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Alginate: Current Use and Future Perspectives in Pharmaceutical and Biomedical Applications.

1. Introduction

Alginates (ALG) are a group of naturally occurring anionic polysaccharides derived from brown algae cell walls, including Macrocystis pyrifera, Laminaria hyperborea, Ascophyllum nodosum [1, 2], and several bacteria strains (Azotobacter, Pseudomonas) [3]. This term usually referred to alginic acid and its salts, but it can also be used for all derivatives of alginic acid. ALG are linear biopolymers consisting of 1,4-linked [beta]-D-mannuronic acid (M) and 1,4 [alpha]-L-guluronic acid (G) residues (Figure 1) arranged in homogenous (poly-G, poly-M) or heterogenous (MG) block-like patterns [1-4]. With regard to the initial source material, commercial ALG may differ in composition and the sequence of G- and M-blocks.

ALG extraction process from seaweeds is uncomplicated but multistage procedure, which usually starts with treating the dried raw material using diluted mineral acid. After further purification, the obtained alginic acid is converted into water-soluble sodium salt in the presence of calcium carbonate, which is next transformed back into acid or its expected salt (Figure 2) [2, 4].

Commercial ALG are exclusively possessed from algal sources, although alternative production by microbial fermentation has been recently explored in order to provide ALG with more defined physicochemical properties [3].

Among various ALG, sodium alginate is one of the most widely investigated ones in the pharmaceutical and biomedical field and its monograph is included into both the European Pharmacopeia and the United States Pharmacopeia [5, 6]. The current pharmacopoeial requirements regarding sodium alginate are presented in Table 1.

2. General Properties of ALG

Currently used ALG possess a high degree of physicochemical heterogeneity which influences their quality and determines potential applicability. ALG are commercially available in various grades of molecular weight, composition, and distribution pattern of M-block and G-block, the factors responsible for their physicochemical properties such as viscosity, sol/gel transition, and water-uptake ability. The molecular weight, expressed as an average of all the molecules present in the sample, of commercial ALG varies between 33 000 and 400 000g/mol. ALG extracted from different sources differ in M and G residues as well as the length of each block. Generally, by raising the ALG G-block content or molecular weight, more stronger and brittle ALG gels maybe achieved [67]. Alginic acid is insoluble in water and organic solvents, whereas ALG monovalent salts and ALG esters are water-soluble forming stable, viscous solutions [1-4]. The 1% w/v aqueous solution of sodium alginate has a dynamic viscosity 20-400 mPa-s at 20[degrees]C. ALG solubility is limited by the solvent pH (a decrease in pH below pKa 3.38-3.65 may lead to polymer precipitation), ionic strength, and the content of "gelling ions" [2, 68]. ALG with more heterogeneous structure (MG-blocks) are soluble at low pH compared to poly-M or poly-G ALG molecules, which precipitate under these conditions [69, 70]. Apart from molecular weight, the ALG capability of creating viscous solutions may vary according to their concentration, solvent pH (a maximum pH is reached around 3.0-3.5), temperature, and the presence of divalent ions [1-3, 68].

ALG can be easily formed into diverse semisolid or solid structures under mild conditions because of their unique ability of sol/gel transition. Therefore, ALG are commonly used as viscosity increasing agents, thickeners, and suspension and emulsion stabilizers in food and pharmaceutical industry (Table 2).

ALG gelation can be induced in the presence of divalent ions, which cross-link the polymer chains through the "eggbox" model [68, 71, 72] or by lowering the pH value below the pKa of ALG monomers using lactones like d-glucono-[delta]-lactone [2, 4]. It should be noted that calcium chloride, most frequently used source of [Ca.sup.2+] ions, is responsible for rapid and uncontrollable ALG gelation. The gelation rate is a critical parameter in controlling gelation process. Slow gelation provides creating uniform gel structures with mechanical integrity [67]. One approach to reducing the rate of gel forming process is to apply to phosphate buffers (e.g., sodium hexametaphosphate). In the reaction with ALG carboxylate groups, phosphate groups present in the buffer compete with calcium ions and as a result ALG gelation process is retarded [73]. Additionally, calcium sulfate and calcium carbonate with lower solubility also prolong the gel formation. The gelation rate is also dependent on temperature; at lower temperatures, the reactivity of [Ca.sup.2+] is reduced [74]. Recently, a freeze-thaw technique has been examined as an advanced controlled method for ALG hydrogels formation [75]. Gelling properties are strongly associated with ALG structure and proportions of M-, G-, and MG-blocks [67, 71, 76]. In addition, ALG gels with an increased amount of repeating G-block units are regarded as stiffer, brittle, and mechanically more stable [71, 72]. In contrast, ALG characterized by high proportion of M-blocks form gradually soft and more elastic gels. However, MG-blocks in ALG gel determine its shrinkage and higher flexibility [77]. Nevertheless, ALG with predominated M-block content, as a result of high water absorption, exchange ions more easily in comparison to ALG with higher amount of G-block residues [68, 71, 72, 78]. It should be noted that a number of studies revealed that ALG solution/gel transition occurred under physiological conditions, for example, in the presence of divalent ions and under acidic environment of body fluids [72]. For instance, nonwoven dressings of calcium alginate capable of exchange ions with the wound fluid have been commonly utilized for the treatment of exuding injuries or infected surgical wounds [79-81]. Formation of a highly absorbent soluble gel effectively maintains a physiologically moist environment and aids healing process through facilitating growth of fresh epidermis [75, 79]. Due to mechanical stability and proper viscoelastic behavior, ALG are also applied as structural supporting biomaterials for tissue (teeth, bone, and cartilage) reconstruction [79].

