Applications of Alginates: Comparison
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Alginates (ALG) have been used in biomedical and pharmaceutical technologies for decades long time. ALG are natural polymers occurring in brown algae and feature multiple advantages, including biocompatibility, low toxicity and mucoadhesiveness. Moreover, ALG demonstrate biological activities per se, including anti-hyperlipidemic, antimicrobial, anti-reflux, immunomodulatory or anti-inflammatory activities. ALG are characterized by gelling ability, one of the most frequently utilized properties in the drug form design. ALG have numerous applications in pharmaceutical technology that include micro- and nanoparticles, tablets, mucoadhesive dosage forms, wound dressings and films. However, there are some shortcomings, which impede the development of modified-release dosage forms or formulations with adequate mechanical strength based on pure ALG. Other natural polymers combined with ALG create great potential as drug carriers, improving limitations of ALG matrices. 

  • alginate
  • polymer blends
  • biomedical applications

1. Introduction

Beneficial properties of alginates (ALG) enable their wide application in the pharmaceutical, medical, and food industries [1]. ALG were discovered at the end of the nineteenth, century and their commercial production started in the United States in 1929. In 1983, the Food and Drug Administration (FDA) approved the use of ALG as a food ingredient [2]. Since then, ALG have been investigated thoroughly and have been the subject of many studies. ALG are polymers of natural origin, and their main source of acquisition is brown algae (Phaeophyta). They occur most frequently in algae cell walls [2]; however, they can be found in the intracellular matrix in Laminaria and Fucus species [3]. The most common form of ALG, which appears in cell walls, is calcium salt [4], with sodium or potassium salts appearing less frequently. The algae species most commonly used for ALG acquisition are inter alia: Ascophyllun, Macrocystis, Laminaria, Eisenia, Ecklonia, Fucus, Alario, Necrocystis, Sargassum, Ascophyllum nodosum, Macrocystis porifera, and Laminaria [1,2,5,6][1][2][5][6]. Another valid means of obtaining ALG is technology using bacteria from Pseudomonas sp. or Azotobacter (Acetobacter) sp.

2. Pharmaceutical Applications of ALG

Among many advantages of ALG, SA monographs are included in both European Pharmacopeia and United States Pharmacopeia [61,62][7][8]; thus, their properties for pharmaceutical and biomedical use are strictly regulated. Due to the low toxicity, biocompatibility and inert character, European Food Safety Authority (EFSA) approved ALG for use in a wide range of products, even in young children with special delivery requirements. The versality of ALG leads them to be widely applied in drug delivery systems, such as micro-, nanoparticles, tablets, semi-solid drug forms (as thickener and suspending agent), in tissue engineering, bone and cartilage regeneration, and in wound treatment (ALG dressings). Drug dosage forms designed with the use of ALG are mainly micro-, nanoparticles, tablets, capsules, hydrogels, and beads [63,64][9][10]. Such a wide application of ALG is also possible due to other numerous advantages, such as gelation properties, cell affinity, and high capacity to incorporate and release various active substances, including proteins [63][9]. Moreover, ALG are natural and relatively inexpensive polymers. Mucoadhesiveness of ALG makes them a promising excipient for mucosal (ocular [65][11], nasal [66][12], vaginal [67][13], oral [68][14]) delivery systems.

