Biopolymers are the polymers extracted from living organisms either from renewable plant or animal sources are gaining importance due to their better biodegradability, biocompatibility, less/no immunogenicity, less/no toxicity, and availability. Polysaccharides (e.g., chitosan, cellulose), polypeptides (e.g., collagen, silk), and polynucleotides are the important class of biopolymers that are finding multidisciplinary applications in biomedical fields. At the other end, lipid-based systems are having their special concern in drug delivery due to their advantages over other excipient systems. In this present review, various classes of biopolymers and their fusion with conventional lipids for amalgam entity using advanced techniques for futuristic biomedicine applications are outlined. The comprehensive focuses on upbringing the importance and types of functionalization techniques explored for designing deliverable for various unmet clinical needs. Along with recent trends, the scrutiny even addresses the future perspective of these hybrid systems impacting in addressing the pharceutical, formulational and clinical challenges in treating gasteroentric diseases.
Lipid, Biopolymers, Functionalization, Drug delivery, Gastro retentive systems
Biopolymers have earmarked their importance in the biomedical and pharmaceutical applications. Researchers are still working for the facilitation of better therapeutic effects and medical benefits. In this context, several strategies are on a play like functionalization of biopolymers with physicochemical modification, functionalization of lipids with biopolymers, development of composites or hybrid systems for bringing together the benefits of individual moieties/systems (e.g., a combination of polymers or combination of systems) and technical advancements. Different categories of biopolymers are well established physically, chemically, and biologically to let them useful in biomedical avenues. The drawbacks, if any, existing with the developed systems are being circumvented with the initiation of these composite/hybrid concepts with proven scientific responses worldwide. One such concept is the combined application of biopolymers with lipids and lipid-based systems . Several lipid-based systems have gained wide-spread usage in the treatment and management of health. Examples include solid lipid nanoparticles, liposomes, micelles, and lipid hydrogels. These systems can provide controlled drug delivery, gene delivery, wound healing, and tissue engineering. Lifethreatening diseases like cancer, immune disorders are being handled with such advanced lipid-based systems in addition to the particulate systems. However, they do suffer from certain drawbacks like low stability, less production feasibility, lack of hydrophilic properties, poor mechanical strength, and high processing costs [2,3]. To overcome the aforementioned drawbacks, the lipid systems are conjugated as composite systems with biopolymers to keep the hybrid composite stable, enhance the functionality, impart the properties of biopolymers and modulate the characteristics of the lipid system. Biopolymers are the polymers obtained from natural resources and are biocompatible, biodegradable, no or less antigenic, bioactive, easy to fabricate, comparatively stable, and supporting to cell growth and proliferation [3,4].
Biopolymers are the naturally arising polymeric materials from the living organisms either plant or animal or organism sources. They have predominant thrust in the pharmaceutical and biomedical fields of clinical application [5-7]. Biopolymers are classified as polysaccharides such as chitosan, cellulose, starch, xanthan, dextran, alginate; polypeptides such as collagen, gelatin, silk, zein, albumin; polynucleotides such as DNA, RNA and polyesters like polylactic acid, polyhydroxyalkanoates [1,8,9]. Physicochemical properties, structural factors, and composition of the biopolymer that defines its functional efficiency can be modulated to obtain the appropriate efficiency. For example, the electrical characteristics of the biopolymer influence the repulsion rate, aggregation, and interaction with other molecules [2,10]. Biopolymers obtained from renewable sources are easily biodegradable due to their structural backbone comprising of oxygen and nitrogen atoms. Upon biodegradation, biopolymers release water, carbon dioxide, biomass, humid mass, and some natural substances as metabolites that are naturally recycled by biological processes .
Polysaccharide based biopolymers are abundantly available and are highly used in pharmaceutical and biomedical fields. They are cheap, biocompatible, and show low or no toxicity. For tailoring of the functional attributes, the natural polysaccharides can be modulated by physical, chemical, or enzymatic alterations [12,13]. Different polysaccharides used as biopolymers are Agarose, Gum Arabic, Tragacanth, Alginate, Gellan gum, Chitin/Chitosan, Starch, Carrageenan, Dextran, Bacterial Cellulose, Nanocellulose, Xanthan gum.
Agarose: Agarose is a natural polysaccharide obtained from the Gelidium and Gracilario species of seaweed. Agarose hydrogel nanoparticles are potential systems for the delivery of protein and peptide drugs due to their high biocompatibility .
Gum arabic: Gum arabic is a complex exudate obtained from the stems and branches of Acacia senegal and Acacia seyal. It is highly used to cover the inflamed surfaces on the external application and for the treatment of intestinal mucosal inflammation on internal application. It is used as a promising agent in tissue engineering and drug delivery. Gum arabic is also tailorable to suit pH-responsive features and magnetic biomaterial development [1,15]. It is also claimed to have a gut, cardio, dental, nephronprotective effects along with antimicrobial and antioxidant properties .
Alginate: Alginate is one of the abundantly available biopolymers obtained from brown seaweed. This is a water-soluble exudate that has been extensively biosynthesized and used in the development of several drug delivery and biomedical systems. Alginate is an anionic charge biopolymer comprising of mannuronic acid and guluronic acid blocks [17-19]. Properties like solubility, hydrophobicity, and biological functionality are altered by modifying the availability of hydroxyl and carboxyl groups in its structure . Alginate hydrogels are of high interest in the research area due to its unique properties of porosity, swelling nature, biocompatibility, biodegradability, non-antigenicity and is also useful in tissue engineering and regeneration. Alginates are also having applications in dentistry . Being approved by the U.S. Food and Drug Administration (FDA), alginate is used as a biomaterial in pharmaceutical, regenerative medicine, and biomedical applications. Alginate’s ability to rapidly convert as a gel in the presence of divalent cations e.g., calcium made it a highly used biopolymer for nanoparticles and microparticles preparation through the ion-gelation method. The formation of polyelectrolyte complexes due to anionic charge of alginate and cationic charge of chitosan has been widely reported .
Carrageenan: Carrageenan, a gelling and viscous polysaccharide, is obtained from the seaweeds of the Rhodophyceae family . It is a sulphated polygalactan showing 3 types (κ-, ι- and λ-) with varied percentage of ester sulfate content, 15-40 %. The difference in gelling properties of carrageenan is attributed to the variation in sulfate groups and anhydrous links .
Hyaluronic acid: Hyaluronic acid, a biocompatible and biodegradable mucoadhesive biopolymer of polysaccharide category, is a U.S. FDA approved material and is present in the extracellular matrix and joints of mammals . It shows a negative charge and is used in polyelectrolyte complex formation with other opposite charged polymers. It is also used as a copolymer for better drug delivery. It is known for several applications like wound healing, tissue regeneration, ophthalmic treatment, intraarticular injections, etc [24-27]. Modified hyaluronic acid has been reported for its application as a dental implant, ocular lenses, catheters, dermal regeneration, etc [1,28,29].
