**Aquacoat** ® **ECD**

It contains primarily EC with a surfactant and a stabilizer from the emulsion stage (sodium lauryl sulfate (SLS) and cetyl alcohol (CA)). Depending on type it consists of EC (24.5–29.5%), CA (1.7–3.3%), and SLS (0.9–1.7%). Traces of dimethylopolysiloxane to enhance foaming during distillation may also be present. EC is dissolved in a water-immiscible organic solvent with CA addition as a dispersion stabilizer. The solution is then emulsified into an aqueous SLS solution. The resulting crude emulsion is homogenized to yield a submicron emulsion which is then distilled to remove the organic solvent and water to yield a solid dispersion. EC is present in the dispersion as spherical particles in the size range of 0.1–0.3 μm. It exists as a milky white liquid with the characteristic odor of EC. Product does not contain plasticizer. Recommended plasticizers include dibutyl sebacate, acetylated monoglycerides, triacetin or glyceryl triacetate, acetyltriethyl citrate, and triethyl citrate. It is used for the aqueous film coating of solid dosage forms to extend drug release, taste mask, or to protect against moisture [26].

> \* The table presents examples of selected, most commonly used, products.

**Figure 2.** SEM pictures of ( **A**) EC in powder form; (**B**) spray-dried ethanolic solution of EC (inlet temperature 65 ◦C, aspirator flow 98%, feed flow 3.5 mL/min); ( **C**) spray-dried Surelease ®; and ( **D**) spray-dried Aquacoat ™ ECD-30 (author's pictures under magnification 10,000× (**A**,**B**); 5000× (**C**,**D**)).

#### **4. Applicability of EC in Pharmaceutical Formulations**

#### *4.1. EC as An MR Coating Material in Oral Delivery Systems*

Because of EC's potential to modify drug release, it is widely studied as a coating agent. EC as release retardant was employed in a once-a-day sustained-release system of tacrolimus. The pellets were coated with EC using a fluid bed granulator. Drug release was markedly impeded by the outer EC-based coating layer, displaying about 60% drug release after 8 h, regardless of the acidity of the medium. It was assessed that there were no statistical differences between the obtained pellets and the marketed sustained-release capsules (Advagraf®) [29,30]. Shah et al. developed a multiunit formulation for the colon-targeted delivery of metronidazole using EC and Eudragit® S 100 as coating polymers to prevent initial drug release in the gastric region (Figure 3). Cores of mini tablets containing drug were prepared using suitable swelling agents to provide pH-sensitive pulsatile drug delivery [31].

**Figure 3.** Schematic illustration of coated modified release (MR) minitablets.

A double-layer coated colon-specific drug delivery system was developed by Kim et al. The system consisted of a chitosan-based polymeric subcoating of the core tablet (containing citric acid for microclimate acidification), followed by an enteric EC coating. The system showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon [32]. The example of utilizing EC as a release-retarding coating is a commercially available preparation called Micro-K® in hard gelatin capsules, containing small crystalline particles of potassium chloride (KCl). Each crystal of KCl is microencapsulated by a patented process with an insoluble EC polymeric coating which functions as a semi-permeable membrane ensuring controlled release of K<sup>+</sup> and Cl− ions. Fluids pass through the membranes and gradually dissolve KCl within the microcapsules. As a result, drug slowly diffuses outward through the membrane over an 8–10 h period [33,34]. Another example is Theo-24®—the first commercial product for 24-h theophylline therapy launched on the market. The technology utilized in the formulation uses a chemical timing complex (protected by patent) to produce very small theophylline-coated beads that provide dependable zero-order controlled drug release. Tiny spheres of a sugar and starch blend form the core of the beads. The core is first coated with theophylline and then with a timing complex utilizing EC. The resulting beads are put into capsules. When the capsule dissolves in the gastrointestinal tract, the insoluble coating on the bead slowly erodes. The drug, which is highly soluble, moves through the coating. In the core, the starch swells and pushes the drug out while the dissolving sugar also helps carry the drug through the chemical timing complex, which results in a constant release [33,35].

