 2025, 15(2), 240; https://doi.org/10.3390/coatings15020240
Submission received: 17 November 2024 / Revised: 8 February 2025 / Accepted: 15 February 2025 / Published: 18 February 2025
(This article belongs to the Section Surface Coatings for Biomedicine and Bioengineering)
Browse Figures
Figure 1
<p>Corona discharge system: 1. high voltage source; 2. corona electrode; 3. grid; 4. grounded plate electrode; 5. sample on a metal pad; and 6. voltage divider.</p> "> Figure 2
<p>Schematic representation of the multilayer deposition process.</p> "> Figure 3
<p>Time dependencies of the normalized surface potential for PDLA substrates charged (<b>a</b>) in a positive corona and (<b>b</b>) in a negative corona.</p> "> Figure 4
<p>Time dependencies of the normalized surface potential for 50/50 substrates charged (<b>a</b>) in a positive corona and (<b>b</b>) in a negative corona.</p> "> Figure 5
<p>Time dependencies of the normalized surface potential for PCL substrates charged (<b>a</b>) in a positive corona and (<b>b</b>) in a negative corona.</p> "> Figure 6
<p>Steady-state values of the normalized surface potential at a time of 360 min for all investigated positively charged substrates.</p> "> Figure 7
<p>Steady-state values of the normalized surface potential at a time of 360 min for all investigated negatively charged substrates.</p> "> Figure 8
<p>SEM images of all investigated substrates.</p> "> Figure 9
<p>Surface free energy of all investigated substrates.</p> "> Figure 10
<p>Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on PDLA substrates treated with positive (+) or negative (−) corona.</p> "> Figure 11
<p>Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on substrates obtained from equal amounts of PDLA and PCL treated with positive (+) or negative (−) corona.</p> "> Figure 12
<p>Release profiles of benzydamine hydrochloride encapsulated in multilayer structures built on PCL substrates treated with positive (+) or negative (−) corona.</p> ">
Review Reports Versions Notes

Abstract

:
Polyelectrolyte multilayers (PEMs) deposited on non-porous and porous blend substrates were studied. Films, prepared from two biodegradable polymers poly (D-lactic acid) (PDLA) and poly(ε-caprolactone) (PCL) and their blends were used as substrates in the present paper. All films were initially charged in a corona discharge (positive or negative corona). After charging, the initial surface potential of the samples V0 was measured and the normalized surface potential was calculated. The dependencies on time of the normalized surface potential for electrets, possessing either positive or negative charges, were studied. It was found that the steady-state values of the normalized surface potential for the porous substrates were higher than those of the non-porous ones, independently of material type and corona polarity. It was also shown that the values of the normalized surface potential for the PCL electrets were the highest and decreased when the content of PDLA increased. Scanning electron microscopy (SEM) was utilized for the determination of the substrates’ surface morphology. With the largest pore size, PCL substrates allowed for a greater capture of charges on their surface and facilitated the retention of said charges for prolonged periods of time. Differential scanning calorimetry (DSC) measurements were performed to determine the degree of crystallinity, which was very high for PCL substrates, when compared to the other investigated substrates. The wettability of the investigated substrates was measured using the static water contact angle method. The obtained results demonstrated that the created blends were more hydrophilic than the pure films. The two chosen polyelectrolytes were layered onto the surface of the substrates with the use of the layer-by-layer (LbL) technique and benzydamine hydrochloride was loaded in the multilayers as a model drug. Its loading efficiency and release profile were carried out spectrophotometrically. It was determined that for non-porous substrates, independently of the corona polarity, the best fitting model was Korsmeyer-Peppas, while for the porous substrates the best fitting model was Weibull.