2.1. Microparticles

ALG microparticles are being studied to protect the drug from degradation as well as modify, release, and increase drug bioavailability. Drugs encapsulated in microparticles can be both hydrophilic and hydrophobic. Due to biocompatibility, biodegradability, non-toxicity, relatively low cost, properties favorable for the spray-drying process, and ease of gelation, SA presents itself as an excellent matrix material for microparticles technology [15,69,70,71][15][16][17][18]. ALG microparticles are biocompatible and highly bioavailable dosage forms [72][19], they are relatively small (1–500 μm), possess a large surface area, protect the core from external agents, mask taste and odor, and enable different release modification [73,74,75,76][20][21][22][23]. Microparticles are also delivery platforms for proteins, nucleic acids, enzymes, cells, growth factors and genes in tissue engineering [77,78,79,80][24][25][26][27]. However, disadvantages of microparticles include relative high production costs, specialized equipment, low reproducibility of the process and instability of the final product [81][28]. External gelation is one of the most often used methods to obtain microparticles by dropping ALG solution into the crosslinking medium [13][29]. Particle size is a key parameter in the context of drug distribution in the gastrointestinal tract, drug release and degradation process [15]. Currently, the tendency is to receive the finest possible microparticle size by enhancing the dripping method through the involvement of external forces, such as vibration, electrostatic force, or coaxial air flow. It is also possible to improve the emulsification method by using sonification, membrane emulsification, or microfluidic methods [82,83][30][31]. Microcapsules obtained by external gelation provide a protective coating for sensible components such as living cells, cytokines, growth factors and proteins [84,85,86,87,88][32][33][34][35][36]. ALG microparticles are semi-permeable and provide immune protection to cells, which allows them to differentiate and proliferate [89][37]. Martin et al. [90][38] proposed a novel mucoadhesive system consisting of ALG microparticles loaded with nystatin for the treatment of oral candidiasis to increase residence time on the buccal mucosa and to improve the effectiveness of the treatment. Designed microparticles demonstrated antifungal activity for up to 48 h in an in vitro study. An interesting approach to the topic was demonstrated by Benavides et al. [91][39], Faidi et al. [92][40] and Fermandizz et al. [93][41], who proposed thyme, clove essential and cedar wood oil-loaded ALG microparticles to protect against evaporation and disintegration under the influence of oxygen, UV, and heat. All the researchers obtained microparticles with relatively high encapsulation efficiency, however further studies are required to refine the conditions for microparticle production. Hussein N. et al. [94][42] designed ALG microparticles loaded with ropinirole hydrochloride using the spray-drying method for intranasal delivery. Ropinirole is an agonist of D2 dopamine receptors in the brain, employed in the treatment of Parkinson’s disease in monotherapy or in combination with other drugs, most frequently levodopa. The drug possesses an approximately 50% hepatic first-pass effect; thus, it is characterized by low bioavailability. ALG microparticles were utilized as a drug form for intranasal use to increase ropinirole bioavailability by reducing the first-pass effect, since the nasal mucosa possesses a relatively large absorption area (approx. 150 cm2), and the drug reaches its target site of action faster: the nervous system. In addition, ALG microparticles, due to their mucoadhesive properties, prolonged the contact of the formulation with the mucosa. The study showed that designed particles were non-toxic to an isolated sheep mucosa and were stable for 2 months of storage at 5 °C ± 1 and 20 °C ± 2. There have also been attempts to load insulin into ALG microparticles [95,96,97,98][43][44][45][46]. To improve the comfort of insulin administration, novel drug delivery systems, including ALG microparticles, are being developed to protect insulin from degradation. Mild conditions for producing microparticles by the internal gelation method did not damage its secondary structure [96][44], and microparticles prepared from SA blended with mucin showed a hypoglycemic effect in diabetic rats comparable to subcutaneous administration of insulin [97][45]. Insulin loaded into microparticles by the spray drying maintained its bioactivity [98][46]. ALG microparticles were also utilized to improve the stability of papain during storage and enteral release, which extended the shelf life of papain during storage to about 3.6 years, compared to free papain (about 0.48 years) and a higher rate of drug release at pH >6.8 than at pH <5 [99][47]. A similar premise supported the design of hydrogel beads with subtilisin on a matrix of SA blended with guar gum [100][48] or the encapsulation of plasmid DNA (pDNA) encoding a green fluorescent protein (GFP)-reported gene using SA [101][49]. Szekalska M. et al. [102][50] designed ALG microspheres with ranitidine hydrochloride to improve their bioavailability after oral administration, and the obtained formulations were characterized by sustained drug release and beneficial mucoadhesive properties. Microparticles can also provide protection for orally administered probiotic bacteria from harmful environmental factors, such as stomach acidic pH, and high temperature during the manufacturing and storage process. Faarez I.M. et al. [103][51] placed Lactobacillus plantarum lactic acid bacteria (LAB)12 cells in ALG microcapsules encapsulated with cellulose derivatives: methylcellulose (MC), sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) to increase heat resistance. Bacteria cells gained higher survivability during storage when HPMC or MC were blended with ALG. Mirmazloum I. et al. [104][52] encapsulated Lactobacillus acidophilus with Reishi medicinal mushroom (Ganoderma lingzhi) extract as a prebiotic for the bacteria in a matrix composed of SA blended with maltose, HPMC or hydroxyethyl cellulose (HEC) to increase the stability of the formulation and to mask the bitter taste of the fungus, which resulted in increased stability of the formulation during storage and slower release, especially with the addition of maltose.