The fact that ALG may undergo in situ gelation makes ALG materials promising tools for a wide range of applications, including injectable vehicles for tissue engineering or topical drug delivery systems [41, 79, 82]. Moreover, due to gelling properties, ALG have been investigated as taste masking agents [83, 84]. Studies performed with using potentiometric electronic tongue [85] have proved that spray-dried microspheres with sodium alginate hid the bitter taste of ranitidine hydrochloride through physical gel-barrier formation (Figure 3). Figure 3 presents final chemical image, which shows that for all samples distinctive clusters are easily observable. They are formed by chemical images of samples of various types, where ALG microspheres with ranitidine hydrochloride are easily discernable from pure drug, which indicates masking effect obtained with the use of sodium alginate.

Greatly porous three-dimensional ALG hydrogel structure displays favorable swelling properties arising from the presence of hydrophilic functional groups [86]. ALG ability of hydration and gel formation gives the opportunity to prolong release of the active substance at the administration site. Hence, these polymers have been extensively studied for prolonged or controlled release drug delivery systems [87, 88].

In addition, owing to the mild conditions during gel formation, ALG (especially calcium alginate) appear to be favorable tools for cell entrapment used in tissue engineering or regeneration [89-91]. ALG barrier protects immobilized material toward physical stress (maintaining its viability during long-term culture) and enables avoiding immunological reactions with the host. Currently, ALG microparticulate systems are also being developed for the treatment of a variety of diseases, including cancer, diabetes, or Parkinson's disease [92, 93].

ALG possess good mucoadhesive properties resulting from the presence of free carboxyl groups allowing the polymer to interact with mucin by hydrogen and electrostatic bonding. Environmental pH has a strong impact on ALG solubility and consequently on their mucoadhesive character as only ionized carboxyl groups are capable of interacting with mucosal tissue. In addition, soluble ALG facilitate solvent penetration through polymer matrix resulting in formation of more viscous and cohesive gel structure responsible for strengthening the mucoadhesive bonds. In contrary, too excessive hydration of ALG matrix in physiological fluids might weaken mucoadhesiveness as a result of attenuation of ALG functional groups available for interactions with mucosal tissue [94-96].

Owing to mucoadhesive properties, ALG are regarded as proper polymer excipients to prepare buccal [97-99], nasal [100,101], ocular [102,103], and gastrointestinal dosage forms [104-108]. Recently, several studies have shown favourable mucoadhesiveness of ALG-based applications in contact with vaginal mucosa tissue [108,109]. Furthermore, an increased drug residence time at the ocular mucosal surface and prolonged release of active agents from microparticulate delivery systems with ALG were displayed [110]. Due to large surface area, which may favour an intimate contact between the polymer and mucin, multiunit dosage forms with sodium alginate are also explored as gastroretentive drug carriers (Figure 4), especially for substances, which are unstable or degraded in the alkaline pH [111,112].

ALG have been extensively evaluated as vaccine adjuvants or coadjuvants as these polymers were displayed to enhance bioavailability and immunogenicity of antigens after nasal and oral administration [101,113,114].

3. ALG Modification for Drug Delivery Systems and Biomedical Devices

ALG can be easily modified through chemical or physical cross-linking in order to form ALG hydrogels and improve physicochemical properties and/or biological activity. Many methods have been described for ALG cross-linking, which includes ionic cross-linking, covalent cross-linking, cell cross-linking, phase transition (thermal gelation), "click" reaction, and free radical polymerization [89]. An alteration of the M- to G-block proportion or an enrichment of polymer backbone in M-, G-, or MG-blocks is being practiced by modification through enzymatic epimerisation catalysed by mannuronan C-5 epimerases. This enzyme, isolated from the soil bacterium Azotobacter vinelandii and expressed in Escherichia coli, converts mannuronic acid residues into guluronic acid residues in the polymer backbone without breaking of the glycosidic bond [87, 115, 116]. Additionally, from ALG backbone, oligosaccharides might be isolated, which are polymer fragments containing three to ten of simple monosaccharides. There are two methods, which might be used to prepare ALG oligosaccharides: enzymatic depolymerization and acid hydrolysis [56]. The common chemical modification of ALG hydroxyl groups includes oxidation, sulfation, graft copolymerization, acetylation, and phosphorylation process [117, 118]. Modification of the carboxyl groups may be achieved by esterification and amidation [89,117,118]. A list of the commonly used chemical changes of ALG structure for biomedical and pharmaceutical application is presented in Table 3. ALG solubility might be changed by modification of hydroxyl groups (in positions C2 and C3) or the carboxyl groups (in C6 position) through covalent attachment of long alkyl chains or aromatic groups to the polymer backbone. Increasing ALG hydrophobicity provides decreasing polymer dissolution and erosion. Additionally, there are many studies, which include production of ALG derivatives by grafting with different substances such as polyacrylamide, methacrylate, galactose, lectin, sulfate, cysteine, cyclodextrins, propylene glycol, and dodecylamine [117-119].