1. Introduction

Ever since their creation, polymers have found their way into all aspects of human life. The development of the polymer industry has allowed the creation of various materials that have revolutionized many industries, but with the numerous benefits come a number of drawbacks. A major one is the ecological impact of the industry on the environment, which has led to an increased interest in the development of biodegradable and biocompatible alternatives to most synthetic polymers [1,2,3]. Biopolymers, such as Poly (D-lactic acid) (PDLA) [4,5,6,7] and poly (ε-caprolactone) (PCL) [8,9], are some of the more investigated materials and have been utilized in a variety of applications [10,11], especially in the field of medicine [12,13]. As biopolymers they all possess highly desirable properties, which would allow their utilization in a number of different end products. However, their benefits are often combined with a number of drawbacks that do not allow for the wider spread of these biodegradable materials and often require additional modifications [14,15,16].
As one of the widest spread biopolymers, poly-lactic acid offers an excellent alternative to a wide number of petrol-based products. With its excellent biodegradability and biocompatibility, this thermoplastic aliphatic polyester is becoming a highly sought after option for the generation of biodegradable applications. Alongside its high cell affinity and good hydrophilicity, poly-lactic acid is also fully biodegradable, with its byproduct lactic acid being completely harmless to the environment. PDLA is also often used as a base product for a number of copolymers and blend biomaterials [17,18,19].
Another often utilized biodegradable polymer, poly (ε-caprolactone) or (PCL) has various biomedical and environmental applications [20]. Poly (ε-caprolactone) has a semi crystalline structure and lower degradation rate and often finds application in the fields of extended drug delivery and tissue engineering. The absence of chiral atoms, however, prevents any modification of its properties with the use of stereochemistry, which reduces the number of potential applications. Because of that, (PCL) can usually be combined with PDLA with the purpose of altering its properties [21,22,23].
Apart from varying the creation conditions and components, the properties of the biopolymer blends can further be enhanced with the use of other widespread surface modification techniques. These techniques can vary from copolymerization and the addition of additives to the investigated polymers (creating different blend combinations with porous structures), to more complex methods such as different coatings, plasma treatment, irradiation with high energy particles, chemical modification, etc. All of these types of modifications can be utilized for the controlled modification of the surface of different polymers and polymer blends, enhancing their desired properties. Plasma treatment is one of the particularly popular novel modification techniques that offer easy to use and highly controlled methodology, and it has also been shown to often enhance the desired properties of the treated polymers [24]. The plasma treatment (such as the application of corona discharge) of the surface of biopolymers has been proven to enhance their biocompatibility and hydrophilicity, thus further enhancing the biopolymer [25,26] and allowing the creation of different multilayered structures on their surface [27,28,29]. The plasma treatment of different porous membranes in particular has been shown to be a fast and reliable method for the creation of new materials for filtration processes [30]. Overall, the methodology of the plasma treatment offers a wide variety of modification options when working with PDLA [31]. The development of novel medical applications [32] creates the need for further research in the biopolymer field and plasma treatment offers a more controllable and variable method for surface modification, when compared to others (like chemical modification). As a relatively new methodology, plasma treatment has the potential to become a major factor in the future development of the field of biopolymers [33]. In our review, we have chosen the corona discharge method as our primary method of the surface modification of the investigated blended polymers, due to its ease of use, high controllability, and repeatability, as well as due to the fact that it is the main methodology our team has been utilizing throughout the majority of our research on poly (D-lactic acid) as a base polymer for the creation of drug delivery multilayered structures.
In our review, we focus on the application of biopolymer blends, composed of different ratios of poly-lactic acid and poly (ε-caprolactone), for the creation of controlled and targeted completely biodegradable drug delivery systems. The creation of these systems is often done utilizing the layer-by-layer (LbL) deposition technique, which can be used for the formation of thin polyelectrolyte multilayers with tailored properties, that would allow the loading of a number of active biomolecules, such as a variety drugs, enzymes, nanoparticles, etc. [34,35,36,37,38]. The described multilayers are also created with the use of completely biodegradable and biocompatible materials, such as chitosan and casein, and in no way interfere with the desired properties of the base blend biopolymers. In fact, both polyelectrolytes offer a number of beneficial properties, with chitosan, being a cationic polyelectrolyte, offering excellent mucoadhesive [39] and antimicrobial properties [40], and having been shown to work in synergy with the incorporated bioactive material [41]. Casein, on the other hand, is amongst the widest spread natural proteins and is a fitting choice for the progress of polyelectrolyte complexes as drug delivery systems [42].
In our paper, we aim to summarize our research on the investigation of poly (D-lactic acid) (PDLA) and poly (ε-caprolactone) (PCL) blends, used as substrates on which polyelectrolyte multilayers are deposited, for the creation of controllable completely biodegradable drug delivery systems.

2. Materials and Methods

2.1. Materials

Poly (ε-caprolactone) (PCL, Mw = 80 kDa) was obtained from Lactel Absorbable Polymers (Birmingham, AL, USA). Poly (D-lactic acid) (PDLA, Mw = 230 kDa), polyethylene glycol (PEG, Mw = 400 Da), chitosan (high molecular mass and a degree of deacetylation > 75%), sodium caseinate (casein sodium salt from bovine milk), and benzydamine hydrochloride were delivered from Sigma-Aldrich (St. Louis, MI, USA) and were utilized without the need for additional purification. All remaining chemicals were of high purity and suitable for analytical applications.

2.2. Methods

2.2.1. Substrates Preparation

Three different creation methods were used for the production of the reviewed substrates. All of the substrates were created using mixtures of poly (D-lactic acid) and poly (ε-caprolactone) at a ratio of 50/50 as well as two pure samples of both polymers.
For the first method, all three polymer ratios were dissolved in chloroform and then poured onto metal plates. The resulting solutions were then placed on a level surface and left to dry at standard atmospheric pressure and room temperature until the complete evaporation of solvent.
For the second method, the solvent was changed to 1,4-dioxane, and the resulting solutions were poured in glass petri dishes and placed in a freezer at −16 °C until frozen solid. The frozen solutions were then placed in a lyophilizer and freeze dried under vacuum for 3 days.
The third method used dichloromethane (DCM) as its solvent. After the complete dissolvement of the polymer mixtures, polyethylene glycol (PEG) was added to all solutions at a ratio of 150% w/v. All mixtures were then stirred until the complete homogenization of the resulting mixture. The created mixtures were then poured in glass petri dishes and left to dry on a flat horizontal surface at room temperature until the complete evaporation of the solvent. Afterwards, the dry samples were additionally placed in an incubator for 24 h at 35 °C to guarantee that any residual moisture is evaporated from their surface.
After their creation, the blended polymer substrates from all three methods were kept in a dry desiccator at room temperature and standard atmospheric pressure until further use.

2.2.2. Corona Charging and Surface Potential Measurement

All created film blends were cut into 30 × 30 mm samples and charged under corona discharge in normal atmospheric conditions. The charging of the samples in a corona discharge was carried out by means of a conventional corona triode system consisting of a corona electrode (needle), a grounded plate electrode and a grid placed between them (Figure 1).
For the charging process, positive or negative 5 kV voltage was applied to the corona electrode and 1 kV of the same polarity was applied to the grid. All films were charged for 1 min. The electrets surface potential of the charged samples was measured by the vibrating electrode method with compensation and the estimated error was less than 5%. The normalized surface potentials V/V0 were calculated, as the value V0 is the initial surface potential measured just after charging the electrets.