Matrix tablets of hydrochlorothiazide were coated with an insoluble barrier membrane using aqueous EC coating (Surelease®) and HPMC-based Opadry® as a pore former, at 85:15 *w*/*w* ratio. The combination of barrier membrane and hydrophilic matrix system was utilized as a strategy to modulate drug diffusion from hydrophilic matrices and to reduce the overall variability in release [36]. The aims of another study were to control the release of a water-soluble theophylline from mini matrices made of HPMC by applying an EC film coating (Surelease®) and to assess coating load on release rates. At low coating weight gains, tablets released the entire drug within 0.5 h, while at high coating weight gains only a very small amount (<5%) of drug was released after 12 h [17].

EC has found its application as a coating material in commercially available modern MR solid dosage forms (Diffucaps, DiffCORE™, SODAS®, or Geomatrix® systems). It is also used in medicines dedicated to patients suffering from ADHD: Adzenys XR®-ODT and Cotempla® XR-ODT [16,33,37–42]. Diffucaps are a multiparticulate system, where drug profiles are created by layering a drug onto a neutral core (e.g., sugar spheres, crystals, or granules) followed by the application of a rate-controlling functional EC membrane. Such a system is applied in Metadate CD® capsules (Figure 4) [16,37].

**Figure 4.** Schematic illustration of Diffucaps system in a Metadate CD® capsule. Reprinted with permission from Reference [16]. Copyright 2019 MDPI.

Another example of an EC-coating-based oral system is DiffCORE™ (Lamictal® XR) (Figure 5). DiffCORE™ is a technology developed to achieve extended release by delivering drug from a tablet core through one or several apertures in an impermeable coat made of EC. The technology combines the use of apertures that are mechanically drilled into functional film-coated tablets (on both faces of the tablet's structure) with a polymer coating that controls the mechanism of diffusion. This combination is designed to ensure the dissolution rate of drug over a period of approximately 12–15 h [16,38].

**Figure 5.** Schematic illustration of DiffCORE™ system. Reprinted with permission from Reference [16]. Copyright 2019 MDPI.

Adzenys® XR-ODT and Cotempla® XR-ODT are examples of orally disintegrating tablets which dissolve quickly in the mouth, maintaining extended drug release along gastrointestinal tract. The technology utilized in the medicines uses two different types of particles (in different ratios depending on the formulation): immediate release and extended release. Two different polymer coatings are applied to the extended release beads: interior polymer coating as diffusion barrier (EC) and pH-dependent exterior polymer coating (methacrylic acid) (Figure 6) [16,41,42].

**Figure 6.** Schematic illustration of XR-ODT system. Reprinted with permission from Reference [16]. Copyright 2019 MDPI.

Inderal® LA, long-acting capsules with propranolol, uses polymer-coated controlled diffusion technology to achieve 12 h release of drug for hypertension treatment. Inderal® LA consists of small spheroids placed in a gelatin capsule. Each spheroid containing propranolol and a microcrystalline cellulose is coated with a porous membrane made of a mixture of EC, HPMC, and plasticizer [33,43]. Dilacor XR® is a one-per-day oral formulation of diltiazem provided in capsule. The capsules contain degradable, controlled-release tablets designed based on Geomatrix® technology to release diltiazem over a 24 h period. Geomatrix™ is a patented controlled-release system incorporated in the tablets. Each capsule contains multiple extended-release diltiazem tablets, consisting of two inactive surfaces sandwiched around the drug core (made of HPMC and hydrogenated castor oil) swellable in an aqueous medium. The inactive surfaces are composed of a methylcellulose–EC combination. The drug is released as a result of the swelling of the core, which acts as a drug reservoir. Controlled release of diltiazem begins within 1 h, with maximum plasma concentrations being achieved 4–6 h after administration. The inactive surfaces hydrate at a rate much slower than the core, thus regulating the drug release and assuring constant 24 h medicine delivery (Figure 7) [33,44].

**Figure 7.** Schematic illustration of drug release from Geomatrix™ system modified from Wan et al. [33].

An interesting example of applying EC as a coating is SODAS® (Spheroidal Oral Drug Absorption System), utilized in Cardizem® CD. The medicine is formulated as capsules and consists of two populations of sustained-release beads that differ only by the thickness of the polymer (EC) surrounding them. The EC membrane contains added water-soluble polymers which dissolve and create pores in the membrane. The polymer beads release 40% of the total diltiazem amount in the first 12 h (Figure 8) [33,39,40,45].