Gellan gum: Gellan gum a biopolymer obtained from Pseudomonas elodea (or Sphingomonas elodea). It is used in colon-specific drug delivery as it is stable over the upper GI environment. It is preferred for better application in combination with other biopolymers like xanthan gum and chitosan [12,30-33].
Inulin: Inulin is a natural substance obtained from vegetables and is recognized for its probiotic effect. It is applicable for colon targeted delivery due to its stable nature in the stomach and intestine on partial hydrolysis .
Chitosan: Chitosan, a cationic polysaccharide is a derivative of chitin which is initially isolated from the mushroom. Chitin is insoluble and its deacetylated form chitosan is water-soluble. After cellulose, chitin is the most abundant biopolymer obtained from different sources like yeast, fungi, insects, crustaceans (e.g., crabs, lobsters, shrimps), shellfish, and nematodes. Chitosan has gained its importance in several biomedical and pharmaceutical applications and also reported with some therapeutic actions (anti-bacterial, anti-acid, dental). Its electrostatic properties are favorable for the development of hybrid systems. The availability of chitosan in different molecular grades and degree of acetylation enable it for the fabrication of biocomposites [1,12,34-44].
Glucans: Glucan is a natural abundant homopolymer mainly obtained from the yeast Saccharomyces cerevisiae. In addition to its use as a biopolymer, glucan is reported for several therapeutic advantages like anti-viral, antitumor, and anti-infective actions [34,45-47].
Cellulose: Cellulose is the most abundant polysaccharide biopolymer of glucose available as the main constituent of plants and natural fibers like cotton and linen. Chemically identical cellulose is also obtained from bacterial sources like Acetobacter xylinum however there are some differences in macromolecular structure and physical properties . Cellulose comprises of linear chains of β (1→4) linked D-glucose units ranging from hundreds to thousands . Biomedically relevant cellulose fibers in use are natural cotton fibers, regenerated cellulose fibers like modal, viscose, and lyocell . Cellulose is a resource for the development of several other derivatives like methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, etc. which are very popular in many pharmaceutical and biomedical applications .
Xylan: Xylan, another abundant biopolymer, is a hemicellulose polysaccharide predominantly available in plants and cereals. It is of high consideration in the development of colonic drug delivery systems because colonic microflora produces enzymes that can cause its biodegradation. Hence, xylan issued as a colonic specific biopolymer . Xylans are also reported for their physiological effects like the bulking effect of feces, lowering of blood cholesterol, decreasing of postprandial glucose, and immune responses .
Starch: Starch is the cheap and abundant biopolymer available in nature and is obtained from plant sources (e.g., cereals/grains/tubers/legumes/roots/fruits) with cereals being the main source [52-55]. It contains two polysaccharides namely amylose (linear) and amylopectin (branched). Starch is suitable for physical, chemical, or enzymatic modifications to achieve specific functional characteristics as modified starch that suit the biomedical and pharmaceutical applications . Starch is widely used in targeted as well as controlled delivery of drugs and bioactive through its fabrication as nanoparticles, microparticles, inclusion complexes, composites, etc. [56-58]. Thermoplastic starch is blended with fatty acids of a long-chain component to enhance its compatibility .
Xanthan: Xanthan gum is another natural biopolymer of the polysaccharide category that is obtained from Xanthomonas campestris bacteria. It has a thickening ability and shows pseudoplastic flow .
Dextran: Dextran is a polysaccharide biopolymer of neutral hydrophilic nature. Modification of dextran is possible due to its huge number of hydroxyl moieties which may alter the characteristics like solubility [12,60-62].
Pectin: Pectin is a natural heteropolysaccharide present in the cell walls of the primary level in terrestrial plants (almost all non-woody parts). The major component of pectin includes galacturonic acids. Pectin has multiple biomedical and pharmaceutical applications in combination with other polymers. The modified pectin shows altered gelation, degradation, and physical characteristics based on the degree of esterification. Pectin is of prime importance in developing colon-specific drug delivery systems, tissue engineering, and controlled release systems [1,12,63,64].
Pullulan: Pullulan is a water-soluble biopolymer obtained from fungus Aurobasidium pullulans. Its main component is maltotriose. It shows solubility in organic solvents, unlike other polysaccharides. Pullulan is having pharmaceutical and biomedical applications with modifications and composite forms (e.g., antitumor, anticancer effects, and medical devices) [65-70].
Polypeptide biopolymers are of emerging filed in addition to polysaccharides for biomedical and pharmaceutical applications. Polypeptides are of natural origin and can be modified to alter the functional attributes by physical, chemical, or enzymatic changes. These are biodegradable, biocompatible, and ensures wide applications in the fields of medicine and pharmacy. However, more stability concern is required for polypeptides (e.g., environments like varying pH, ionic strength, temperature) [12,71-76].
Albumin: Albumin is the animal-derived protein with functional groups like carboxylic acid, thiol, and amino groups which allows addition/entrapment of active substances. Albumin is a water-soluble globular protein with slight solubility in salt solutions [12,72].
Casein: Casein is the natural protein obtained from milk and is used in combination with other biopolymers for its biomedical and pharmaceutical applications .
Collagen: Collagen is the most abundant mammalian protein and is the primary structural material of vertebrates. Its contribution counts for about 20-30% of the total body proteins. It has very low antigenicity in addition to properties like biodegradability, biocompatibility, nontoxicity and is also easily absorbable in the body due to its high affinity towards water [1,77-80].
Gelatin: Gelatin is a cheap and water-soluble protein obtained from collagen (derived from skin, bones, connective tissues of animals like sheep, pig, cattle, and fish) upon acidic or alkaline hydrolysis. It is available with varying strengths, isoelectric points and can undergo cross-linking with glutaraldehyde or formaldehyde which shows a decrease in dissolution or solubility for controlled release of the encapsulated agent favoring prolonged therapeutic effect. It is also used in combination with other biopolymers [1,81].
Fibroin: Fibroin is one of the widely used biopolymers in the biomedical field due to its thermal stability in addition to biocompatibility and biodegradability. It has also been reported for its anti-microbial properties. It is also used in combination with other biopolymers like albumin to fabricate the particular systems [12,82].
Whey protein: Whey protein is also commonly used for the formation of biopolymer particulate systems through thermal treatments like denaturation or cold-set gelation. It is used for the encapsulation of probiotics. It is also used in combination with other biopolymers like alginate to develop carriers for the delivery of bioactive compounds .