2.2.3. Layer-by-Layer Deposition

For the purpose of polyelectrolyte multilayers (PEMs) creation, the previously obtained charged substrates (with an effective area of 2 × 2 cm) were secured on sample holders and placed in the deposition apparatus (SLEE MCM Carousel Slide Stainer, manufactured by SLEE medical GmbH, Nieder-Olm, Germany). A pair of distinct polyelectrolyte solutions were produced for the deposition procedure: 300 mL of 0.1% w/v chitosan solution in acetate buffer (pH 5, 100 mM) and 300 mL 1% w/v casein solution in phosphate buffer (pH 8, 100 mM). All mediums, used during the deposition, were maintained at room temperature and standard air pressure for the duration of the procedure. The chosen bioactive substance (benzydamine hydrochloride) was dissolved in the chitosan solution at a predetermined ratio. The creation of the multilayers was performed using the layer-by-layer (LbL) deposition technique with steps of 15 min of dipping in the first polyelectrolyte solution, a 5 min washing step in deionized water, followed by 15 min of dipping in the second polyelectrolyte solution, and another washing step of 5 min. This sequence created 2 layers on the surface of the investigated film with 8 layers deposited in total. The sequence of the polyelectrolyte solutions was chosen with regards to the sample charges, with positively charged samples beginning the dipping process in the casein solution and negatively charged ones beginning in the chitosan solution (Figure 2). The resulting multilayer samples were left to dry until further testing.

2.2.4. Differential Scanning Calorimetry (DSC)

The glass transition and melting phenomena of the PDLA/PCL blend were explored by the method of differential scanning calorimetry (DSC). A DSC 204F1 Phoenix instrument manufactured by Netzsch Gerätebau GmbH, Selb, Germany was utilized in the experiments. It was calibrated by an Indium standard (Tm = 156.6 °C, ΔHm = 28.5 J/g) for both heat flow and temperature. A total of 15 mg of the PDLA/PCL films were measured carefully with the use of an analytical balance and sealed in aluminum pans. An identical empty pan was used as a reference. The measurements were conducted under argon atmosphere. The research was conducted at the following temperature regime: cooling from 25 °C to −70 °C at a cooling rate of 2 K/min; an isothermal step at −70 °C for 15 min; and heating from −70 °C up to 300 °C at a heating rate of 10 K/min. The experimental DSC curves were evaluated by Netzsch Proteus—Thermal Analysis software Version 6.1.0B, Selb, Germany.
The degree of crystallinity of PCL χ P E C in the films was determined by utilizing Equation (1)
χ P E C = ∆ H m ∆ H m 0 · ω P E C · 100
where ∆ H m is the specific melting enthalpy [J·g−1]; ∆ H m 0 is the melting enthalpy of 100% crystalline PCL ( ∆ H m 0 = 139.3   J · g − 1 [43]), and ω P E C is the mass fraction of PCL in the blend.
The degree of crystallinity of PDLA χ P D L A was determined by subtracting the enthalpy of crystallization from the enthalpy of melting—Equation (2):
χ P D L A = ∆ H m ∆ H m 0 · ω P D L A · 100
where ∆ H m is the melting enthalpy of PDLA [J·g−1]; ∆ H m 0 is the melting enthalpy of 100% crystalline polymer ( ∆ H m 0 = 93.6   J · g − 1 [44], and ω P D L A is the mass fraction of PDLA.

2.2.5. Scanning Electron Microscopy (SEM)

The morphology determination of the obtained blend substrates was performed with the use of scanning electron microscopy (SEM) (Prisma E SEM, Thermo Scientific, Waltham, MA, USA). Two milligrams of each investigated sample were secured onto an aluminum holder, after which a fine coating of carbon and gold was applied using a vacuum evaporator Quorum Q150T Plus (Quorum Technologies, West Sussex, UK). The captured images were taken using a back-scattered electron detector (Prisma E SEM, Thermo Scientific, Waltham, MA, USA) at different levels of magnification and an accelerating voltage of 15 kV.

2.2.6. Water Contact Angle Measurement

A static water contact angle method was used in order to investigate the surface wettability of the investigated substrates. Measurements of the water contact angle were carried out under standard atmospheric conditions (at room temperature and normal air pressure). Small droplets of 2 μL were carefully placed on the surface of the substrates using a precise 10 μL micro syringe (Innovative Labor System GmbH, Ilmenau, Germany). Six droplets were deposited on each sample, after which the results were averaged and used to determine the hydrophobicity of each sample. The contact angles were measured by taking the value of the tangent of the drop profile by using images, captured by a camera with a high resolution capability. A public domain ImageJ software (ImageJ v1.51k software, National Institutes of Health, Bethesda, MD, USA) was used for the processing of the captured images. The results from the water contact measurement were used for the determination of the surface free energy of different substrates. All calculations were done by following the theory of Owens and Wendt [45] with the following formula:
γ l v 1 + cos ⁡ θ = 2 γ s d γ l v d 1 / 2 + 2 γ s p γ l v p 1 / 2
where γ l v = γ l v p + γ l v d .
The surface free energy of a solid, γ s , can be expressed as a sum of contributions from γ s d and γ s p components. Both can be determined from the contact angle data of polar and non-polar liquids with known dispersion, γ l v d , and polar, γ l v p , parts of their interfacial energy.

2.2.7. Benzydamine Hydrochloride Drug Release

Phosphate buffer saline (PBS) buffer with pH 7.4 and an ionic strength of 100 mM was used for the establishment of the rate of release of the encapsulated drug. Twenty milliliters of the buffer were poured in covered glass beakers and placed in a water bath at 37 °C during the entire experiment. A triplicate of samples for each variant of the multilayer films was deposited in sample holders and stirred at 150 rpm for 6 h. At predetermined time intervals, 3 mL of the buffer was removed from the total and replaced with the same amount of clean buffer. The gathered samples were filtered through a 0.45 µm syringe filter and their absorption was determined at 306 nm using a spectrophotometer Metertech SP-8001 (Metertech Inc., Nangang, Taipei, Taiwan). The obtained results were utilized for the determination of the drug release time rate. The obtained experimental data were mathematically processed following the Korsmeyer-Peppas or Weibull kinetic models. The Korsmeyer-Peppas model is given by the equation:
M = K t n
where M = the percentage of the released drug after time t, K describes the release velocity constant, and the exponent n is related to the release mechanism—if n = 0.50, the release is due to Fickian diffusion, when 0.50 < n < 1, the drug transport is anomalous, and for n = 1, the transport is Case-II [46].
Weibull kinetic models:
M = M 0 1 − e x p − t − T b a
In this formula, M—the amount of dissolved drug as a function of time M0—the total amount of released drug, t—time, T—lag time caused by dissolution process, and a—the scale parameter of the time dependence b—the shape of dissolution curve progression. For b = 1, the shape of the curve corresponds exactly to the shape of an exponential profile. If b > 1, the shape of the curve turns into a sigmoid with a turning point, whereas the shape of the curve at b < 1 would show a steeper increase than the one where b = 1 [47].

