Handbook of polymers for pharmaceutical Technologies Volume 3, Biodegradable Polymers 

Handbook of polymers for pharmaceutical technologies volume 3, biodegradable polymers

clinical trials. Moreover, there are already several commercial polysaccharides available, although most of them are marketed as natural products and their clinical use is still not widespread. Biodegradable polymeric systems as drug carriers are being envisioned as an appropriate tool for temporal and spatial controlled drug delivery. Th e targeted delivery of drugs has been made possible by confi ning drugs inside biodegradable nontoxic capsules by numerous techniques. Th ese approaches are demonstrated to be particularly eff ective in the treatment of cancer cells.
Unfortunately, despite impressive features and incontestable importance, the high pro-duction costs and inferior physico-mechanical properties of certain biodegradable poly-mers in comparison to other polymers are still obstacles for their widespread applications in industries and needs to be addressed. Th us, dedicated eff orts are still required for replac-ing various items of common usage with biodegradable materials, and the main future concern will be regarding the materials used for pharmaceutical applications. In medicine, where function is more important than cost—biobased materials have already been used in a few crucial applications. Scientists in collaboration with pharmaceutical industries are extensively developing diff erent types of biodegradable pharmaceutical materials. Th is third volume of Handbook of Polymers for Pharmaceutical Technologies is primarily focused on the biodegradable pharmaceutical polymers and deals with their diff erent physio-chemical, processing and application aspects. Numerous critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of biodegradable pharmaceutical polymers.  Th e prime topics extensively described herein include: bioactive polysaccharides of vegetable and microbial origins: an overview; chitosan: an emanating polymeric carrier for drug deliv-ery; fungi as sources of polysaccharides for pharmaceutical and biomedical applications; environmentally responsive chitosan-based nanocarriers (CBNS); biomass-derived and biomass-inspired polymers in pharmaceutical applications; current state on the potential use of chitosan as pharmaceutical excipient modifi cation of cyclodextrin for improvement of complexation and formulation properties; modifi cation of gums: synthesis techniques and pharmaceutical benefi ts of cellulosic, ethylene oxide and acrylic-based polymers in assembled module technology: structured biodegradable polymers for drug delivery; bio-materials for functional applications in the oral cavity via contemporary multidimensional science; role of polymers in ternary drug cyclodextrin complexes; collagen-based materials for pharmaceutical applications; and natural polysaccharides as pharmaceutical excipients.
We would like to thank Martin Scrivener of Scrivener Publishing for the invaluable help in the organization of the editing process.  We would also like to thank our parents for their continuous encouragement and support.

clinical trials. Moreover, there are already several commercial polysaccharides available, although most of them are marketed as natural products and their clinical use is still not widespread. Biodegradable polymeric systems as drug carriers are being envisioned as an appropriate tool for temporal and spatial controlled drug delivery. Th e targeted delivery of drugs has been made possible by confi ning drugs inside biodegradable nontoxic capsules by numerous techniques. Th ese approaches are demonstrated to be particularly eff ective in the treatment of cancer cells.
Unfortunately, despite impressive features and incontestable importance, the high pro-duction costs and inferior physico-mechanical properties of certain biodegradable poly-mers in comparison to other polymers are still obstacles for their widespread applications in industries and needs to be addressed. Th us, dedicated eff orts are still required for replac-ing various items of common usage with biodegradable materials, and the main future concern will be regarding the materials used for pharmaceutical applications. In medicine, where function is more important than cost—biobased materials have already been used in a few crucial applications. Scientists in collaboration with pharmaceutical industries are extensively developing diff erent types of biodegradable pharmaceutical materials. Th is third volume of Handbook of Polymers for Pharmaceutical Technologies is primarily focused on the biodegradable pharmaceutical polymers and deals with their diff erent physio-chemical, processing and application aspects. Numerous critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of biodegradable pharmaceutical polymers.  Th e prime topics extensively described herein include: bioactive polysaccharides of vegetable and microbial origins: an overview; chitosan: an emanating polymeric carrier for drug deliv-ery; fungi as sources of polysaccharides for pharmaceutical and biomedical applications; environmentally responsive chitosan-based nanocarriers (CBNS); biomass-derived and biomass-inspired polymers in pharmaceutical applications; current state on the potential use of chitosan as pharmaceutical excipient modifi cation of cyclodextrin for improvement of complexation and formulation properties; modifi cation of gums: synthesis techniques and pharmaceutical benefi ts of cellulosic, ethylene oxide and acrylic-based polymers in assembled module technology: structured biodegradable polymers for drug delivery; bio-materials for functional applications in the oral cavity via contemporary multidimensional science; role of polymers in ternary drug cyclodextrin complexes; collagen-based materials for pharmaceutical applications; and natural polysaccharides as pharmaceutical excipients.
We would like to thank Martin Scrivener of Scrivener Publishing for the invaluable help in the organization of the editing process.  We would also like to thank our parents for their continuous encouragement and support.