4. ALG Biological Activity and Application in Pharmaceutical Products

ALG are regarded as biocompatible, nonimmunogenic, and nontoxic materials [2]. Although ALG gel is not degradable in mammalian digestive tract (alginase/lyase enzyme involved in depolymerization of ALG is present only in prokaryotic and eukaryotic microorganisms) [120], it simply dissolves as a result of elution of cross-linking calcium ions. It should be noted that only small ALG molecules are excreted by renal clearance threshold. To enable complete elimination of ALG from the body, partial oxidation of polymer backbone is necessary [121]. ALG biocompatibility was confirmed in vivo after ocular [122], nasal [114], topical [123], local [124, 125], and oral administration [126]. Food and Drug Administration has recently affirmed several ALG salts (calcium, sodium, ammonium, and potassium) as well as propylene glycol ALG derivative as GRAS (generally regarded as safe) ingredients for oral administration [127]. Nevertheless, several data reported that chemical composition of ALG may affect polymers' immunogenicity. For instance, Otterlei et al. described that ALG with high M-block were much more potent in inducing cytokine production compared with ALG with high G constituents [128]. In addition, various impurities such as heavy metals, endotoxins, proteins, and polyphenol compounds present in ALG material could potentially exert immunogenic response [129, 130]. Therefore, to assure high purity of ALG, proper decontamination methods should be applied concomitantly with extraction procedure [130].

ALG have been extensively studied for a wide range of applications. They include in situ gel formation, controlled release, targeted drug delivery, and medical purposes [2, 87, 88]. List of the pharmaceutical products based on ALG is presented in Table 4.

ALG are known to act as a physical barrier in order to reduce reflux episodes [131,132]. A number of available ALG-based pharmaceutical products used for the symptomatic treatment of heartburn and oesophagitis exist [132]. As ALG formulations generally contain bicarbonate salt, it converted to carbon dioxide (entrapped within the gel matrix) enabling polymer to float on the surface of the gastric fluid. ALG-based products may retain in the stomach for several hours providing long-lasting relief [132-134]. Several studies revealed that sodium alginate is able to move to the oesophagus ahead of gastric contents and hence might be helpful in decreasing the number of acid esophageal episodes. Additionally, owing to mucoadhesive properties, ALG was demonstrated to protect gastric mucosa from harmful activity of gastric fluid [131,132, 134]. Antacid ALG products are generally regarded as safe and may be used in children and pregnant women [134].

ALG are also considered as promising candidates in obesity and type 2 diabetes treatment as they are able to attenuate the postprandial glycemic response by modulation of gastric emptying [135-138] or inhibition of glucose transporters and glucose intestinal absorption rate [137]. Additionally, there are studies which have also revealed that ALG mode of hypoglycemic action might be associated with the reduced activity of a-amylase, intestinal enzyme responsible for hydrolyzing the bonds between glucose residues in carbohydrate polymers [106, 139].

Superior anti(hyper)lipidemic efficacy of ALG was also displayed. ALG were found to combine bile acids in the digestive tract and to reduce their intestinal reabsorption [140], which in consequence enhance their excretion [141-143]. Furthermore, Houghton et al. suggested that ALG are capable of reducing pancreatic lipase activity by protonating active sites in enzyme's structure [144]. Calcium alginate was also reported to show hypocholesterolemic activity after oral administration as it was found to reduce plasma cholesterol level effectively in the rat model [140].

Numerous data have drawn attention to the use of ALG derivatives as antibacterial, antiviral, and anti-fungal agents [145, 146]. Several mechanisms have been proposed to explain ALG antimicrobial activity. Negatively charged ALG were found to interact with the outer bacterial cellular surface, leading to its disruption and leakage of intracellular substances [147, 148]. A decrease in membrane function by formation a viscous ALG layer around the cell preventing nutrient transport was also demonstrated [147]. In addition, antibacterial efficacy could be related to ALG chelation capacity responsible for modulating the production of toxins, microbial growth, and factors crucial for microorganisms stability. Bacteriostatic activity of ALG was proved against a wide variety of species, including Pseudomonas, Escherichia, Proteus, and Acinetobacter [42, 43]. Nonetheless, it ought to be point out that the antimicrobial activity of ALG differs substantially according to a number of factors, namely, molecular weight, M/G-block ratio, modification of their structure, environmental pH, and the state of applied formulation [145].

Sulfated polysaccharides and alginic acid-containing fractions extracted from algae were found to exert antiviral efficacy against a number of viruses families, including Flaviviridae, Togaviridae, Rhabdoviridae, and Herpesviridae and might be helpful in treatment of virus infections [146, 149-151]. The mode of action may be related to the strong anionic charge of sulfated ALG capable of interacting with the positively charged host cell and, as a result, virus contact with the host cell is prevented and the viral material could not enter in the cells [61,152-154]. In contrary, Meiyu et al. indicated that virus penetration was inhibited by physical barrier created by ALG around the cell [154]. Furthermore, studies performed by Son et al. revealed that ALG with high Mblock content possessed immunostimulating properties by activating macrophages responsible for excreting cytokines and cytotoxic factors [155].

Haemostatic efficacy of calcium alginate through platelets activation and thrombin generation was also displayed [156-159] enabling polymer application in wound dressings [30-33]. Furthermore, sulfated ALG derivative propylene glycol alginate sodium sulfate (PSS) is the first oral heparinoid approved by Chinese Food and Drug Administration and has been used as an anticoagulant drug for over 30 years [160].

Sodium alginate oligosaccharides have been reported to lower blood pressure [64]. The hypotensive mechanism appeared to be associated with calcium antagonist activity, especially toward voltage-operated calcium channels [65]. Sodium alginate oligosaccharides in dose 60 mg/day were found to decrease blood pressure and to eliminate hypertension after 14 days of treatment, whereas Moriya et al. displayed polymers facility to prevent early-stage of kidney injury by decreasing the rate of glomerular filtration [66]. In addition, alginate potassium might be considered as promising agent for preventing cardiovascular complications associated with hypertension, including cardiac, renal hypertrophy in the risk of stroke occurrence [161].