2.2.8. Benzydamine Hydrochloride Drug Content

Films, loaded with benzydamine hydrochloride were submerged in 20 mL phosphate buffer saline (pH 7.4) and stirred continuously for three days on a magnetic stirrer. The resulting samples were sonicated for 5 min and filtered with the use of a ChromafilVR syringe filter (0.45 μm syringe filter Sigma-Aldrich, Taufkirchen, Germany). During the test, all measurements of the samples were done in triplicate. The quantity of benzydamine hydrochloride was evaluated with the use of a UV/Vis spectrophotometer (Metertech SP-8001, Metertech Inc., Nangang, Taipei, Taiwan) measuring the band at a wavelength of 306 nm. The concentration of the drug was determined with the use of a standard calibration curve of benzydamine hydrochloride in phosphate buffer saline (pH 7.4).

3. Results and Discussion

All of the substrates that were described in this review consist of pure Poly (D-lactic acid) (PDLA), pure poly (ε-caprolactone) (PCL), or a blend with a ratio of 50/50 of both polymers. Three different creation methods were used for the creation of porous and non-porous variants of each of the described substrates. The first method (drying in standard atmospheric conditions and room temperature) resulted in the non-porous variants of the substrates, while the other two methods (the lyophilization and addition of polyethylene glycol (PEG)) were used to obtain the two porous varieties of the investigated substrates.
Polyelectrolyte multilayer films were constructed from two biopolyelectrolytes, namely chitosan and casein. Chitosan is the only polycation in nature that is known as a biocompatible biodegradable polysaccharide with proven antimicrobial properties [48]. Casein enhances the functionality and versatility of PEMs due to its biocompatibility, anionic nature, and ability to enable controlled release and adhesion. This makes it a valuable component in drug delivery systems and biomedical coatings. In our previous research we have already developed polyelectrolyte multilayers from chitosan and casein [39,49] that offer a versatile and promising approach for developing drug delivery systems, particularly for buccal administration. Their properties can be finely tuned by adjusting assembly conditions, enabling the design of tailored delivery platforms for a range of therapeutic agents.

3.1. Time Storage Influence on the Electrets Surface Potential Decay

The electret properties of the created non-porous and porous blend substrates were studied. Time dependencies of the normalized surface potential PDLA, PCL, and PDLA/PCL electrets, possessing either positive or negative charges, were investigated during a period of 360 min. Measurements of the surface potential were taken every 5 min during the initial 30 min, during which period the charge was decreasing at a rapid pace. Afterwards, measurements of the surface potential were taken at longer intervals, due to the steady-state values of the normalized surface potential reaching a stable value for all studied electrets. Time dependencies of the normalized surface potential for PDLA, PCL, and 50/50 substrates obtained from the three methods used and charged in a positive or a negative corona are presented in Figure 3, Figure 4 and Figure 5, respectively.
Each point in the figures is a mean value from five samples. The calculated standard deviation was better than 5% from the mean value with a confidence level of 95%.
The experimental results presented in Figure 3, Figure 4 and Figure 5 show the following:
-
The normalized surface potential values were decaying exponentially for the first 75 min for positively charged substrates and 120 min for negatively charged ones. After this, the rate of decay decreases and is practically stabilized within 360 min. These results demonstrate the existence of different surface states that were localized on the surface of the sample and that contain entrapped charges within them. The initial exponential decrease can be accredited to the release of weakly captured charges from any shallow energy states. After this period, the potential becomes stable at a steady-state value, which can be due to the remaining tightly entrapped charges in deeper traps. Similarly, exponential decay with a subsequent slow linear reduction in the electrets charge was observed in [50,51].
-
The values of the normalized surface potential for the PCL electrets were the highest and begin to decrease with the increase in the PDLA content. This can be explained with the differing crystallinity degrees that were determined with the use of the DSC method. The degree of crystallinity of PCL substrates is very high compared to the other investigated substrates (see Table 1) [52]. On the other hand, it was established that pure PCL substrates have the largest pore sizes, when compared to all other substrates. The largest pore size, observed for PCL substrates, facilitates a greater capture of charges on the surface and helps with the retention of said charges for prolonged periods of time (see Section 3.3) [53].
The steady-state values of the normalized surface potential at a time of 360 min for all investigated positively charged substrates are shown in Figure 6 and for all investigated negatively charged substrates, in Figure 7.
The experimental results presented in Figure 6 and Figure 7 demonstrate the following:
-
The steady-state values of the normalized surface potential for samples charged in a positive corona were higher than those charged in a negative corona for all investigated samples. It was found, in [54], that during the corona discharge in air, at atmospheric pressure, different types of ions are deposited on the substrate, since the charging in a corona discharge depends on the corona polarity. In the case of a positive corona, the ions were mainly H+(H2O)n and the ones for a negative corona were CO3−. These ions are bound in traps of various depths and their release depends on the surrounding conditions.
-
The steady-state values of the normalized surface potential were the highest for the lyophilized substrates, independently of material type and corona polarity. This could be explained with the morphology of the investigated substrates since the largest pore size was observed for the lyophilized substrates (Section 3.3). The anticipated values for the crystallinity and morphology, that were used for the explanation of the aforementioned values, are presented in the next two sections of the review (Section 3.2 and Section 3.3).