Bioactive Polysaccharides of Vegetable and Microbial Origins: An Overview

Th e bioactive compounds that are synthesized in nature, in order to protect a liv-ing organism, have been selected from a wide variety of possibilities until reaching optimal activity aft er several hundreds of million years. Th e high potential for some of these products suggested that they could play a dominant role in the discovery of lead compounds for the development of drugs for the treatment of human desease. Recently, some bioactive polysaccharides isolated from natural sources have attracted much attention in the fi eld of biochemistry and pharmacology: polysaccharides or their glycoconjugates were shown to exhibit multiple biological activities, including anticar-cinogenic, anticoagulant, immunostimulating, antioxidant, etc. 
Nowadays, the increased demand for the exploration and use of natural sources for white biotechnology processes has led to a renewed interest in biopoly-mers, in particular, in polysaccharides both of vegetable and microbial origins. Polysaccharides are naturally occurring polymers of aldoses and/or ketoses con-nected together through glycosidic linkages. Th ey are essential constituents of a living organisms and are associated with a variety of vital functions which sustain life. Th ese biopolymers possess complex structures because there are many types of inter-sugar linkages involving diff erent monosaccharide residues. In addition, they can form secondary structures which depend on the conformation of component sugars, molecular weight, inter- and intrachain hydrogen bondings. On the basis of structural criteria, it is possible to distinguish homoglycans and heteroglycans, if they are made up by the same type or by two or more types of monomer units; lin-ear and branched polymers, with diff erent degrees of branching; neutral or charged (cationic or anionic). Moreover, on the basis of their biological role, polysaccharide from vegetables can also be distinguished in structural elements, such as cellulose and xylans, and in energy-reserve polysaccharides such as starch and fructans. In the case of polysaccharides produced by microorganisms, they can be classifi ed into three main groups according to their location in the cell: cytosolic polysaccharides, which provide a carbon and energy source for the cells; polysaccharides that make up the cell walls, including peptidoglycans, techoid acids and lipopolysaccharides, and polysaccharides that are exuded into the extracellular environment in the form of capsules or slime, known as exopolysaccharides (EPSs). Since the latter are com-pletely excreted into the environment, they can be easily collected by cell culture media precipitation by cold ethanol aft er removal of cells [1]. Th e elucidation of the polysaccharide structures are very important to clarify the physicochemical and bio-logical properties of these biopolymers and to attribute, and in some cases predict, their biotechnological applications. Several chemical and physical techniques are used to determine the primary structure of these molecules: chemical degradation and derivatization, combined with chromatographic methods and mass spectrom-etry analysis, are used to determine the sugar composition, their absolute confi gura-tion and the presence and the position of possible substituents. 