Plant-derived proteins: Plant-derived proteins show the lesser risk of contamination and infection in comparison with animal-derived proteins and also these are cheaper. These proteins gain values in vegetarian or vegan products. Zein and gliadin are the best examples for water-insoluble, biodegradable, and biocompatible plant-derived proteins that are useful in the development of biopolymer particles for encapsulation of active ingredients. These systems are further stabilized by emulsifiers to have good physical stability across varying pH conditions [84-90].
Soy protein and pea legumin: These proteins derived from plants are also useful in the development of biopolymer particles. Combinations of these substances with other biopolymers are also reported for the fabrication of certain particulate systems to deliver active ingredients like nutraceuticals [12,91-93].
Silk sericin: Silk sericin is the natural protein biopolymer obtained from silkworm namely Bombyx mori. It surrounds two fibroin filaments and keeps them together in a cocoon. The sericin discarded by the textile industry has been noted for recovery and reuse in scientific applications like the biomedical field, food, and cosmetic industry. It is known as a biomaterial for its wound healing, tissue engineering, cell proliferation, drug delivery, and some therapeutic effects [94-100].
Polynucleotides like DNA and RNA (comprising of 13 or even more nucleotide monomers) are also a part of biopolymers that have applications in the biomedical field .
Lipids and Biopolymer Functionalization
Type of lipids used in biopolymer composites
Being natural resources, the application of lipids has been enormously growing in the area of biomedical and pharmaceutical applications. The main reason for the interest shown by the researchers is that lipids play a key role in cellular construction and functions. Hence, the biocompatibility of lipid biopolymers is well appreciable with less toxicity. Different categories of lipids include simple, compound, and derived lipids are presented in (Figure 1) .
Searching for or synthesizing a new material is always a tedious and cumbersome strategy to meet the desired properties. Rather, it is comparatively better to tailor the properties of existing and established materials to achieve the expected outcomes. In a scientific sense, it can be called “functionalization”, which means adding new properties, functions, features, or capabilities to the existing material by modulating the physical, chemical or biological parameters of the material. Sometimes a compromising achievement can be obtained by such a concept. In the present chapter, functionalization through physical and chemical means of blends/composites by forming hybrid structures will be discussed, with more emphasis on biopolymer-lipid based systems. The main aim of using composites of different polymers is to establish combined functions in the hybrid system. The positive features of each polymer will be combined to the system thereby neutralizing or minimizing the undesired functions, hence, increasing the performance of the developed system. For example, the addition of polyethylene glycol chains to liposomes renders them sterically stable and increases the circulation times for prolonged therapy.
Polysaccharide with polysaccharide composite: Alginate composite with chitosan is a well-reported combination of biopolymers for improved properties of the system. This composite is used for bone tissue repair. The cationic chitosan combines with the anionic alginate forming a polyelectrolyte complex showing improved mechanical properties and cell proliferation. The concentration of alginate in the composite defines the pore size of the alginate-chitosan scaffold .
Polysaccharide with protein composite: Alginate has been chemically modified (by methacrylate) to obtain control over the degradation rate, mechanical and swelling properties. It is further combined with the collagen to develop hydrogels demonstrating higher mechanical moduli, improved cell proliferation, osteogenic differentiation, decreased swelling ratios on comparison with pure methacrylated alginate hydrogel [101-103]. The gelatin in combination with sodium alginate as scaffolds for bone tissue engineering has shown better cell proliferation, mineral modules formation, and type 1 collagen expression . Cell adhesion and proliferation of the chemically developed sodium alginate-gelatin scaffolds (using a saturated ethanolic solution of calcium chloride) were found to be better than with conventionally developed scaffolds. So, the preparation method of systems also influences performance [101,105]. Alginate covalently cross-linked with heparin (by using ethylenediamine) has produced a new matrix that has shown a controlled release of active basic fibroblast growth factor for 1 month in cell-based experiments . Microcrystalline cellulosesilk fibroin composite films were developed for improved tensile strength which is 5 times more than that of films prepared by cellulose alone or fibroin alone .
Biopolymer-synthetic polymer functionalization: Chitosan in combination with biodegradable polymers, polylactic acid (PLA), and keratin has been used for the development of a novel composite as a PLA matrix for tissue engineering and artificial bone reconstruction. The combination of chitosan with PLA matrix has shown improved Young modulus, increased hardness, and decreased tensile strength of PLA. Keratin incorporation resulted in enhancement of impact strength, increased hardness, decreased tensile properties, and increased resistance to degradation. In addition to these mechanical properties, the biological assessment using a cell line (human osteosarcoma) also revealed that there area good viability and proliferation outcome. So, it is proved that the composite of chitosan-PLA-keratin has shown improved mechanical behavior and in vitro osteoblast response . Adding synthetic polymer to the biopolymer normally increases the mechanical strength of the composite system. For example, a combination of poly(Nisopropylacrylamide) with aminated alginate has produced a thermosensitive copolymer showing biocompatibility with mesenchymal stem cells .
Biopolymer-bioglass functionalization: Bioglass is a bioactive osteoconductive material (allogenic and alloplastic bone graft substitutes) that shows osteoproductive effects. The drawback of the bioglass material is lack of cohesiveness. Hence, the composite formation of bioglass with biopolymers has been augmented. One such development is the combination of bioglass with medium molecular weight dextran which shown putty consistency and improved handling features without any adverse influence on the bioactive functions of bioglass or bone regeneration .
Biopolymer-ceramic functionalization: Scaffolds for tissue and bone engineering are developed in a combination with biopolymer with ceramic materials due to their biocompatibility and osteoconductive properties. Since alginate scaffolds alone have poor mechanical strength, the combination of alginate with inorganic substances has shown improved properties. Alginate mixed with hydroxyapatite is one such combination that has shown excellent applications in bone tissue engineering, cell delivery, growth factor delivery, and wound healing in biomedicine. Thus, the obtained composite scaffold can provide suitable optimal conditions for new bone tissue generation via cell proliferation, mechanical strength, and surface morphology [111,112].