3.2. Degree of Crystallinity of PDLA/PCL Blend Films

The phase state of the PDLA, PCL, and PDLA/PCL films were studied by the use of differential scanning calorimetry (DSC). The degrees of the crystallinity of the investigated samples were calculated based on the enthalpy of melting during the heating process. Detailed results from the experiment were already discussed in our previous works [51,52,53]. They can be summarized as follows:
  • The melting of the blend films, independently of the preparation method, takes place at two temperatures, which are the characteristic melting temperature of PCL and PDLA. Based on this result, it can be assumed that PDLA and PCL are immiscible at the molecular level and formed heterogeneous areas. Similar results were already reported by other authors [55,56].
  • The glass transition temperature of PCL (Tg ≈ −63 °C) was not measured during any of the experimental series, which may be a result of the very high crystallinity degree.
  • The glass transition temperature of non-porous and porous lyophilized PDLA was found to be 61.4 °C and its melting temperature was 151.4 °C. These values were close to previously reported ones [57].
  • The glass transition temperature (Tg) of PDLA for porous samples with added PEG was found to be 50 °C, which is less than the values found in other sources [58]. This is likely due to polyethylene glycol’s plasticizing effect.
  • The melting phenomenon of PCL in the porous films with added PEG occurred at a lower temperature compared to a system where PEG is not present. This may be a result of the increase in the free volume within the polymer solution, in addition to the increased number of interactions between the molecules of polyethylene glycol and the polymer, which hinder the formation of larger and more stable crystallites.
The values calculated for the degree of crystallinity are presented in Table 1.
The formation of pores in the films of PDLA, PCL, and their blends leads to an increase in the degree of crystallinity. Similar results were discussed by Sheng et al., who examined the effect of foaming air on melting and crystallization behaviors of microporous PDLA scaffolds [59]. The porosity of the films could significantly affect their crystallinity in several ways. Increased porosity leads to higher free volume within the polymer matrix. This additional space can affect the mobility of polymer chains, facilitating their ability to reorganize into crystalline structures during the cooling process. For example, in the samples with added PEG plasticizer, which increases the free volume, a drastic increase in the degree of crystallinity from 6% do 40% was observed. Porous structures can also provide nucleation sites that can promote crystallization. The presence of these sites can enhance the rate at which PDLA crystallizes, leading to higher degrees of crystallinity.

3.3. Scanning Electron Microscopy (SEM) Images

The morphology of all investigated substrates was studied using scanning electron microscopy (SEM). The images obtained are presented in Figure 8.
Results shown in Figure 8 demonstrate that the non-porous PDLA and PCL substrates are characterized by a smooth homogeneous structure. The PDLA and PCL lyophilized substrates and PDLA and PCL + PEG 400 substrates, on the other hand, displayed a porous structure that could be attributed to the specific method used during their creation.
Research on the single-step production of biocompatible porous materials without harsh chemical modification is continuously increasing. A number of different methods can be used for the production of such porous structures, such as lyophilization, salt leaching, the incorporation of nano- and microparticles or even the use of solvents, unfavorable for the polymers [60,61]. A better approach is the utilization of liquid materials that allow the creation of stable solutions and minimize the chance of drop merger in order to guarantee the homogeneous formation of pores. Due to PEG 400’s water-soluble nature, low molecular weight, and availability in liquid form, it is an excellent choice for the creation of microporous structures from water insoluble polymers like PDLA, PCL, and their blend.
As seen in Figure 8, pure PDLA substrate possessed the smallest pore size diameter when compared to all other samples. Phaechamud and co-author [62] have previously reported comparable mean pore diameter and distribution. Wang et al. (2019) hypothesizes that the mechanism of formation of voids in PDLA can be attributed to its plastic deformation in aqueous conditions [63]. The inclusion of PCL within the substrates caused an increase in the pore sizes. A trend of enlarging void diameters emerged with the increase in the concentration of PCL and the largest pore diameter was reported for pure PCL substrates. A similar type of behavior is reported by Tsuji et al. (2006) [64]. The pore formation process takes place during the solvent evaporation phase and can be attributed to the phase separation of the immiscible solvents, namely PEG 400 and DCM. It is suggested that up to a certain polymer concentration, PDLA molecules possess increased mobility that is caused by the partial miscibility with PEG, resulting in reduced void sizes. When combined with PCL, PEG created bigger particles, and subsequently pores, within the matrix, by reducing the surface energy of the contact surface between the two polymers [65].
With the largest pore size, the lyophilized PCL substrates allow for a greater capture of charges on their surface and assist with the retention of said charges for prolonged periods of time.

3.4. Surface Free Energy of the Investigated Substrates

The wettability of the investigated blend substrates was measured using the static water contact angle method. Following the theory of Owens and Wendt [45], the total surface free energy of all investigated substrates was calculated. The results obtained are presented in Figure 9.
The results presented in Figure 9 show that the surface free energy of PLDA substrates was lower than that of PCL ones, independently of the method used during their creation. Similar results were obtained in [66]. It was also determined that the surface free energy of PDLA/PCL blend substrates registered an increase in comparison to pure PDLA and PCL substrates. Upon the addition of PCL into PDLA at a ratio of 50/50, the surface free energy increased and reached values of 50.30 mJ/m2 for non-porous substrates, 35.45 mJ/m2 for porous lyophilized substrates, and 54.79 mJ/m2 for porous + PEG 400 substrates. A similar behavior in the values of surface free energy and contact angle for the PDLA/PCL blend was observed by Alam [67]. This increase in the surface free energy with the increase in the PCL content was likely due to the increase in the pore sizes, as shown in the surface morphology measurements (see Section 3.3).
The values of the surface free energy significantly increased for the porous + PEG films compared to non-porous ones as well as for the blend substrates (50/50) compared to pure PDLA and PCL substrates. Therefore, the blend obtained possessed better hydrophilic properties than the original films [68].