Antioxidant and anti-inflammatory activity of alginate oligosaccharides was also observed. Alginate oligosaccha-rides were found to attenuate the production of nitric oxide, reactive oxygen species (ROS), prostaglandin E2, and cyclooxygenase COX-2 [57, 162-166]. Yamamoto et al. demonstrated that the mechanism underlying antioxidant effect of high mannuronic alginate was based on stimulating monocytes to secrete anti-inflammatory cytokines [164]. Additionally, because of chelating capacity, ALG are capable of binding toxins and heavy metals in the intestine, protecting cells from the carcinogenesis process [57, 60,163-166]. Furthermore, Jeong et al. indicated that alginic acid exerted antianaphylactic activity relating to inhibition of histamine release from mast cells followed with downregulation of histidine decarboxylase and proinflammatory cytokines expression [167]. Moreover, studies performed by Uno et al. showed that alginic acid reduced IgE production in the serum of mice immunized with [beta] lactoglobulin [168]. Additionally, alginic acid at concentration of 0.01 [micro]g/ml was found to reduce histamine release from rat peritoneal mast cells up to 60%[167].

5. Future Perspectives

5.1. ALG-Based Three-Dimensional (3D) Cell Culture Systems. 3D culture systems, macroporous structures prepared from using natural, synthetic polymers or their composites, with ability to reflect the native extracellular matrix and natural physiological conditions have been regarded as advanced technology for complex cellular physiology investigations, drug evaluation, and tissue engineering [169-171]. Among natural polymers, ALG, with regard to gel formation ability, mechanical strength, and interactions with cell via bio-adhesive bonds, are considered to be promising material for cell and tissue culture and have been employed as 3D systems [89]. 3D material based on ionically gelled and dried ALG macroporous scaffolds creates favorable conditions for cellular attachment, proliferation, and differentiation. ALG scaffolds are able to turn into hydrogels upon rehydration following cell seeding. At present, two ALG-based 3D products for cell culture AlgiMatrix[R] (Thermo Fisher Scientific/Life Technologies, USA) and NovaMatrix[R] 3D (NovaMatrix, Norway) are commercially available in different formats of standard cell culture well plates [172, 173]. AlgiMatrix is a lyophilized sponge prepared of pharmaceutical-grade ALG extracted from brown seaweed. After application of the cell suspension on the top surface of porous ALG-platform, the lyophilisate becomes hydrated and entraps cells inside its porous structure [174]. Unopened product is stable at room temperature up to 12 months. In contrary, NovaMatrix 3D comprises sterile ALG foam structure, a source of gel forming ions to initiate polymer gelation, and a vial of lyophilized ALG to be dissolved in a culture medium. Once the pores are filled with the ALG solution, in situ hydrogel is formed which enables fast and gentle cell immobilization under physiological conditions [170,173].

5.2. Cell-Based Microparticles for Therapeutic Applications. Immobilization of living cells or cell inducing factors in ALG matrix is commonly used technique in tissue and cartilage engineering. Over the last ten years, an advanced research has been conducted on the development of cell transplantation therapy in long-term diabetes and neurodegenerative diseases treatment with using ALG-encapsulation technology Immupel[TM] (LCT, Living Cell Technologies Limited, Australia). This selectively permeable system with ability to protect the encapsulated living cells from host immune system manages them to function and differentiate accurately [175-177]. Currently, two ALG-based products, DIABECELL[R] and NTCELL[R], are in advanced stage of clinical investigations.

DIABECELL implant consists of microencapsulated neonatal porcine islets capable of secreting insulin. The single system is designed to be delivered into the patients abdomen during laparoscopy procedure. Each multilayer microcapsule comprises the inner core of ALG (M/G ratio 60 :40) cross-linked with calcium chloride and coated with polyL-ornithine-(PLO-) polycationic polymer responsible for strengthening the capsule wall. To reduce the risk of immunogenicity arisen from the presence of PLO, the additional outer layer prepared of ALG is present [178, 179]. Recently additional modification of microcapsules shell by cross-linking the PLO surface with genipin has been employed in order to improve microcapsules biocompatibility. The clinical data displayed a statistically significant efficacy of DIABECELL in reduction of hypoglycemic episodes in patients with type 1 diabetes after transplantation [179]. Another example of porcine pancreatic islet cells encapsulation is monolayer cellular device (MCD) technology. A single capsule contains collagen matrix base and monolayer of porcine islet cells (monolayer allows for a faster kinetic diffusion relative to the cluster of islands) and then coated by gelled layer built of 3% (w/v) ALG. The capsules are formatted to a 1-32 cm sheet for subcutaneous implantation. The MCD was histologically examined after a resection. Surrounded tissues graft fibrosis or ALG degradation has not been observed. In comparison to nonencapsulated porcine islets, less level of lymphocytes and macrophages has been noted [180, 181].

NTCELL with choroid plexus cells encapsulated within Immupel platform has been displayed to regenerate damaged tissue and significantly restore function in humans with Parkinson's disease. Following implantation into an impaired site within the brain of model animals, NTCELL was found to promote the production of cerebrospinal fluid as well as nerve growth factors. In addition to Parkinson's disease, the product may have the potential to be utilized in a number of other neurodegenerative disorders, including Huntington's, Alzheimer's or motor neuronal diseases [182,183].