Biopolymer-lipid functionalization: The combination of biopolymers with lipids has been emerged as a novel concept a decade ago and still a promising area for improvements in the field of biomedical and pharmaceutical applications (Fig.2). Lipids contribute their positive factors to the biopolymers and the biopolymers enhance the properties of lipids which in total result in the functionalization of the composite for better performance. Not only with biopolymers, but it is also the case with synthetic polymers too. For example, unsaturated polyester resin, a synthetic polymer is of thermosetting nature which is abundantly available, cheap, easy to process, and shows good mechanical, chemical, and electrical properties, however, it suffers from the problem of being hard in nature. To gain flexibility in that synthetic polymer, it is mixed with lipid (e.g., castor oil) [59,113]. Another example from the biopolymer category is starch, which is a thermoplastic natural polymer (thermoplastic starch) obtained by extrusion of native starch using water, sorbitol, or glycerol as plasticizers).  The drawback of such thermoplastic starch utility in bioplastics is its hydrophilicity and strong brittle nature. Upon the formation of starch triacetate, the hydrophobic nature is obtained but the brittleness problem became still worse even after adding plasticizers . Hence, esterification of the starch with fatty acids was attempted and got successful with the result of strong hydrophobicity, flexibility with low glass transition temperature, film formability, even in the absence of plasticizers [116,117]. In the above example, properties of the polymer are modulated by mixing with lipids. As a vice versa strategy, here is an example. Chitosan can be added to olive oil emulsion films to obtain stable olive oil emulsion with homogeneous, thin, and translucent films formation as reported by Pereda et al. The enhanced properties were confirmed by examination of its tensile properties like tensile strength, Young modulus, and maximum elongation. The emulsifying property of chitosan resulted in stability enhancement of emulsion .
Spotlight on Biopolymer- Lipid Functionalised Carriers Designed for Gastro Retentive Drug Delivery Systems
Selenium (Se) is recognised for gastroprotection and in a recent study Selenium nanoparticles embedded chitosan microspheres (SeNPs-CM) were developed and their gastroprotective potential was evaluated. SeNPs with a nanosize range of 60 nm were loaded into CS-microspheres sucessfully and Se released from the microspheres was confirmed in gastric conditions. SeNPs-CM pre-treatment significantly attenuate the ethanol-induced gastric mucosal damage, based on histological evaluation. Further reduction in lipid peroxidation, the augmentation in antioxidant enzymatic activity as well as decreasing aggressive nitric oxides (NO) were even observed . In another study, amoxicillin that is most commonly used for H.pylori infection is often degrdaded by acidic pH of stomach, therefore to prevent his amoxicillin was encapsulated in biopolymer functionalised with lipid for more retention at site of infection and protect from stomach acids. ween 80 and linolenic acid were used as potential therapeutic adjuvants and dioleoylphosphatidylethanolamine as a targeting agent to Helicobacter pylori. The optimised formulation was found to be stable for at least 6 months at 4°C. In vitro release studies revealed a high resistance to harsh conditions, including acidic pH and physiologic temperature as well. The studies even confirmed that these nanoparticles have a low cytotoxicity effect in both fibroblasts and gastric cell lines, and indicated potential to be retained at the gastric mucosa . In another study, a polymeric nano-micelle was prepared to prevent antibiotic clarithromycin degradation against H.pylori infection. The conjugate is carboxymethyl chitosan (CMCS) that was hydrophobically modified with stearic acid (SA), and the obtained CMCS-g-SA co-polymers was further conjugated with urea to acquire U-CMCS-g-SA co-polymers. The conjugate showed no cell toxicity to AGS cells and was able to maintain a stable particle size for 6h in simulated gastric fluid and for 24h in PBS. The grafted ureido groups conferred effective targeting to H. pylori and in vitro inhibitory assay indicated enhanced anti-H. pylori activity by using the developed nano-micelle .
Using a liquid multi-layering process, floating and bioadhesive drug delivery system was designed and composed of a hollow spherical shell, a waterproof layer (Stearic acid), a drug layer (Ofloxacin), a release retarding film (the novel blended coating materials) and a bioadhesive layer (Carbomer 934P) was prepared. The formulation was suceesful and solved the problem of the initial burst release of the formulation and indicated sustained release with a retention in stomach for more than 6 h . In a different study, novel composite sponges of chitosan (CH)- chondroitin sulfate (CS) as a low-density gastroretentive delivery system for lornoxicam (LOR) was reported. The triple anti-inflammatory therapy-loaded matrices was able to expand and float upon contact with gastric fluids for prolonged time upto 12 h. Further, the magnetiteloaded sponges was monitored in healthy volunteers via MRI proving their gastroretentivity for at least 5h . To enhance the oral bioavailability of atorvastatin and protect from incomplete intestinal absorption and gut wall extraction, a optimised tablet formulation containing hypromellose, sodium bicarbonate, polyethylene oxide, docusate sodium, mannitol, crosscarmellose sodium, and magnesium stearate was prepared. The tablet gave floating lag time of 56 ± 4.16 s and good matrix integrity with in vitro dissolution of 98.2% in 12 h. The in-vivo rabbit studies revealed that floating tablets showed 1.6 times more bioavailability in comparison to the conventional tablet (Storvas® 80 mg tablet) . Hollow and bioadhesive microspheres composed fo ethylcellulose (matrix), Eudragit and glyceryl monooleate (GMO) as polymer in-situ were developed and had proved lengthen drug retention time in the stomach. The microspshere showed strong mucoadhesive properties with good buoyancy both in vitro and in vivo indicating advantageous in the treatment of stomach diseases . Oil entrapped floating microbeads as gastro retentive controlled release system composed of polymer ratio of 2.5:1.5 (pectin/ sodium alginate) by mass, 15% (m/V) of oil (mineral oil or castor oil) and 0.45 mol L(-1) calcium chloride solution was prepared for loratadine. In vitro drug release in the fed state conditions demonstrated sustained release of loratadine for 8 h, which best fitted the Peppas model with n<0.45 .
With the existing reports and successful journey, there is a lot of scope for future progress utilizing the probabilities of a combination of biopolymer and lipid systems for better therapeutic efficiency with minimized or no adverse effects in treatment of gastric diseases. There is a need to understand the complete mechanism for the enhanced properties and optimization strategies. Applying the existing concepts in different routes of administration and different disease conditions has yet to be explored to identify the best-synchronized applications. The utilization of the novel analytical methods for a better understanding of the influence of formulation parameters on the performance of the hybrid systems has to be established well. Even with the high-end technologies available today, there is the least commercialization of the products which indicates that the research
Biopolymer-lipid-based systems have shown remarkable applications in the pharmaceutical fields covering several areas drug delivery, and gene delivery. The reasons for the versatility of these hybrid systems include biocompatibility, biodegradability, improved stability, combined advantages of individual systems, well-defined control over drug release, prolonged residence, and targeted delivery especially for gastric diseases. With the advancements in the technology and availability of abundant biopolymers and lipids, this area has more scope for the development of novel systems with commercializing features.
Conflict of Interest
The authors declare no conflicts of interest.
2. Wróblewska-Krepsztul J, Rydzkowski T, MichalskaPożoga I, Thakur VK. Biopolymers for biomedical and pharmaceutical applications: recent advances and overview of alginate electrospinning. Nanomaterials. 2019 Mar;9(3):404.’