**Figure 8.** Scheme illustration of SODAS® delivery system modified from Elan drug technologies [39]. Reprinted with permission from Reference [16]. Copyright 2019 MDPI.

Core elements of drugs coated with a water-insoluble polymer such as EC offer reduced dissolution profiles, and as a consequence provide a taste-masking effect [46,47]. EC was used as taste-masking agen<sup>t</sup> for quinine, utilizing a spray drying method. The obtained results showed that the quinine dissolution rate was altered, the bitter taste of quinine was successfully masked, and its intestinal absorption was simultaneously controlled [48]. EC for taste-masking purposes was tested in organic (Ethocel™) and aqueous form (Surelease®). To determine whether the designed particles effectively masked the bitter taste of rupatadine fumarate, three independent methods were used: a human taste panel, an in vitro release test conducted in conditions mimicking the oral cavity environment, and an electronic taste sensing system (electronic tongue). It was clearly confirmed that particles formulated from aqueous dispersions of EC provided a very effective taste-masking barrier [49]. Evaluation of the use of Surelease® as a barrier membrane coating with pediatric precedence of use on the taste-masking of immediate-release acetaminophen granules was also conducted. The dissolution profiles of obtained granules were successfully modified using a Surelease® and Opadry® blend as a barrier membrane, providing slow initial drug release [50]. Another study concerned the development of orally disintegrating caffeine citrate tablets utilizing hot melt extrusion technology (EC was used as a polymeric taste-masking carrier) [51]. EC was also applied as a taste-masking and release-slowing agen<sup>t</sup> to develop a gabapentin nanosponge-based controlled release dry suspension for pediatric use, using the suspension layering technique [52].

Utilizing of EC as release modifier in marketed oral formulations is presented in Table 2.


**Table 2.** Examples of commercially available oral solid dosage forms with EC as release modifier.

#### *4.2. EC as a Sustained Release Material in Topical Delivery Systems*

The utilization of EC to obtain a sustained release profile is also exploited in preparations for external use (e.g., transungual, ocular, vaginal, or transdermal). Successful topical therapy depends on effective drug release and penetration into the objective area, which can be achieved using an adequately developed drug dosage form [1–5,65]. EC can be applied in transungual delivery systems as a release modifier and a biocompatible agen<sup>t</sup> ensuring optimal viscosity of the formulation. An isotretinoin nail lacquer intended for the treatment of nail psoriasis was developed, and its penetration e fficiency across the nail plate was accessed. Lacquer with EC (at 6% concentration) possessed improved handling characteristics and enhanced drug distribution across the nail [66]. Another study documented an antifungal nail lacquer with miconazole developed with 0.5% EC which extended drug release up to 48 h [67]. Šveikauskaite et al. studied naftifine hydrochloride release from experimental nail lacquer ˙ formulations obtained from EC and Eudragit. By using microcalorimetry they revealed possible interactions between naftifine and EC [68].

Eye administration is a demanding issue in pharmaceutical technology, and to enhance ocular bioavailability, sustained-release drug dosage forms such as hydrogels, inserts, contact lenses, or minitablets are designed. Among the materials employed in developing ophthalmic formulations, EC can be utilized as a polymer extending drug release [69] (Table 3).

Reports have also documented the application of EC as matrix material for transdermal patches for systemic delivery, showing desired permeation enhancement and flexibility [1–5]. Interestingly, EC has also been indicated in the formulation of a transdermal spray with clotrimazole to improve drug transport through the skin up to 12 h and to promote its in vivo antifungal activity [70].

Table 3 presents literature examples of EC utilization in ocular and transdermal drug delivery systems.