3.5. Benzydamine Hydrochloride Drug Release

Multilayered structures have proven their potential as sustained drug delivery systems in many different studies and for a wide variety of active agents [38,69,70,71].
However, the multilayered structure itself was very thin and its properties depended not only on the complex forming partners, but on the substrate type and properties that were used as a platform to build it on. Therefore, our research team has focused on preparation multilayered structures between the same partners, namely casein and chitosan, but on substrates with different composition, porosity, and polarity as a result of corona discharge treatment. Finally, we have evaluated the outcome of these factors on the release profile and transport mechanism of benzydamine hydrochloride as well as on the encapsulation efficiency and total amount of released drug for 6 h.
As the porosity of the polymer substrate would affect the amount of stored charge, this would have also influenced the properties of the final structure, due to the electrostatic nature of the multilayer build-up process. The pore size and type of pore-forming approach should also be taken into account. As presented in Table 2, the pore formation process impacted the polymer substrate in different manners depending on the composition. For example, PDLA-based substrates that were negatively charged had a higher amount of encapsulated drug when there was no porosity modification in comparison to porous structures with PEG 400, while substrates made out of PCL had better encapsulation efficiencies for porous and positive charge modification. In all combinations of porosity and substrate composition, positive corona discharge was stored for longer periods at higher normalized surface potential values; hence, encapsulation efficiencies for positive polarity were greater than the same for negative polarity. In general, substrates constituted of a mixture of PDLA, 50/50, and PCL had the least amount of drug encapsulation, compared to the bare materials. This could be due to the formation of immiscible regions with different crystallinity structure, existing in metastable conditions [72]. Also, when the substrates were based on solely PCL, the amount of encapsulated benzydamine was higher, no matter the modification or corona discharge polarity, due to its better ability to store these charges [52]. The data for the encapsulated amount of benzydamine in multilayers, built onto non-porous substrates, were similar with the results reported in our previous work [49]. Depending on the pH and ionic strength of the used polyelectrolyte solution, the encapsulated drug varied in the range of 40–105 µg/4 cm2. However, they were far from satisfactory in the context of therapeutic doses. Therefore, another approach to ensure a higher amount of bound benzydamine was proposed, namely the crosslinking of the layers. Pilicheva et al. 2020 [73] reported the outcome of crosslinking with calcium chloride, sodium tripolyphosphate, and glutaraldehyde and double crosslinking by the combination of glutaraldehyde and one of the other cross linkers. Single crosslinking by glutaraldehyde did not make any significant improvement, due to the too compact structure preventing benzydamine from being incorporated. In cases of physical crosslinking with either calcium chloride or sodium tripolyphosphate there was a 2-fold increase, resulting in the encapsulation of around 152 µg/4 cm2. The highest values were reported for double-crosslinked films by sodium tripolyphosphate and glutaraldehyde, resulting in the encapsulation of nearly 800 µg/4 cm2. As it can be seen from Table 2, these values are comparable to the presented results for the PDLA porous and non-porous modification. Substrates based on PCL with the same polarity, but lyophilized, showed a significantly higher amount of encapsulated benzydamine—2526 µg/4 cm2, showing around a 3-fold increase in comparison to double-crosslinked films. When comparing the results for the encapsulated amount of benzydamine in single-crosslinked films to the porous modification of the substrate, it turned out that the porosity of the substrate had higher positive influence in terms of drug encapsulation efficiency.
The porosity of the substrate and polarity of corona discharge also influenced the release profiles of benzydamine hydrochloride. All of the curves for the porous samples were characterized with biphasic behavior, constituted by an initial phase of “burst” release within the timeframe of less than 60 min. The next phase was the so-called sustained release one, extending the whole release window for up to 6 h and longer. The presence of such a fast release phase, resulting in a large amount of drug being released for a short time, is usually undesired, but in the case of benzydamine hydrochloride, it may be helpful. Such fast release would ensure pain relief within a shorter time frame [74]. The next phase of the drug release profile, also called sustained release, would be required to maintain the drug concentration within the therapeutic window with a minimal amount of drug administration [75]. Such sustained release typically results from the gradual migration of drug molecules through the layers [39]. Another positive outcome of the porous modification of the substrates in terms of application was the improved wettability. Higher surface energy values are good indicators for the proper adhesion of the structures onto the area of application [49].
The non-porous ones lacked a “burst” phase in their release patterns. Figure 10 shows the release patterns for PDLA-based substrates with both polarities of corona discharge. They follow the same trend, namely, the fastest release was observed for the lyophilized type of substrates, followed by the ones with PEG 400, and the least amount of released drug was present for the non-porous substrate. The final amount of released drug was statically different only for the non-porous samples; in the porous modification, this value was either identical or similar. For PDLA 50/50 PCL (Figure 11), the lowest amount was again for the non-porous films, but there was dependency on the corona polarity and the pore mechanism formation for the fastest releasing system. A similar tendency as for PDLA-based substrates, is observed in the PCL-based substrates, presented in Figure 12, but in this case, porous substrates made with PEG 400 presented the highest amount of released drug, followed by the lyophilized ones. Lyophilized samples, possessing positive polarity, had a higher amount of released benzydamine, when compared to the same samples, charged negatively. The fact, that the non-porous substrates demonstrated the least amount of released active agent, was expected. Regardless of the pore-forming approach, their existence eases the molecular diffusion of the low molecular drug and therefore these differences in the trends for the released amount of benzydamine may be correlated to the pore size.
Pore existence, size, and distribution were found to impact the transport mechanism as well [76]. Pore presence impacted the major transport mechanism, despite the usage of the same materials for all multilayered films’ creation. In samples without porosity independently of the corona polarity, the mechanism responsible for the drug release process was found to be Fickian diffusion and the best fitting model was Korsmeyer-Peppas with R2 = 0.99 [52]. For the porous samples, the best fitting model was the Weibull one, but obeying different transport mechanisms [53]. Another important factor for the alternation of main transport mechanism was the type of corona discharge. For the majority of obtained films, when treated under positive polarity, the resulting release phenomena obeyed Fickian diffusion or Fickian diffusion combined with swelling controlled transport. In these cases, as shown in Figure 6, steady-state values of the normalized surface potential for positive corona was higher, ensuring the formation of tightly bound layers onto the substrate [53]. In addition to this, the type of charge used for the substrate treatment leads to the alternation in the sequence of dipping solutions; hence, for each of the investigated polarities, the final layer is made of a different polylelectrolyte. In the case of positive corona, the final layer consisted of chitosan with incorporated benzydamine. As this layer was in direct contact with the acceptor media, the water solubility of benzydamine and the chitosan’s proneness to swelling lead to Fickian diffusion, combined with swelling controlled transport. In the case of lyophilized samples, the mechanism depended on the corona discharge polarity and sample composition. In both polarities for PDLA substrates, it was found to be Fickian diffusion. Resulting from the lower values of normalized surface potential in the case of negative corona discharge (Figure 7), the electrostatic interactions between the substrate and the first layer were weaker, compared to the positive corona treatment. This leads to a lower number of bonds between the substrate and the first layer (consisting of a common solution of chitosan and benzydamine). In the case of negative corona treatment and a lack of pores, the major transport mechanism was Fickian diffusion for all three types of substrates. However, when some modification of the substrates was applied and combined with negative corona discharge, it shifted to a complex release mechanism in the majority of cases, and in one case, it was Fick diffusion and swelling controlled transport. A complex mechanism of release implies that the rate of the release of the drug rises non-linearly up to an inflection point, decreasing asymptotically afterwards [53]. This could indicate drug molecules with a different depth of tightness within the structure. The complexity of the release process in the case of negative corona was a result of two major factors: more loosely formed layers due to the lower surface charge and a higher porosity of the networks, resulting in enhanced swelling and chain mobility. For the same polarity, with a substrate composition of solely PCL or 50/50, it stayed the same; in the case of negative charge, for the same substrates it shifted into a combined release mechanism between Fick diffusion and swelling controlled transport. A similar behavior and release mechanism were described for porous films, when PEG 400 was used. In the case of positive charge treatment, the β parameter had values close to one, suggesting again a combined release mechanism, while negative ones possessed values exceeding one, indicating a complex release mechanism [77]. In general, after going through all of these values it can be concluded that the lowest values for corona discharge and higher porosity resulted in a more complex transport mechanism for benzydamine hydrochloride.