5.3. Biological Activity of ALG Oligosaccharides. In recent years, ALG oligosaccharides, low molecular polymer fragments obtained by enzymatic depolymerization or acid hydrolysis at elevated temperatures, have received much attention because of their unique opportunity for combination treatment in which the polymer acts as the drug vehicle and concomitantly as an active part of the therapy [116]. Examples of ALG oligosaccharides with biological activity and pharmaceutical application were presented in Table 5.

OligoG[R], the highly purified oligomer with a high content of G-blocks and a relatively narrow molecular weight distribution, represents a novel therapeutic approach for treatment of microbial infections [184]. The unique mode of OligoG action is related to mucolytic activity and modification of biofilm formed by bacteria during colonization process. OligoG (at concentration of 10%) is able to alter the biofilm surface charge and porosity, weakening its growth and as a result to damage pathogens cell membranes. OligoG was demonstrated to increase the efficiency of conventional antibiotics against several resistant pathogens, including Pseudomonas, Acinetobacter, and Burkholderia sp. [184, 185]. In addition, Tondervik et al. indicated that OligoG improved antifungal activity of commonly used polyenes, azoles, and allylamines against Aspergillus and Candida strains [186]. OligoG is currently being tested as novel inhaled polymer therapy for the treatment of chronic respiratory disease. The advantage of OligoG is its suitability for pulmonary administration after simple dissolution in isotonic solvents followed with effective lung deposition and resistance to enzymatic degradation [43].

It should be noted that ALG oligosaccharides might be also considered as promising probiotic and prebiotic agents due to their beneficial effect on promoting the growth of Bifidobacterium sp. with simultaneous inhibition of Salmonella enteritidis colonization in the large intestine [187]. The influence on the balance of commensal bacteria could be attributed to immunostimulatory activity of oligosaccharides through ability to upregulate the production of anti-inflammatory factors [61, 62].

Additionally, considerable research effort has been made to explore the usability of heparinoid ALG derivatives to support HIV treatment. At present, drug 911, sulfated high mannuronic and guluronic heterogeneous fragments of ALG, belonging to a group of heparinoid polysaccharides, is in advanced phase of clinical investigations in China as anti-AIDS drug [45-48]. Heparinoid 911 possesses an average molecular weight of 10 kDa and 1.5 sulfates and 1.0 carboxyl groups per sugar residue [48]. Heparinoid 911 was demonstrated to interact with the positively charged regions of glycoproteins present on the cell surface, leading to the shielding effect on these regions, thus counteracting HIV-virus binding to the cell surface [45, 46]. The unique mode of 911 action was found to be related to the inhibition of viral reverse transcriptase and prevention of viral adsorption. Furthermore, a significant inhibitory effect on DNA polymerase of hepatitis B virus was also reported which gives the opportunity to apply 911 in hepatitis B treatment [47].

6. Conclusions

Owing to unique properties, swelling capacity, mucoadhesiveness, and ability of sol/gel transition ALG have gained a preferential place in the development of advanced drug delivery systems. These natural, multifunctional polymers are widely studied in the design of microparticulate systems for controlled release, targeted drug delivery, and biomedical application (as matrix for three-dimensional tissue cultures, adjuvants of antibiotics, and antiviral agents or in cell transplantation in diabetes and neurodegenerative diseases treatment). Additionally, highly absorbent ALG-based hydrogels with mechanical stability and viscoelastic properties are applied as wound dressing. This paper also describes ALG chemical modifications, ALG biological activity, and application in pharmaceutical products.

http://dx.doi.org/10.1155/2016/7697031

Competing Interests

The authors declare no conflict of interests.

Acknowledgments

This study was supported by Medical University of Bialystok Grant (no. N/ST/MN/16/001/2215).

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Marta Szekalska, (1) Agata Pucilowska, (1) Emilia Szymanska, (1) Patrycja Ciosek, (2) and Katarzyna Winnicka (1)

(1) Department of Pharmaceutical Technology, Medical University of Biaiystok, Mickiewicza 2c, 15-222 Biaiystok, Poland

(2) Department of Microbioanalytics, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

Correspondence should be addressed to Marta Szekalska; marta.szekalska@umb.edu.pl

Received 26 September 2016; Revised 16 November 2016; Accepted 5 December 2016

Academic Editor: Muhammet U. Kahveci

Caption: FIGURE 1: The structure of ALG: monomers (a), chain conformation (b), and blocks distribution (c).

Caption: FIGURE 2: The procedure of sodium alginate extraction from brown algae [2].

Caption: FIGURE 3: Potentiometrie electronic tongue plot showing taste clusters of reference solution (0.0001 M Ca[(N[O.sub.3]).sub.2], 0.0001 M NaCl) (REF), pure ranitidine hydrochloride (RNT), microspheres placebo (ALG), and microspheres prepared with using 1% and 2% ALG solution (RNT + ALG 1% and RNT + ALG 2%, resp.). Samples were placed in 100 mL of deionized water; measurement time was 7 min with signal acquisition every 5 s. The data were processed using Principal Component Analysis (PCA) with autoscaling (author's original unpublished data).

Caption: FIGURE 4: SEM images of alginate microspheres obtained by the spray drying method with metronidazole under magnification x20 000 (a), ranitidine hydrochloride under magnification x10 000 (b), and metformin hydrochloride under magnification x20 000 (c) (author's unpublished images).
TABLE 1: Sodium alginate characteristic recommended by the European
Pharmacopeia (Eur. Ph.) and United States Pharmacopeia (USP) [5, 6].