**Table 3.** Examples of ocular and transdermal delivery systems based on EC.

#### *4.3. EC-Based Solid Dispersions*

In preparation of MR dosage forms, the concepts of solid dispersions and drug incorporation in an insoluble EC carrier have been also explored [81–85]. Tsunashima et al. aimed to prepare MR formulation of tacrolimus to achieve both an extended release profile and improved drug solubility. Extended release solid dispersions of tacrolimus were successfully prepared via the solvent evaporation method using EC and HPMC as polymeric materials [82]. Sadeghi et al. compared characteristics of EC matrices prepared from solid dispersion systems with those prepared from a physical mixture of drug and polymer. Sodium diclofenac was used as a model drug. It was shown that matrices prepared from physical mixtures were harder than those prepared from solid dispersion systems, and their release rates were considerably faster. In the solid dispersion system, drug particles were incorporated in an EC matrix, which caused a grea<sup>t</sup> delay in drug di ffusion through the polymer and made di ffusion a rate-retarding process in the drug release mechanism [83]. Evaluation of the release mechanism of a poorly water-soluble drug (indomethacin) from extended-release solid dispersion systems with EC and HPMC was performed by Ohara et al. The dissolution behavior of indomethacin depended on the structures of EC–HPMC matrices and showed pH dependency—the drug dissolution rate was slower in an acidic environment than in a neutral one. The obtained results revealed that hydrophobic interaction between indomethacin and EC occurred under lower pH and strongly delayed the dissolution rate of the drug [84]. Sustained-release solid dispersions with EC and Eudragit RSPO were designed to control the release of verapamil hydrochloride. Solid dispersions obtained by a simple solvent evaporation technique and physical mixture formulations were compressed to tablets. The in vitro drug release study revealed that solid dispersions containing a combination of EC and Eudragit RSPO extended the release rate for 20 h compared to the physical mixtures at the same ratio, and that the release of verapamil from tablets containing solid dispersion could be e ffectively controlled [85].

#### *4.4. EC-Based Micro- and Nanocarriers*

A common approach to modifying drug release is preparing polymeric micro- or nanocarriers which contain drug enclosed in the polymer shell or incorporated in the polymer matrix (Figure 9). Micro- and nanoparticles have gained significant interest for their use in various drug formulations not only to sustain drug release, but also in order to improve bioavailability, decrease side e ffects, or increase drug stability [86]. An extended-release oral flexible tablet (ER-OFT) formulation was developed using carbamazepine as model drug for pediatric and geriatric compliance. Microparticles of carbamazepine were prepared using EC as a matrix polymer and HPMC as a hydrophilic pore former utilizing a high-shear granulator fitted with an atomizing spray system. Granulation of carbamazepine and EC with ethanolic binder solution resulted in obtaining microparticles with 16 h extended release [87]. EC microparticles can be formulated using a variety of techniques: interfacial and in situ polymerization, coacervation phase separation, spray drying, spray congealing, or by rotary fluidization bed granulator method [88].

**Figure 9.** Schematic illustration of microparticles as a drug delivery system. Reprinted with permission from Reference [16]. Copyright 2019 MDPI.

As the extreme acidic environment of the stomach contributes to poor success in the treatment of *Helicobacter pylori* infections, Pan-In et al. encapsulated clarithromycin into particles made of pH-resistant polymer (i.e., EC). Nanoparticles were prepared via a simple anti-solvent particle induction method [89]. Similarly, EC nanocomposites containing rifampicin obtained by supercritical anti-solvent process prolonged drug release and increased its bioavailability [90]. Interestingly, EC was also tested as a carrier for protecting the L-alanyl-L-glutamine peptide and simultaneously providing its prolonged release [91].

Shankar et al. formulated EC microparticles for the vaginal delivery of metronidazole by thermal change method [92]. EC was also utilized in the development of nanoparticles for the topical delivery of corticosteroids [93] or to modulate the release and reduce the ulcerogenicity of piroxicam after oral administration [93]. A reduction of 66% in mean ulcer index was observed, indicating that the obtained particles had a significant potential of offsetting deleterious side effects common in piroxicam use [94]. Similarly, as etoricoxib has many side effects when taken orally, EC nanoparticles produced by a nanoprecipitation technique were designed. Etoricoxib-loaded EC nanoparticles for local drug delivery in arthritis provided sustained drug release, thereby improving patient compliance [95]. Interestingly, nanocapsules of beclomethasone were prepared for pulmonary delivery using EC as a protective polymer. They were characterized by delayed drug photodegradation, prolonged drug release without burst effect, and insignificant cytotoxic effect [96].

EC can also be utilized to prepare sustained-release oral liquids, such as syrup with hydrocodone and chlorpheniramine (Tussionex®) or suspension with mirabegron based on ion-exchange technology [97–99].