2.2. Nanoparticles

Nanoparticles are characterized by the same order of size as proteins and by a relatively large surface area, which creates the possibility of placing specific ligands [105,106,107][53][54][55]. In addition, nanoparticles enable modifications in drug pharmacokinetics, they can reduce drug toxicity and the possibility of damaging healthy cells, and they enable precise drug delivery to the targeted site of action, especially in targeted cancer therapy [107][55]. Nanoparticles can also improve solubility and bioavailability of poorly water-soluble substances and can provide modified drug release while reducing toxicity [15,64][10][15]. Moreover, nanoparticle size enables passage through the smallest capillaries [15], and they are characterized by the ability to inhibit P-glycoprotein activity, thus to reduce the resistance of tumor cells to cytostatics [108][56]. In order to improve the bioavailability of metformin, to reduce its side effects and to obtain sustained drug release, Kumar S. et al. [109][57] developed metformin-loaded ALG nanoparticles. The study conducted on adult Wistar albino rats showed sustained drug release from nanoparticles (up to 30 h), and a lower dose of the drug was needed. Thomas D. et al. [110][58] proposed ALG nanoparticles loaded with rifampicin to improve drug bioavailability after oral administration and to obtain controlled drug release. The study showed a pH-dependent release profile with controlled release of the drug for 6 h at pH 7.4. Ahmad Z. et al. [111][59] developed ALG nanoparticles with isoniazid, rifampicin, pyrazinamide or ethambutol as an oral delivery system for tuberculosis treatment to improve pharmacokinetics of these drugs and to reduce the high potential of side effects. The researchers created nanoparticles with high encapsulation efficiency and higher bioavailability of encapsulated drugs compared to free drugs. Higher tissue concentrations of drugs were observed on a Laca mice model after administration in encapsulated form compared to free drugs. In addition, tissue concentrations were maintained at >MIC levels for 15 days, making it possible to use these drugs less frequently than daily. Kirtane A.R. et al. [68][14] developed ALG nanoparticles for a chemiotherapeutic drug, doxorubicin, in order to improve its oral bioavailability. A study on Madin–Darby Canine Kidney II cells (MDCK) showed improved doxorubicin transport across tumor cells overexpressing P-glycoprotein after nanoparticle administration. Studies on a mice model showed higher oral drug bioavailability during nanoparticle administration compared to free drugs. Bakhshi M. et al. [112][60] designed a vaccine against Escherichia coli 0157:H7 consisting of IgY encapsulated within ALG nanoparticles. The study showed that IgY was released from the nanoparticles in the stomach in a minimal amount (up to 10%); thus, the formulation managed to protect the drug against low pH and did not adversely affect the biological activity of immunoglobulins.

2.3. Tablet Technology

ALG are used in a variety of applications in tablet technology. SA at a concentration of 1–5% acts as a disintegrating agent in powder form and in the form of a 1% solution as a binder. ALG are also used as fillers as well as taste and odor maskers. Controlled drug release might be achieved through the application of ALG matrix tablets, which undergo superficial swelling and slow dissolution. Thus, drugs that are well soluble in water slowly dissolve in water, flowing into the tablet interior, and such a solution diffuses to the outside of the tablet. In contrast, substances that hardly dissolve in water are released from the matrix by erosion of the tablet as it passes through the gastrointestinal tract [12][61]. The biopharmaceutical properties of ALG tablets significantly depend on intrinsic factors, namely the properties of the ALG itself. The molecular weight directly proportionally affects the viscosity of the ALG solution, and thus, an increase in viscosity entails a slower release from the matrix tablet [113][62]. The concentration of ALG in the tablet affects the release rate in a similar way [114][63]. The M/G ratio is also not without influence, ALG with higher G-content form stiffer gel structures, which slow down drug release [13,115][29][64].