Parameter              Eur. Ph. 8.0               USP 32-NF 27

Appearance of solid    White or pale                  n.d.
product                yellowish-brown
                       powder

Content                n.d.                     90.8%-106.0% of
                                                  dried basis

Packaging and          n.d.                    preserved in tight
storage                                            containers

Solubility             Slowly soluble in              n.d.
                       water, practically
                       insoluble in ethanol
                       96%

Appearance of          Not more opalescent            n.d.
solution               than reference
                       formazin suspension
                       in water and not
                       more intensely
                       coloured than
                       intensity 6 of the
                       range of reference
                       solutions of the
                       most appropriate
                       colour

Heavy metals           [less than or equal    [less than or equal
                       to] 20ppm                   to] 0.004%

Chlorides              [less than or equal            n.d.
                       to] 1.0%

Calcium                [less than or equal            n.d.
                       to] 1.5%

Arsenic                n.d.                   [less than or equal
                                                  to] 1.5 ppm

Loss on drying         [less than or equal    [less than or equal
                       to] 15.0%                   to] 15.0%

Total ash              n.d.                       18.0%-27.0%

Sulfated ash           30.0%-36.0%                    n.d.

Microbial limits       TAMC: [less than or    [less than or equal
                       equal to] 1000 cfu/g      to] 200 cfu/g

                       TYMC: [less than or
                       equal to] 100 cfu/g

Absence of specified   Salmonella sp.,          Salmonella sp.,
microorganisms         Escherichia coli         Escherichia coli

n.d.: not determined, TAMC: total aerobic microbial count, and TYMC:
total yeast/moulds count.

TABLE 2: The use of alginic acid and its salts in food and
pharmaceutical industry.

Code     Ingredient          Application in      Application in
                             food industry       pharmaceutical
                                                 industry

E400     Alginic acid [1]    Emulsifier,         Tablet binder and
                             formulation aid,    disintegrant,
                             stabilizer,         sustained release
                             thickener           and
                                                 release-modifying
                                                 agent, taste
                                                 masking agent,
                                                 thickener,
                                                 suspending and
                                                 viscosity
                                                 increasing agent,
                                                 stabilizer

E401     Sodium alginate     Texturizer,         Suspending and
         [4]                 stabilizer,         viscosity
                             thickener,          increasing agent,
                             formulation aid,    tablet and
                             firming agent,      capsule
                             flavour adjuvant,   disintegrant,
                             emulsifier,         tablet binder,
                             surface active      stabilizer,
                             agent               sustained release
                                                 agent, diluent in
                                                 capsule
                                                 formulation,
                                                 thickener

E403     Ammonium alginate   Stabilizer,         Color diluent,
         [7]                 thickener,          emulsifier, film
                             humectant           former, humectant

E404     Calcium alginate    Stabilizer,         Tablet
         [8]                 thickener           disintegrant

E405     Propylene glycol    Emulsifier,         Stabilizer,
         alginate [9]        flavoring           emulsifier,
                             adjuvant,           suspending and
                             formulation aid,    viscosity
                             stabilizer,         increasing agent
                             surfactant,
                             thickener

TABLE 3: Examples of chemically modified-alginate based drug delivery
systems and biomedical devices.

Type of modification   Material               Active substance

Oxidation              Oxidized-NaALG         Limbal epithelial
                                              stem cells

                                              Flurbiprofen

Reductive-amination    ALG-g-poly(ethylene    Human foreskin
of oxidized alginate   glycol)                fibroblasts

Sulfation              Sulfated ALG           --

Phosphorylation        Phosphorylated ALG     --

Graft                  NaALG-co-              Famotidine
copolymerization       polyacrylamide

                       Starch-g-              Diclofenac sodium
                       poly(acrylic
                       acid)-NaALG

                       ALG-glycidyl           Human endothelial
                       methacrylate           cell lines HUVEC and
                                              L929

                       Galactosylated ALG     Hepatocytes

                       [alpha]-               Sphingomonas cloacae
                       Cyclodextrin-ALG
                       conjugate

                       [beta]-                Ondansetron
                       Cyclodextrin-ALG
                       conjugate

Esterification         Propylene glycol ALG
                       Lysozyme

Type of modification   Biomedical or           Dosage form
                       pharmaceutical
                       application

Oxidation              Improvement of           Hydro gel
                       corneal wound
                       healing therapy

                       Sustained oral             Beads
                       delivery

Reductive-amination    Specific cell           Microspheres
of oxidized alginate   microencapsulation

Sulfation              Reduction of            Microspheres
                       secretion
                       inflammatory
                       cytokines,
                       improvement of the
                       biocompatibility

Phosphorylation        Mineralization of           Gel
                       hydroxyapatite and
                       participation in the
                       chelation process
                       for tissue
                       engineering

Graft                  Sustained release        Hydro gel
copolymerization       gastroretentive
                       carrier

                       pH-sensitive           Hydrogel beads
                       matrices for the
                       oral drug delivery

                       Thermal                   Hydrogel
                       polymerizable
                       injectable hydrogel
                       for tissue
                       engineering,
                       especially for
                       myocardial repair

                       Cell carrier with      Microcapsules
                       mechanical stability
                       and selective
                       permeability

                       Immobilization of          Beads
                       bacteria

                       Controlled drug             Gel
                       delivery systems

Esterification         Protein                Microparticles
                       encapsulation with a
                       sustained release

Type of modification        Reference

Oxidation               Wright et al. [10]
                        Maiti et al. [11]

Reductive-amination     Mahou et al. [12]
of oxidized alginate

Sulfation               Arlov et al. [13]

Phosphorylation        Coleman et al. [14]

Graft                  Tripathi and Mishra
copolymerization               [15]

                            Chang [16]
                         Wang et al. [17]
                         Tian et al. [18]
                       Pluemsab et al. [19]
                        Izawa et al. [20]

Esterification         Hurteaux et al. [21]

TABLE 4: List of the pharmaceutical products based on ALG.