Maulavi et al. tested EC-based-microparticles-laden hydrogel contact lenses to provide the sustained ocular delivery of timolol. Prototype poly(hydroxyethyl methacrylate) hydrogel contact lenses improved drug bioavailability due to the increase in ocular residence time [100]. Timolol-encapsulated EC nanoparticles lenses for controlled sustained ocular drug delivery were also evaluated in vivo using rabbits. Nanoparticles were prepared by a double emulsion method and incorporated into acrylate hydrogel, then implanted in hydrogel contact lenses. They exhibited extended timolol release and an intra-ocular pressure lowering effect for 192 h in rabbits without significant ocular complications [101].

Application of EC microparticles containing naproxen to textile materials was studied by Arici et al. Microparticles were prepared by spray-drying using an aqueous EC dispersion and applied to orthopedic support materials. Since these materials are used for traumatic irritations, over-forced ligaments and tendons, and specific problems of various joints, it was concluded that they can serve as potential drug delivery systems [102].

Another approach to obtaining microcarriers is microsponge development. Microsponges are novel drug delivery systems, which ensure effective sustained drug release. They possess unique properties including self-sterilizability, due to the minimal pore size which does not allow bacteria to enter and contaminate the formulation. Microsponges can entrap drugs up to three times their weight due to their very high porosity. EC is utilized as a foundation material for microsponges and for microsponge engineering due to its nonirritating, nontoxic, and nonallergic nature [103–105]. Bothiraja et al. focused on the development of an EC microsponge gel as a topical carrier for the controlled release and cutaneous drug deposition of eberconazole. The microsponges were prepared using the quasi emulsion solvent diffusion method. An in vivo skin deposition study demonstrated higher retention in the stratum corneum layer as compared with commercial cream with eberconazole [106]. Jelvehgari et al. developed a microsponge delivery system to facilitate the topical delivery of benzyl peroxide. As benzyl peroxide has many side effects when applied per se in gel form, such a delivery system to the skin could reduce those effects while reducing its percutaneous absorption [107]. EC was also utilized to prepare microsponges to overcome problems connected with the poor water solubility, low stability, and high volatility of tea tree oil. Microsponges loaded with tea tree oil were prepared using EC and polyvinyl alcohol and incorporated into carbopol

gel [108]. Another study describes the development of the topical delivery of oxybenzone—one of the most widely used chemical filters found in commercial sunscreens—using a microsponge-loaded gel. As the ingredient can cause dermatitis and skin irritation, oxybenzone-loaded microsponges were successfully formulated by a quasi emulsion solvent di ffusion method with EC utilization. It was shown that controlled release of oxybenzone from the microsponge structures and barrier e ffect of gel resulted in prolonged retention with reduced permeation, reduced irritation, and enhanced sun protection factor [109]. The aim of another study was to develop a sustained-release delivery system of tacrolimus, formulated using a microsponge base, employing EC and xanthan gum by modified double emulsification techniques [110]. EC microsponges can be designed for ocular delivery; acetazolamide formulated in a microsponges–Pluronic F-127 in situ gel was characterized by improved therapeutic efficacy and reduced systemic side e ffects of oral acetazolamide. The obtained formulation showed higher therapeutic e fficacy compared to free drug in gel [111].

EC has also been studied as a material for nanofibers, which possess a broad range of new applications in pharmaceutical technology [112]. Over the past years, electrospinning has been attractive as a simple, reproducible, versatile, and cost-e ffective technique for nanofiber production. Electrospun nanofibers have been extensively used for di fferent biomedical applications, including wound dressing, tissue engineering, and drug delivery. The fiber morphology can be manipulated by changing the solvent ratio, resulting in a decreased fiber diameter. Membranes made of EC nanofibers possess good physical properties and are characterized by beneficial air permeability [113,114]. Drug delivery rate is a ffected by the polymer type, fiber diameter, and drug concentration in the fiber [114,115]. EC as a filament-forming matrix was tested in ketoprofen nanofiber delivery systems designed by triaxial electrospinning [116]. EC was also utilized for creating a 5-fluorouracil loaded core for the fabrication of electrospun fibers [117] and in preparing water-stable composite nanofibers loaded with indomethacin with a sustained, di ffusion-controlled release profile [118]. The inclusion of EC as a matrix former improved mechanical properties of the entire delivery system [118]. Another study employed blend fibers of poly(N-vinylcaprolactam) and EC with the aim of developing thermoresponsive sustained release formulations fabricated by twin-jet electrospinning containing ketoprofen. The obtained fibers were largely smooth and homogeneous, and the addition of a drug did not a ffect their morphology [115]. Additionally, Liu et al. reported that nanofibers obtained by electrospinning using blends of EC and gelatin were characterized by fine morphology and possessed improved thermal stability [119].