4. Conclusions

In this review, the benzydamine hydrochloride release from PEMs, built on non-porous and porous blend PDLA/PCL substrates, was studied. Different methods were used to characterize the substrates. The electrets properties of all investigated substrates were studied. It was established that the normalized surface potential values were practically stabilized within 360 min. The steady-state values of the normalized surface potential for PCL electrets were the highest, when compared to other investigated substrates, and decrease with the increase in the PDLA content. This could be explained with the differing crystallinity degrees and the morphology of the investigated substrates. The largest pore size observed at PCL substrates facilitates a greater capture of charges on its surface and helps with the retention of said charges for prolonged periods of time, thereby creating the most stable electrets. The conducted studies related to the release of the drug substance benzydamine hydrochloride demonstrated that non-porous PDLA substrates possessed higher amounts of encapsulated drug, while substrates made out of PCL had better encapsulation efficiencies for lyophilized and positively charged modification. In all combinations of porosity and substrate composition, positive corona discharge was stored for longer periods at higher normalized surface potential values, resulting in greater encapsulation efficiencies for positive polarity than those for negative polarity. For non-porous samples, independently of the corona polarity, the mechanism responsible for the drug release process was found to be Fickian diffusion and the best fitting model was Korsmeyer-Peppas with R2 = 0.99. On the other hand, the best fitting model for porous samples was the Weibull one, obeying different transport mechanisms.
In general, after going through all of these values it can be concluded that the lowest values for corona discharge and higher porosity result in a more complex transport mechanism for benzydamine hydrochloride.

Author Contributions

Conceptualization, A.V., M.M. and T.Y.; methodology, A.V. and M.M.; software, A.G. and S.M.; validation, A.V., M.M. and S.M.; formal analysis, T.Y.; inves-tigation, A.V., M.M., A.G. and S.M.; resources, T.Y.; data curation, A.G. and S.M; writing—original draft preparation, A.V., M.M., T.Y., A.G. and S.M.; writing—review and editing, A.V., M.M. and T.Y.; visualization, M.M.; supervision, A.V.; project administration, A.V.; funding acquisition, A.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Acknowledgments

The authors gratefully acknowledge the support of the project MUPD23-FTF-014/25.04.2023, Department of Scientific Research at the Plovdiv University.

Conflicts of Interest

The authors declare no conflict of interest.