Product           Main              Description        Indications
                  ingredients

        Oral administration

Gastrotuss[R]     Magnesium         Creates a          Children and
baby syrup [22,   alginate,         mechanical         infants from
23]               simethicone,      barrier between    the first days
                  fructose,         the stomach and    of life reflux
                  xanthan gum,      the esophagus      treatment
                  honey, D-         which prevents
                  panthenol,        the reflux,
                  fluid extracts    recurrent
                  of Althaea        symptoms of
                  officinalis,      respiratory,
                  Papaver rhoeas,   choking,
                  zinc oxide,       dysphagia,
                  sodium            heartburn,
                  bicarbonate,      belching,
                  sodium            irritability;
                  hydroxide         accelerates
                                    gastric
                                    movement,
                                    regenerates
                                    mucous
                                    membranes of
                                    the esophagus
                                    and ensures its
                                    protection

Algicid[R]        500 mg sodium                        Adult reflux
suspension/       alginate, 100                        treatment
tablets [24]      mg potassium
                  bicarbonate per
                  5 ml/per 1
                  tablet

Gaviscon Double   250 mg sodium
Action            alginate, 106.5
Liquid[R] [25]    mg sodium
                  bicarbonate,
                  and 162.5 mg
                  calcium
                  carbonate per 5
                  ml

Gaviscon Double   250 mg sodium     Dermal
Action            alginate, 106.5   application
tablets[R] [26]   mg sodium
                  bicarbonate,
                  and 187.5 mg
                  calcium
                  carbonate per
                  tablet

Flaminal          Hydrated          Dissolution of     Leg and
Forte[R] gel      alginates         dry scab and       diabetic
[27]              polymers in a     necrotic           ulcers,
                  polyethylene      material,          pressure sores,
                  glycol (PEG)      absorption of      complex grazes,
                  matrix with a     lysed material     burns, oncology
                  biologic enzyme   and bacteria by    and wounds
                  system based on   alginates in       dermatosurgery
                  glucose oxidase   hydrated form
                  and
                  lactoperoxidase
                  stabilized by
                  guaiacol

Purilon Gel[R]    Carboxymethyl-
gel [28]          cellulose,
                  calcium
                  alginate

Saf-Gel[R] gel    Carbomer,         Provides moist     Dry and sloughy
[29]              propylene         environment at     necrotic
                  glycol sodium/    wound surface      wounds,
                  calcium                              pressure and
                  alginate                             venous ulcers,
                                                       second-degree
                                                       burns, cuts,
                                                       abrasions and
                                                       skin tear,
                                                       noninfected
                                                       diabetic foot
                                                       ulcers

Hyalogran[R]      Ester of          Exudate absorbs    Variety of
dressing [30]     hyaluronic acid   and transforms     exuding wounds
                  (HA) and sodium   to soft gel;       including leg
                  alginate          removes            ulcers,
                                    necrotic tissue    pressure sores,
                                                       ischemic and
                                                       diabetic
                                                       wounds,
                                                       particularly
                                                       those which are
                                                       covered with
                                                       slough and
                                                       necrotic tissue
                                                       or areas that
                                                       are difficult
                                                       to dress

SeaSorb[R]        Calcium           Creates moist      Heavily exuding
dressing [31]     alginate          environment at     wounds
                                    wound surface,     including leg
                                    conversion soft    and pressure
                                    fibres to wet      ulcers,
                                    gel                diabetic ulcers
                                                       and second-
                                                       degree burns,
                                                       cavity wounds

Tromboguard [R]   Two-layer         Strong             Control of
dressing [32]     dressing built    haemostatic and    bleeding
                  from              antibacterial      traumatic and
                  hydrophilic       activity           postoperative
                  polyurethane                         wounds
                  sponges and
                  biologically
                  active layer
                  containing
                  chitosan,
                  sodium
                  alginate,
                  calcium
                  alginate, and
                  silver cations

Fibracol          90% collagen      Provides moist     Exuding wounds
Plus[R]           and 10% calcium   environment at     including:
dressing [32]     alginate          wound surface,     full-thickness
                                    tissue             and partial-
                                    granulation,       thickness
                                    epitheliali-       wounds;
                                    sation, and        pressure
                                    healing            ulcers; venous
                                                       ulcers; ulcers
                                                       caused by mixed
                                                       vascular
                                                       etiologies;
                                                       diabetic
                                                       ulcers; second-
                                                       degree burns

Algivon[R]        Calcium           Binds of           Sloughy,
dressing [33]     alginate          exudate,           necrotic, and
                  dressing          regeneration       malodorous
                  impregnated                          wounds
                  with Manuka
                  honey

Guardix-SG[R]     Sodium            Creates            In spine and
[34, 35]          alginate,         thermosensitive    thyroid
                  poloxamer,        viscous gel in     surgeries to
                  calcium           contact with       reduction of
                  chloride          body               the incidence
                                    temperature and    postoperative
                                    forms              adhesions
                                    mechanical
                                    barrier
                                    separates
                                    injured tissues

TABLE 5: Examples of ALG oligosaccharides with biological activity and
pharmaceutical application.