3. Fernando IS, Kim D, Nah JW, Jeon YJ. Advances in functionalizing fucoidans and alginates (bio) polymers by structural modifications: A review. Chemical Engineering Journal. 2019 Jan 1;355:33-48.
4. Bayer IS. Thermomechanical properties of polylactic acid-graphene composites: A state-of-the-art review for biomedical applications. Materials. 2017 Jul;10(7):748.
5. Udenni Gunathilake TM, Ching YC, Ching KY, Chuah CH, Abdullah LC. Biomedical and microbiological applications of bio-based porous materials: A Review. Polymers. 2017 May;9(5):160.
6. Gigli M, Fabbri M, Lotti N, Gamberini R, Rimini B, Munari A. Poly (butylene succinate)-based polyesters for biomedical applications: A review. European Polymer Journal. 2016 Feb 1;75:431-60.
7. Dubey SP, Thakur VK, Krishnaswamy S, Abhyankar HA, Marchante V, Brighton JL. Progress in environmentalfriendly polymer nanocomposite material from PLA: Synthesis, processing and applications. Vacuum. 2017 Dec 1;146:655-63.
8. Kaewkannetra P. Fermentation of sweet sorghum into added value biopolymer of polyhydroxyalkanoates (PHAs). Products and Applications of Biopolymers. 2012 Mar 7:41-60.
9. Ramesh BN, Anitha N, Rani HK. Recent trends in biodegradable products from biopolymers. Adv Biotechnol. 2010;9:30-4.
10. Jones OG, McClements DJ. Functional biopolymer particles: design, fabrication, and applications. Comprehensive Reviews in Food Science and Food Safety. 2010 Jul;9(4):374-97.
11. Gross RA, Kalra B. Biodegradable polymers for the environment. Science. 2002 Aug 2;297(5582):803-7.
12. Kurakula M, Naveen NR. Prospection of recent chitosan biomedical trends: Evidence from patent analysis (2009–2020). International Journal of Biological Macromolecules. 2020 Oct 15.
13. Oh JK, Lee DI, Park JM. Biopolymer-based microgels/ nanogels for drug delivery applications. Progress in Polymer Science. 2009 Dec 1;34(12):1261-82.
14. Wang N, Wu XS. Preparation and characterization of agarose hydrogel nanoparticles for protein and peptide drug delivery. Pharmaceutical Development and Technology. 1997 Jan 1;2(2):135-42.
15. Paulino AT, Guilherme MR, Mattoso LH, Tambourgi EB. Smart hydrogels based on modified gum arabic as a potential device for magnetic biomaterial. Macromolecular Chemistry and Physics. 2010 Jun 1;211(11):1196-205.
16. Patel S, Goyal A. Applications of natural polymer gum arabic: a review. International Journal of Food Properties. 2015 May 4;18(5):986-98.
17. Hasnain MS, Nayak AK, Kurakula M, Hoda MN. Alginate nanoparticles in drug delivery. InAlginates in Drug Delivery 2020 Jan 1 (pp. 129-152). Academic Press.
18. Agüero L, Zaldivar-Silva D, Peña L, Dias ML. Alginate microparticles as oral colon drug delivery device: A review. Carbohydrate Polymers. 2017 Jul 15;168:32-43.
19. Hasnain MS, Kiran V, Kurakula M, Rao GK, Tabish M, Nayak AK. Use of alginates for drug delivery in dentistry. InAlginates in Drug Delivery 2020 Jan 1 (pp. 387-404). Academic Press, 2020.
20. Yang JS, Xie YJ, He W. Research progress on chemical modification of alginate: A Review. Carbohydrate Polymers. 2011 Feb 11;84(1):33-9.
21. Kurakula M, Rao GK, Kiran V, Hasnain MS, Nayak AK. Alginate-based hydrogel systems for drug releasing in wound healing. InAlginates in Drug Delivery 2020 Jan 1 (pp. 323-358). Academic Press, 2020.
22. Burey P, Bhandari BR, Howes T, Gidley MJ. Hydrocolloid gel particles: formation, characterization, and application. Critical Reviews in Food Science and Nutrition. 2008 May 8;48(5):361-77.
23. Ito T, Iida-Tanaka N, Koyama Y. Efficient in vivo gene transfection by stable DNA/PEI complexes coated by hyaluronic acid. Journal of Drug Targeting. 2008 Jan 1;16(4):276-81.
24. Price RD, Berry MG, Navsaria HA. Hyaluronic acid: the scientific and clinical evidence. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2007 Oct 1;60(10):1110-9.
25. McDonald CC, Kaye SB, Figueiredo FC, Macintosh G, Lockett C. A randomised, crossover, multicentre study to compare the performance of 0.1%(w/v) sodium hyaluronate with 1.4%(w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome. Eye. 2002 Sep;16(5):601-7.
26. Aragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren’s syndrome patients. British Journal of Ophthalmology. 2002 Aug 1;86(8):879- 84.
27. Bray BA. The role of hyaluronan in the pulmonary alveolus. Journal of Theoretical Biology. 2001 May 7;210(1):121-30.
28. Baier LJ, Christine SE. Hyaluronan, Encyclopedia of Biomaterials and Biomedical Engineering. USA, Texas, DO. 2004;10.
29. Abdelhady S, Honsy KM, Kurakula M. Electro spunnanofibrous mats: a modern wound dressing matrix with a potential of drug delivery and therapeutics. Journal of Engineered Fibers and Fabrics. 2015 Dec;10(4):155892501501000411.
30. Coutinho DF, Sant S, Shakiba M, Wang B, Gomes ME, Neves NM, et al. Microfabricated photocrosslinkable polyelectrolyte-complex of chitosan and methacrylated gellan gum. Journal of Materials Chemistry. 2012;22(33):17262-71.
31. Nag A, Han KS, Singh H. Microencapsulation of probiotic bacteria using pH-induced gelation of sodium caseinate and gellan gum. International Dairy Journal. 2011 Apr 1;21(4):247-53.
32. Yang F, Xia S, Tan C, Zhang X. Preparation and evaluation of chitosan-calcium-gellan gum beads for controlled release of protein. European Food Research and Technology. 2013 Oct;237(4):467-79.
33. Singh BN, Kim KH. Effects of divalent cations on drug encapsulation efficiency of deacylated gellan gum. Journal of Microencapsulation. 2005 Jan 1;22(7):761-71.
34. Gopal Rao M, Bharathi P, Akila RM. A Comprehensive Review on Biopolymers, Sci. Revs. Chem. Commun. 2014;4(2):61-8.
35. Kurakula M, El-Helw AM, Sobahi TR, Abdelaal MY. Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy. International Journal of Nanomedicine. 2015;10:321.