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Coatings 15 00240 g001
Figure 1. Corona discharge system: 1. high voltage source; 2. corona electrode; 3. grid; 4. grounded plate electrode; 5. sample on a metal pad; and 6. voltage divider.
Figure 1. Corona discharge system: 1. high voltage source; 2. corona electrode; 3. grid; 4. grounded plate electrode; 5. sample on a metal pad; and 6. voltage divider.
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Coatings 15 00240 g002
Figure 2. Schematic representation of the multilayer deposition process.
Figure 2. Schematic representation of the multilayer deposition process.
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Figure 3. Time dependencies of the normalized surface potential for PDLA substrates charged (a) in a positive corona and (b) in a negative corona.
Figure 3. Time dependencies of the normalized surface potential for PDLA substrates charged (a) in a positive corona and (b) in a negative corona.
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Figure 4. Time dependencies of the normalized surface potential for 50/50 substrates charged (a) in a positive corona and (b) in a negative corona.
Figure 4. Time dependencies of the normalized surface potential for 50/50 substrates charged (a) in a positive corona and (b) in a negative corona.
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Coatings 15 00240 g005
Figure 5. Time dependencies of the normalized surface potential for PCL substrates charged (a) in a positive corona and (b) in a negative corona.
Figure 5. Time dependencies of the normalized surface potential for PCL substrates charged (a) in a positive corona and (b) in a negative corona.
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Figure 6. Steady-state values of the normalized surface potential at a time of 360 min for all investigated positively charged substrates.
Figure 6. Steady-state values of the normalized surface potential at a time of 360 min for all investigated positively charged substrates.
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Figure 7. Steady-state values of the normalized surface potential at a time of 360 min for all investigated negatively charged substrates.
Figure 7. Steady-state values of the normalized surface potential at a time of 360 min for all investigated negatively charged substrates.
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Figure 8. SEM images of all investigated substrates.
Figure 8. SEM images of all investigated substrates.
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Figure 9. Surface free energy of all investigated substrates.
Figure 9. Surface free energy of all investigated substrates.
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Figure 10. Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on PDLA substrates treated with positive (+) or negative (−) corona.
Figure 10. Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on PDLA substrates treated with positive (+) or negative (−) corona.
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Figure 11. Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on substrates obtained from equal amounts of PDLA and PCL treated with positive (+) or negative (−) corona.
Figure 11. Release profiles of Benzydamine Hydrochloride encapsulated in multilayer structures built on substrates obtained from equal amounts of PDLA and PCL treated with positive (+) or negative (−) corona.
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Figure 12. Release profiles of benzydamine hydrochloride encapsulated in multilayer structures built on PCL substrates treated with positive (+) or negative (−) corona.
Figure 12. Release profiles of benzydamine hydrochloride encapsulated in multilayer structures built on PCL substrates treated with positive (+) or negative (−) corona.
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Table 1. Degree of crystallinity of non-porous, porous lyophilized, and porous with added PEG PDLA/PCL blends.
Table 1. Degree of crystallinity of non-porous, porous lyophilized, and porous with added PEG PDLA/PCL blends.
SampleDegree of Crystallinity, %
Non-PorousPorous LyophilizedPorous + PEG
PDLA 6 840
50/50345056
PCL598074
Table 2. Encapsulation of benzydamine, released drug after 6 h, and transport mechanism during drug release.
Table 2. Encapsulation of benzydamine, released drug after 6 h, and transport mechanism during drug release.
Sample
Composition		Corona PolarityModificationEncapsulated
Benzydamine,
µg/4 cm2 		Released Drug After 6 h, %Major Transport Mechanism
PDLAPositiveNone59.3 ± 1.659 ± 5Fickian diffusion
PDLAPositiveLyophilized588 ± 2092 ± 3Fickian diffusion
PDLAPositivePEG 40098 ± 687 ± 2Fick diffusion
and swelling controlled transport
PDLANegativeNone132.0 ± 2.471 ± 5Fickian diffusion
PDLANegativeLyophilized168 ± 1394 ± 4Fick diffusion
and swelling controlled transport
PDLANegativePEG 40050 ± 598 ± 5Complex
release mechanism
50/50PositiveNone48.3 ± 1.769 ± 4Fickian diffusion
50/50PositiveLyophilized499 ± 6095 ± 2Fickian diffusion
50/50PositivePEG 400264 ± 1892 ± 4Fick diffusion
and swelling controlled transport
50/50NegativeNone62.5 ± 2.761 ± 3Fickian diffusion
50/50NegativeLyophilized313 ± 2584 ± 1Complex release mechanism
50/50NegativePEG 400183 ± 1598 ± 3Complex
release mechanism
PCLPositiveNone102.3 ± 6.860 ± 1Fickian diffusion
PCLPositiveLyophilized2526 ± 5082 ± 1Fickian diffusion
PCLPositivePEG 400361 ± 3898 ± 3Fick diffusion
and swelling controlled transport
PCLNegativeNone247.6 ± 6.660 ± 1Fickian diffusion
PCLNegativeLyophilized684 ± 3479 ± 1Complex release mechanism
PCLNegativePEG 400350 ± 4197 ± 2Complex
release mechanism
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Viraneva, A.; Marudova, M.; Grigorov, A.; Milenkova, S.; Yovcheva, T. Multilayered Polyelectrolyte Structures Deposited on Corona-Charged Substrate Blends as Potential Drug Delivery Systems. Coatings 2025, 15, 240. https://doi.org/10.3390/coatings15020240

AMA Style

Viraneva A, Marudova M, Grigorov A, Milenkova S, Yovcheva T. Multilayered Polyelectrolyte Structures Deposited on Corona-Charged Substrate Blends as Potential Drug Delivery Systems. Coatings. 2025; 15(2):240. https://doi.org/10.3390/coatings15020240

Chicago/Turabian Style

Viraneva, Asya, Maria Marudova, Aleksandar Grigorov, Sofia Milenkova, and Temenuzhka Yovcheva. 2025. "Multilayered Polyelectrolyte Structures Deposited on Corona-Charged Substrate Blends as Potential Drug Delivery Systems" Coatings 15, no. 2: 240. https://doi.org/10.3390/coatings15020240

APA Style

Viraneva, A., Marudova, M., Grigorov, A., Milenkova, S., & Yovcheva, T. (2025). Multilayered Polyelectrolyte Structures Deposited on Corona-Charged Substrate Blends as Potential Drug Delivery Systems. Coatings, 15(2), 240. https://doi.org/10.3390/coatings15020240

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