Compound               Mechanism of action    Biological activity
                                              and pharmaceutical
                                              application

OligoG[R] (ALG         Regulation of mucus    Cystic fibrosis,
oligosaccharide)       viscosity by           treatment of chronic
                       induction              obstructive
                       alterations in mucin   pulmonary disease
                       surface charge,        (COPD), improvement
                       formation porosity     of antibacterial and
                       of the mucin           antifungal therapy,
                       networks in cystic     antifungal activity
                       fibrosis sputum;
                       eradication
                       bacterial and fungal
                       lung infections by
                       modification of
                       biofilm structure
                       together with growth
                       inhibition,
                       improvement the
                       efficiency of
                       conventional
                       antibiotics against
                       multidrug resistant
                       bacteria or fungi

Heparinoid 911         Interaction with       HIV/AIDS, hepatitis
(sulfated high         glycoproteins          B virus
mannuronic and         present on the cell
guluronic              surface, which leads
oligosaccharides)      to the counteracting
                       HIV-virus,
                       prevention of viral
                       adsorption and
                       inhibition of viral
                       reverse
                       transcriptase;
                       inhibition of DNA
                       polymerase of
                       hepatitis B virus

ALG                    Inhibition effect on   Alzheimer's disease
oligosaccharides;      neuroinflammation,     and
oligomannuronate       promotion effect on    neurodegenerative
(HS971)                microglial             diseases
                       phagocytosis,
                       protection neurons
                       from cell death by
                       blocking oxidative
                       stress, inhibition
                       of production of
                       nitric oxide and
                       prostaglandin E2,
                       expression of
                       inducible nitric
                       oxide synthase and
                       cyclooxygenase 2,
                       secretion of
                       proinflammatory
                       cytokines, promotion
                       of the phagocytosis
                       of amyloid [beta]
                       protein through its
                       interaction with
                       toll-like receptor 4
                       (TLR4) in microglia

Propylene              Inhibition of          Anticoagulant and
glycol alginate        thrombin by            antithrombotic
sodium sulfate         interfering with the   activity, blood
oligosaccharides       coagulation cascade,   viscosity reduction
(PSS)                  prolongation of the
                       activated partial
                       thromboplastin time,
                       clotting time and
                       reduction platelet
                       aggregation

Guluronate             Reduction of the       Antioxidant and
oligosaccharide        production of nitric   anti-inflammatory
                       oxide, prostaglandin   activity, protection
                       E2, reactive oxygen    cells from the
                       species, the           carcinogenesis
                       expression of          process
                       inducible nitric
                       oxide synthase and
                       cyclooxygenase 2,
                       secretion of
                       proinflammatory
                       cytokines IL-1 and
                       IL-6, reduction of
                       the inflammatory
                       responses through
                       blocking the
                       activation of
                       nuclear factor
                       NF-[kappa]B and
                       mitogen-activated
                       protein kinases,
                       inhibition lipid
                       peroxidation

Unsaturated            Dose and time depend   Immunomodulatory
guluronate             on induction of        activity
oligosaccharide        production of nitric
                       oxide, inducible
                       nitric oxide
                       synthase, reactive
                       oxygen species and
                       TNF-[alpha],
                       induction of
                       macrophage to
                       release nuclear
                       factor NF-[kappa]B
                       and
                       mitogen-activated
                       protein kinase
                       signaling pathways

ALG                    Stimulation cecal      Probiotic and
oligosaccharides       and fecal microflora   prebiotic activity

Sodium alginate        Hypothesis mechanism   Hypertension
oligosaccharides       involves blood
(including             pressure reduction
unsaturated            related to direct
3[alpha]-L-            action on vascular
guluronate and-or      vessels, by effect
[beta]-D-              on the adrenergic
mannuronate)           nervous system or
                       endothelial cell
                       function

Compound               Reference

OligoG[R] (ALG         Khan et al. [42]
oligosaccharide)       Pritchard et al.
                       [43] Powell et al. [44]

Heparinoid 911         Xin et al. [45]
(sulfated high         Xin et al. [46]
mannuronic and         Jiang et al. [47]
guluronic              Wu et al. [48]
oligosaccharides)

ALG                    Tusi et al. [49]
oligosaccharides;      Zhou et al. [50]
oligomannuronate       Manigandan et al. [51]
(HS971)                Hu et al. [52]
                       Wang et al. [53]

Propylene              Ronghua et al. [54]
glycol alginate        Xin et al. [55]
sodium sulfate
oligosaccharides
(PSS)

Guluronate             Falkeborg et al. [56]
oligosaccharide        Zhou et al [57]
                       An et al. [58]
                       Ji et al. [59]
                       Hu et al. [60]

Unsaturated            Xu et al. [61]
guluronate             Xu et al. [62]
oligosaccharide

ALG                    Wang et al. [63]
oligosaccharides

Sodium alginate        Terakado et al. [64]
oligosaccharides       Chaki et al. [65]
(including             Moriya et al. [66]
unsaturated
3[alpha]-L-
guluronate and-or
[beta]-D-
mannuronate)
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Author:Szekalska, Marta; Pucilowska, Agata; Szymanska, Emilia; Ciosek, Patrycja; Winnicka, Katarzyna
Publication:International Journal of Polymer Science
Date:Jan 1, 2017
Words:12315
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