36. Domard A, Domard M. Chitosan: structure-properties relationship and biomedical applications. Polymeric Biomaterials. 2001 Nov 29;2:187-212.
37. Alhakamy NA, Ahmed OA, Kurakula M, Caruso G, Caraci F, Asfour HZ, et al. Chitosan-based microparticles enhance ellagic acid’s colon targeting and proapoptotic activity. Pharmaceutics. 2020 Jul;12(7):652.
38. Campana-Filho SP, Britto DD, Curti E, Abreu FR, Cardoso MB, Battisti MV, et al. Extração, estruturas e propriedades de alfa-e beta-quitina. Química Nova. 2007 Jun;30(3):644-50.
39. Alhakamy NA, Fahmy UA, Ahmed OA, Caruso G, Caraci F, Asfour HZ, et al. Chitosan coated microparticles enhance simvastatin colon targeting and pro-apoptotic activity. Marine Drugs. 2020 Apr;18(4):226.
40. Hamman JH. Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Marine Drugs. 2010 Apr;8(4):1305-22.
41. Kong M, Chen XG, Xing K, Park HJ. Antimicrobial properties of chitosan and mode of action: a state-of-theart review. International Journal of Food Microbiology. 2010 Nov 15;144(1):51-63.
42. Kurakula M, Naveen NR. In situ gel loaded with chitosan-coated simvastatin nanoparticles: Promising delivery for effective anti-proliferative activity against tongue carcinoma. Marine Drugs. 2020 Apr;18(4):201.
43. Sano H, Shibasaki KI, Matsukubo T, Takaesu Y. Effect of chitosan rinsing on reduction of dental plaque formation. The Bulletin of Tokyo Dental College. 2003;44(1):9-16.
44. Naveen NR, Kurakula M, Gowthami B. Process optimization by response surface methodology for preparation and evaluation of methotrexate loaded chitosan nanoparticles. Materials Today: Proceedings. 2020 Mar 6.
45. Seviour RJ, Stasinopoulos SJ, Auer DP, Gibbs PA. Production of pullulan and other exopolysaccharides by filamentous fungi. Critical Reviews in Biotechnology. 1992 Jan 1;12(3):279-98.
46. Klis FM, Groot PD, Hellingwerf K. Molecular organization of the cell wall of Candida albicans. Medical Mycology. 2001 Jan 1;39(1):1-8.
47. McIntosh M, Stone BA, Stanisich VA. Curdlan and other bacterial (1→ 3)-β-D-glucans. Applied Microbiology and Biotechnology. 2005 Aug;68(2):163-73.
48. Tomšič B, Simončič B, Orel B, Vilčnik A, Spreizer H. Biodegradability of cellulose fabric modified by imidazolidinone. Carbohydrate Polymers. 2007 Jun 25;69(3):478-88.
49. Kurakula M, A Ahmed T. Co-delivery of atorvastatin nanocrystals in PLGA based in situ gel for antihyperlipidemic efficacy. Current Drug Delivery. 2016 Mar 1;13(2):211-20.
50. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003 Nov 1;24(24):4337-51.
51. Ebringerová A, Hromádková Z. Xylans of industrial and biomedical importance. Biotechnology and Genetic Engineering Reviews. 1999 Apr 1;16(1):325-46.
52. Odeniyi MA, Omoteso OA, Adepoju AO, Jaiyeoba KT. Starch nanoparticles in drug delivery: A review. Polim. W Med. 2018 Jan 1;48:41-5.
53. Smith AM. The biosynthesis of starch granules. Biomacromolecules. 2001 Jun 11;2(2):335-41.
54. Santana ÁL, Meireles MA. New starches are the trend for industry applications: a review. Food and Public Health. 2014 Oct;4(5):229-41.
55. Ghorui S, Bandyopadhyay NR, Ray D, Sengupta S, Kar T. Use of maleated castor oil as biomodifier in unsaturated polyester resin/fly ash composites. Industrial Crops and Products. 2011 Jul 1;34(1):893-9.
56. de Vos P, Faas MM, Spasojevic M, Sikkema J. Encapsulation for preservation of functionality and targeted delivery of bioactive food components. International Dairy Journal. 2010 Apr 1;20(4):292-302.
57. Kasemwong K, Itthisoponkul T. Encapsulation of flavor compounds as helical inclusion complexes of starch. InAdvances in applied nanotechnology for agriculture 2013 (pp. 235-245). American Chemical Society.
58. Sun-Waterhouse D, Wadhwa SS, Waterhouse GI. Spray-drying microencapsulation of polyphenol bioactives: a comparative study using different natural fibre polymers as encapsulants. Food and Bioprocess Technology. 2013 Sep;6(9):2376-88.
59. Zia KM, Zia F, Ali M, Rehman S, Zuber M. Lipid functionalized biopolymers: A review. International Journal of Biological Macromolecules. 2016 Dec 1;93:1057- 68.
60. Suarez S, Grover GN, Braden RL, Christman KL, Almutairi A. Tunable protein release from acetalated dextran microparticles: a platform for delivery of protein therapeutics to the heart post-MI. Biomacromolecules. 2013 Nov 11;14(11):3927-35.
61. Naveen NR, Gopinath C, Kurakula M. Okra- Thioglycolic acid conjugate—Synthesis, characterization, and evaluation as a mucoadhesive polymer. Processes. 2020 Mar;8(3):316.
62. Broaders KE, Cohen JA, Beaudette TT, Bachelder EM, Fréchet JM. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proceedings of the National Academy of Sciences. 2009 Apr 7;106(14):5497-502.
63. Chen CH, Sheu MT, Chen TF, Wang YC, Hou WC, Liu DZ, et al. Suppression of endotoxin-induced proinflammatory responses by citrus pectin through blocking LPS signaling pathways. Biochemical Pharmacology. 2006 Oct 16;72(8):1001-9.
64. Salman H, Bergman M, Djaldetti M, Orlin J, Bessler H. Citrus pectin affects cytokine production by human peripheral blood mononuclear cells. Biomedicine & Pharmacotherapy. 2008 Nov 1;62(9):579-82.
65. Zhu F, Du B, Xu B. A critical review on production and industrial applications of beta-glucans. Food Hydrocolloids. 2016 Jan 1;52:275-88.
66. Leathers TD. Biotechnological production and applications of pullulan. Applied Microbiology and Biotechnology. 2003 Oct;62(5):468-73.