#### *4.5. EC in Mucoadhesive Delivery Systems*

In the development of dosage forms applied on mucous membranes, the selection of suitable polymers with adhesive properties is a crucial issue. Polymers that are bioadhesive and do not dissolve before releasing the incorporated drug are highly appreciated for sustain drug release. As a water-insoluble polymer, EC is often used as backing membrane for its film-forming property, low water permeability, drug impermeability, and moderate flexibility. It possesses bioadhesive properties, however lesser than Carbopol and chitosan [120]. Bagul et al. evaluated the in vitro mucoadhesive strength of various polymers and reported the following ascending order for force of adhesion expressed in Newtons (N): gelatin (1.42) < gum dammar (1.47) < gum copal (1.52) < ethyl cellulose (1.60) < sodium alginate (1.71) < xanthan gum (1.81) < chitosan (1.91) < HPMC (2.25) < carbopol (2.40) [120].

EC forms a hydrophobic network when the mixture comes into contact with water, resulting in sustained drug release. The utilization of EC as a single polymer or in conjunction with other adjuvants in the preparation of film-like drug carriers is well documented. Drug-loaded EC films are characterized by good adhesion, mechanical strength, and sustained release profile. They provide a flexible di ffusion barrier and its properties can be changed by the amount of pore-forming agent, film thickness, and EC molecular weight [1,3–5]. Abruzzo et al. designed buccal films for propranolol administration. A polymeric layer was prepared by casting and drying with polyvinylpyrrolidone or polyvinylalcohol and the addition of gelatin or chitosan. EC was employed to formulate a second

layer was applied onto the primary one in order to obtain prolonged drug delivery, increase adhesion, and mask the drug's bitter taste [121]. A bilayer mucoadhesive buccal film containing a combination of ornidazole and dexamethasone was prepared using solvent casting to treat oral ulcers, with EC utilized as a backing layer. The formulation showed favorable swelling characteristics, and both drugs were released at 95% after4h[122]. EC was also applied for the preparation of allantoin-loaded films for the managemen<sup>t</sup> of dry mouth syndrome. The findings revealed that the produced films were functional, mucoadhesive, flexible, and stable, with the potential for treating various intraoral diseases [123]. EC-based mucoadhesive buccal films containing fluticasone formulated by solvent casting technique showed acceptable physicochemical properties, homogenous drug distribution, adequate mucoadhesion time, moderate swelling, and sustained drug release up to 12 h [124]. The objective of another study was to develop a two-layered buccal mucoadhesive system consisting of a highly water-soluble drug (i.e., risedronate). Varied concentrations of chitosan, HPMC, and EC acting as an impermeable backing membrane ensuring sustained release were tested. The obtained systems showed good swelling and mucoadhesive characteristics, with 90–100% drug release within 8–12 h [125]. EC, as a biocompatible backing layer, was also utilized in the development of mucoadhesive bi-layered strips used in dental treatment for the controlled delivery of lidocaine [126]. EC dissolved in N-methyl pyrrolidone was successfully used as a polymeric matrix for the in situ forming gel (with doxycycline, metronidazole, and benzyl peroxide) as dosage form applied in periodontal pocket in periodontitis treatment. It turned out that increasing the amount of EC increased the viscosity of system while still exhibiting Newtonian flow and simultaneously decreasing the release of drug [127]. Another prolonged-release mucoadhesive gel containing metronidazole for periodontal application was developed basing on a mixture of glycerylmonooleate and EC. EC reduced the initial metronidazole release and significantly sustained its release profile [128]. Pathak et al. developed a mucoadhesive coating for fluconazole tablets for oral thrush treatment. EC coating reduced fluconazole permeation through the buccal mucosa, thereby ensuring high local drug concentration and faster provision of the fluconazole minimum inhibitory concentration in the oral cavity [129].