3. Biomedical Applications of ALG

3.1. Tissue Regeneration

The application of ALG in tissue engineering and bone and cartilage regeneration seems interesting and potentially promising, as treating damage in these tissues is often a difficult and lengthy process [22][65]. The most desirable strategy is to stimulate osteogenesis and chondrogenesis in situ [91][39], which can be achieved by supplying the site of damage with stem cells capable of proliferation and differentiation [91,116,117,118,119,120,121][39][66][67][68][69][70][71]. As ALG gels are characterized by a structure similar to the extracellular matrix in tissues, they are being studied for potential use in tissue engineering or cell transplantation [22][65]. The principle of gel action is to deliver cells to a specific location in the body and to provide conditions for tissue reconstruction [122,123][72][73]. The influence of cells such as osteoblasts, chondrocytes, or bone marrow mesenchymal cells (MCSs) on osteogenesis and chondrogenesis is being studied [116,124,125,126,127][66][74][75][76][77]. Numerous studies showed bone regeneration using injectable ALG scaffolds containing MCSs [120,121,124,125,126,127,128,129][70][71][74][75][76][77][78][79]. ALG can be inserted into tissues in a non-invasive manner, they fill irregular spaces accurately, are easily chemically modified, and possess good regenerative properties, as proven in an animal model [118,130][68][80]. In mouse embryonic stem cell studies, the ability of ALG to promote stem cell differentiation into bone cells was demonstrated [131][81]. ALG gels are biodegradable and do not possess sufficient mechanical properties to allow for load transfer during the initial stages of regeneration [22][65]. In order to improve mechanical properties, ALG were mixed with ceramides, hydroxyapatite [132[82][83],133], CH [134][84], or bio-glass [135][85]. ALG gels might also be carriers for growth factors such as bone morphogenetic proteins (BMPs) [83][31] or tumor growth factor β (TNF-β) [124,125,126,128][74][75][76][78].

3.2. Wound Care

One of the most common dressings used for centuries has been gauze, which is easy to use, inexpensive, and has a high water absorption capacity. However, it can stick to the wound and cause re-damage during dressing changes [91,136][39][86]. Current emphasis is on modern dressings providing a moist wound environment while managing the exudate. Among many advantages of ALG dressings are biocompatibility, optimal water vapor permeability, mild antiseptic properties combined with non-toxicity, and biodegradability [91,137][39][87]. The principle of ALG dressings is to absorb exudate from the wound, exchange calcium ions from the dressing for sodium ions from the wound, convert to gel form and provide moisture to the wound. These processes promote granulation and epithelialization of the epidermis and thus wound healing [22,138,139][65][88][89]. The ratio of mannuronic to guluronic residues affects the ability to absorb exudate [140,141][90][91]. A high content of mannuronic acid is positively correlated with the ability to retain water; however, the fibers of such dressings are weaker. Some studies have indicated that pathogens from the wound were trapped in the gelled structure of the dressing [142][92]. The manufacturing process of ALG dressings begins with crosslinking the ALG with calcium ions and impregnating the material with the resulting gel. Such a semi-finished product is freeze-dried and mechanically smoothed to obtain flexible, delicate fiber mats [143][93] or foam sheets [144][94]. To improve the properties of ALG dressings, several compounds such as silver [145][95], zinc ions [146,147,148,149,150,151,152,153[96][97][98][99][100][101][102][103][104],154], chitosan (CH), fucoidan, asiaticoside [155][105], gelatin (GEL) [91][39], polyvinyl alcohol (PVA) [156[106][107],157], or cellulose [158][108] can be introduced. The aim of adding these components is to improve antibacterial properties (silver, zinc ions, CH), swelling rate, tensile strength (PVA), and other mechanical properties (fucoidan, GEL, cellulose). Another excipient added to ALG dressings are antibiotics, such as clindamycin [157][107] vancomycin [159][109], aminoglycosides [160][110], curcumin [149][99], aloe vera [154][104], or active carbon [161][111] for the elimination of unpleasant wound odor.

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