67. Su T, Wu L, Pan X, Zhang C, Shi M, Gao R, et al. Pullulan-derived nanocomposite hydrogels for wastewater remediation: Synthesis and characterization. Journal of Colloid and Interface Science. 2019 Apr 15;542:253-62.
68. Popa V. Polysaccharides in medicinal and pharmaceutical applications. Smithers Rapra; 2011 Jun 30.
69. Naguib GH, Hassan AH, Al-Hazmi F, Kurakula M, Al- Dharrabh A, Alkhalidi HM, et al. Zein based magnesium oxide nanowires: Effect of anionic charge on size, release and stability. Digest Journal of Nanomaterials and Biostructures. 2017 Jul 1;12(3):741-9.
70. Mishra B, Vuppu S, Rath K. The role of microbial pullulan, a biopolymer in pharmaceutical approaches: A review. J. Appl. Pharm. Sci. 2011;1(06):45-50.
71. Khan SA, Schneider M. Improvement of nanoprecipitation technique for preparation of gelatin nanoparticles and potential macromolecular drug loading. Macromolecular Bioscience. 2013 Apr;13(4):455- 63.
72. Jahanshahi M, Babaei Z. Protein nanoparticle: a unique system as drug delivery vehicles. African Journal of Biotechnology. 2008;7(25).
73. Sağlam D, Venema P, de Vries R, van der Linden E. Exceptional heat stability of high protein content dispersions containing whey protein particles. Food Hydrocolloids. 2014 Jan 1;34:68-77.
74. David-Birman T, Mackie A, Lesmes U. Impact of dietary fibers on the properties and proteolytic digestibility of lactoferrin nano-particles. Food Hydrocolloids. 2013 May 1;31(1):33-41.
75. Shpigelman A, Cohen Y, Livney YD. Thermallyinduced β-lactoglobulin–EGCG nanovehicles: Loading, stability, sensory and digestive-release study. Food Hydrocolloids. 2012 Oct 1;29(1):57-67.
76. Dhayal SK, Gruppen H, de Vries R, Wierenga PA. Controlled formation of protein nanoparticles by enzymatic cross-linking of α-lactalbumin with horseradish peroxidase. Food Hydrocolloids. 2014 May 1;36:53-9.
77. Harkness RD. Biological functions of collagen. Biological Reviews. 1961 Nov;36(4):399-455.
78. Lee CH, Singla A, Lee Y. Biomedical applications of collagen. International Journal of Pharmaceutics. 2001 Jun 19;221(1-2):1-22.
79. Friess W. Collagen–biomaterial for drug delivery. European Journal of Pharmaceutics and Biopharmaceutics. 1998 Mar 1;45(2):113-36.
80. Maeda M, Tani S, Sano A, Fujioka K. Microstructure and release characteristics of the minipellet, a collagenbased drug delivery system for controlled release of protein drugs. Journal of Controlled Release. 1999 Dec 6;62(3):313-24.
81. Mariod AA, Fadul H. Gelatin, source, extraction and industrial applications. Acta Scientiarum Polonorum Technologia Alimentaria. 2013 Jun 30;12(2):135-47.
82. Subia B, Kundu SC. Drug loading and release on tumor cells using silk fibroin–albumin nanoparticles as carriers. Nanotechnology. 2012 Dec 21;24(3):035103.
83. Chen L, Subirade M. Alginate–whey protein granular microspheres as oral delivery vehicles for bioactive compounds. Biomaterials. 2006 Sep 1;27(26):4646-54.
84. Regier MC, Taylor JD, Borcyk T, Yang Y, Pannier AK. Fabrication and characterization of DNA-loaded zein nanospheres. Journal of Nanobiotechnology. 2012 Dec;10(1):44.
85. Podaralla S, Perumal O. Influence of formulation factors on the preparation of zein nanoparticles. Aaps Pharmscitech. 2012 Sep;13(3):919-27.
86. Kurakula M, Basim P. Biopolymer-Lipid Hybrid Composites and their Advances in Bio-imaging and Drug Delivery. J Radiol Med Imaging. 2021: 4(1):1041.
87. Li KK, Yin SW, Yin YC, Tang CH, Yang XQ, Wen SH. Preparation of water-soluble antimicrobial zein nanoparticles by a modified antisolvent approach and their characterization. Journal of Food Engineering. 2013 Nov 1;119(2):343-52.
88. Chen L, Subirade M. Elaboration and characterization of soy/zein protein microspheres for controlled nutraceutical delivery. Biomacromolecules. 2009 Dec 14;10(12):3327-34.
89. Ezpeleta I, Irache JM, Stainmesse S, Chabenat C, Gueguen J, Popineau Y, et al. Gliadin nanoparticles for the controlled release of all-trans-retinoic acid. International Journal of Pharmaceutics. 1996 Apr 19;131(2):191-200.
90. Duclairoir C, Orecchioni AM, Depraetere P, Nakache E. α-Tocopherol encapsulation and in vitro release from wheat gliadin nanoparticles. Journal of Microencapsulation. 2002 Jan 1;19(1):53-60.
91. Pierucci AP, Andrade LR, Farina M, Pedrosa C, Rocha- Leão MH. Comparison of α-tocopherol microparticles produced with different wall materials: pea protein a new interesting alternative. Journal of Microencapsulation. 2007 Jan 1;24(3):201-13.
92. Liu F, Tang CH. Soy protein nanoparticle aggregates as pickering stabilizers for oil-in-water emulsions. Journal of Agricultural and Food Chemistry. 2013 Sep 18;61(37):8888-98.
93. Chen L, Hebrard G, Beyssac E, Denis S, Subirade M. In vitro study of the release properties of soy− zein protein microspheres with a dynamic artificial digestive system. Journal of Agricultural and Food Chemistry. 2010 Sep 8;58(17):9861-7.
94. Kunz RI, Brancalhão RM, Ribeiro LD, Natali MR. Silkworm sericin: properties and biomedical applications. BioMed Research International. 2016 Nov 14;2016.
95. Kundu SC, Dash BC, Dash R, Kaplan DL. Natural protective glue protein, sericin bioengineered by silkworms: potential for biomedical and biotechnological applications. Progress in Polymer Science. 2008 Oct 1;33(10):998-10 12.
96. Mondal M, Trivedy K, NIRMAL KS. The silk proteins, sericin and fibroin in silkworm, Bombyx mori Linn.,-a review.
97. Padol AR, Jayakumar K, Mohan K, Manochaya S. Natural biomaterial silk and silk proteins: applications in tissue repair. International Journal of Materials and Biomaterials Applications. 2012 Oct 2;2(4):19-24.
98. Altman GH, Diaz F, Jakuba C, Calabro T, Horan RL, Chen J, et al. Silk-based biomaterials. Biomaterials. 2003 Feb 1;24(3):401-16.
99. Nagaraju J, Goldsmith MR. Silkworm genomics– progress and prospects. Current Science. 2002 Aug 25:415-25.
100. Joseph B, Raj SJ. Therapeutic applications and properties of silk proteins from Bombyx mori. Frontiers in Life Science. 2012 Dec 1;6(3-4):55-60.
101. Basim P, Haware RV, Dave RH. Tablet capping predictions of model materials using multivariate approach. International Journal of Pharmaceutics. 2019 Oct 5;569:118548.
102. Jeon O, Bouhadir KH, Mansour JM, Alsberg E. Photocrosslinked alginate hydrogels with tunable biodegradation rates and mechanical properties. Biomaterials. 2009 May 1;30(14):2724-34.
103. Sun J, Xiao W, Tang Y, Li K, Fan H. Biomimetic interpenetrating polymer network hydrogels based on methacrylated alginate and collagen for 3D pre-osteoblast spreading and osteogenic differentiation. Soft Matter. 2012;8(8):2398-404.
104. Xia Y, Mei F, Duan Y, Gao Y, Xiong Z, Zhang T, et al. Bone tissue engineering using bone marrow stromal cells and an injectable sodium alginate/gelatin scaffold. Journal of Biomedical Materials Research Part A. 2012 Apr;100(4):1044-50.
105. Petrenko YA, Ivanov RV, Petrenko AY, Lozinsky VI. Coupling of gelatin to inner surfaces of pore walls in spongy alginate-based scaffolds facilitates the adhesion, growth and differentiation of human bone marrow mesenchymal stromal cells. Journal of Materials Science: Materials in Medicine. 2011 Jun 1;22(6):1529-40.
106. Tanihara M, Suzuki Y, Yamamoto E, Noguchi A, Mizushima Y. Sustained release of basic fibroblast growth factor and angiogenesis in a novel covalently crosslinked gel of heparin and alginate. Journal of Biomedical Materials Research: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials. 2001 Aug;56(2):216-21.
107. Noishiki Y, Nishiyama Y, Wada M, Kuga S, Magoshi J. Mechanical properties of silk fibroin–microcrystalline cellulose composite films. Journal of Applied Polymer Science. 2002 Dec 20;86(13):3425-9.
108. Tanase CE, Spiridon I. PLA/chitosan/keratin composites for biomedical applications. Materials Science and Engineering: C. 2014 Jul 1;40:242-7.
109. Tan R, She Z, Wang M, Fang Z, Liu Y, Feng Q. Thermo-sensitive alginate-based injectable hydrogel for tissue engineering. Carbohydrate Polymers. 2012 Jan 15;87(2):1515-21.
110. Chan C, Thompson I, Robinson P, Wilson J, Hench L. Evaluation of Bioglass/dextran composite as a bone graft substitute. International Journal of Oral and Maxillofacial Surgery. 2002 Feb 1;31(1):73-7.
111. Olderøy MØ, Xie M, Andreassen JP, Strand BL, Zhang Z, Sikorski P. Viscoelastic properties of mineralized alginate hydrogel beads. Journal of Materials Science: Materials in Medicine. 2012 Jul 1;23(7):1619-27.
112. Petrović M, Čolović B, Jokanović V, Marković D. Selfassembly of biomimetic hydroxyapatite on the surface of different polymer thin films. Journal of Ceramic Processing Research. 2012;13(4):398-404.
113. Liu C, Li J, Lei W, Zhou Y. Development of biobased unsaturated polyester resin containing highly functionalized castor oil. Industrial Crops and Products. 2014 Jan 1; 52:329-37.
114. Mitrus M. TPS and its nature. Thermoplastic Starch. 2009 Sep 3:77-104.
115. Whistler RL, Hilbert GE. Mechanical properties of films from amylose, amylopectin, and whole starch triacetates. Industrial & Engineering Chemistry. 1944 Sep;36(9):796-8.
116. Winkler H, Vorwerg W, Rihm R. Thermal and mechanical properties of fatty acid starch esters. Carbohydrate Polymers. 2014 Feb 15; 102:941-9.
117. Wolff IA, Olds DW, Hilbert GE. Triesters of corn starch, amylose, and amylopectin. Industrial & Engineering Chemistry. 1951 Apr;43(4):911-4.
118. Pereda M, Amica G, Marcovich NE. Development and characterization of edible chitosan/olive oil emulsion films. Carbohydrate Polymers. 2012 Jan 15;87(2):1318-25.
119. Bai K, Hong B, Tan R, He J, Hong Z. Selenium Nanoparticles-Embedded Chitosan Microspheres and Their Effects Upon Alcohol-Induced Gastric Mucosal Injury in Rats: Rapid Preparation, Oral Delivery, and Gastroprotective Potential of Selenium Nanoparticles. International Journal of Nanomedicine. 2020; 15:1187.
120. Lopes-de-Campos D, Pinto RM, Lima SA, Santos T, Sarmento B, Nunes C, et al. Delivering amoxicillin at the infection site–a rational design through lipid nanoparticles. International Journal of Nanomedicine. 2019; 14:2781.
121. Cong Y, Geng J, Wang H, Su J, Arif M, Dong Q, et al. Ureido-modified carboxymethyl chitosan-graft-stearic acid polymeric nano-micelles as a targeted delivering carrier of clarithromycin for Helicobacter pylori: Preparation and in vitro evaluation. International Journal of Biological Macromolecules. 2019 May 15; 129:686-92.
122. Zhang C, Tang J, Liu D, Li X, Cheng L, Tang X. Design and evaluation of an innovative floating and bioadhesive multiparticulate drug delivery system based on hollow structure. International Journal of Pharmaceutics. 2016 Apr 30;503(1-2):41-55.
123. Tadros MI, Fahmy RH. Controlled-release triple anti-inflammatory therapy based on novel gastroretentive sponges: characterization and magnetic resonance imaging in healthy volunteers. International Journal of Pharmaceutics. 2014 Sep 10;472(1-2):27-39.
124. Khan FN, Dehghan MH. Enhanced bioavailability of atorvastatin calcium from stabilized gastric resident formulation. Aaps Pharmscitech. 2011 Dec;12(4):1077-86.
125. Liu Y, Zhang J, Gao Y, Zhu J. Preparation and evaluation of glyceryl monooleate-coated hollowbioadhesive microspheres for gastroretentive drug delivery. International Journal of Pharmaceutics. 2011 Jul 15;413(1-2):103-9.
126. Mishra S, Pathak K. Formulation and evaluation of oil entrapped gastroretentive floating gel beads of loratadine. Acta Pharmaceutica. 2008 Jun 1;58(2):187-97.