Chitosan: An Emanating Polymeric Carrier for Drug Delivery

A wide variety of natural, synthetic and biosynthetic polymers containing hydrolyzable chemical bonds, have been extensively studied for various pharmaceutical and biomed-ical applications owing to their biocompatibility and biodegradability. Th e biodegrad-able polymer can be used in drug delivery and controlled drug release systems only if the polymer as well as its degradation products are biocompatible in nature. Natural polymers have fascinated researchers in the past few decades as they are easy to pro-cure, possess high commercial value and can be maneuvered by chemical modifi cations to impart desired characteristics. 
Chitosan, the second most abundant natural polymer aft er cellulose, is a suitable example of such biodegradable, biocompatible, low cost, nontoxic and low immuno-genic polymer [1]. It is produced from chitin, a carbohydrate polymer which is naturally found in the shells of crustaceans such as crabs, shrimps and lobsters and also in the bone plates of squids and cuttlefi sh [2–5]. Chitin and chitosan are also synthesized in the cell walls of fungi [6]. Chitin is a homopolymer consisting of N-acetylglucosamine residues linked by β-(1-4) bonds and chitosan is obtained by the deacetylation of chi-tin, forming a linear chain of 2-acetamino-2-deoxy-β-D-glucopyranose and 2-amino-2-deoxy-β-D-glucopyranose with a 1,4-β linkage [7,8]. Th e diff erence between chitin and chitosan has been vaguely defi ned as some scientists have proposed that if chi-tin is more than 50 percent deacetylated, it is chitosan; whereas others have simply described chitosan to be soluble in one percent acetic acid and chitin being insoluble in it.

Fungi as Sources of Polysaccharides for Pharmaceutical and Biomedical Applications

Over the last decades, a large number of natural polysaccharides have been reported having interesting properties that might render them suitable for use in many diff erent areas. Among those, biopolymers of fungal origin, such as cell wall polysaccharides and extracellular polysaccharides (EPS), have been widely studied and proposed for a large range of applications, including pharmaceutical and biomedical uses.  
Fungal cell wall carbohydrate constituents (e.g., chitin, β-glucans, mannoproteins), as well as secreted biopolymers (e.g., pullulan, scleroglucan, schizophyllan), have been extensively studied and there is a growing commercial interest in their use in diff erent applications. Although great focus has been placed on food applications (e.g., thicken-ing agents, fat replacers, dietary fi bers, etc.), many fungal polysaccharides have been reported to have biological activity, including stimulation of the immune response, antimicrobial activity, cholesterol and triglycerides lowering in the blood, antimuta-genic activity, etc., that potentiate their use in medical applications. Some fungal poly-saccharides can be used as biomaterials for the development of polymeric structures,such as hydrogels or micro/nanoparticles, which may fi nd use in biomedical applica-tions as drug delivery agents.
Only Saccharomyces cerevisiae has been considered as a source of cell wall polysaccha-rides for the development of most of those applications because this yeast is widely used in industry (e.g., baking and brewering industries) and it has been extensively studied. Th e fungi Aureobasidium pullulans, Schizophyllum commune and Sclerotium rolfsii are used for production of pullulan, schizophyllan and scleroglucan, respectively. Despite this, other fungi might be considered as sources of interesting polysaccharides, whose commercial development will be determined by public health (nonpathogenic, safe species) and economic factors (yield of product, content in specifi c polysaccharides).

Environmentally Responsive Chitosan-b ased Nanocarriers (CBNs)

Chitosan exhibits biocompatibility, biodegradability and its degradation products are nontoxic, nonimmunogenic and noncarcinogenic. Th us, it fi nds vast biomedical and biophysical applications. Chitosan off ers a fl exibility of chemical modifi cations to develop a series of nontoxic biocompatible chitosan derivatives because of a large number of hydroxyl and amino groups in its backbone. Some of them have certain functional groups which are oft en sensitive to the conditions of the surrounding envi-ronment, such as temperature, pH, ionic strength of the solution, presence of magnetic field and ultraviolet light are commonly called “smart biomaterials.” Th ey show exploit-able applications in the fi elds of drug delivery, tissue engineering and wound heal-ing. Th ese fabricated forms can be used as antimicrobial agents, as metal chelaters, in enzyme immobilization, and in food-processing technology, etc. [1]. Derivatization of chitosan using graft  copolymerization permits graft ing at two types of reactive groups, fi rstly, the free amine groups on deacetylated units, and secondly, the hydroxyl groups on the C-3 and C-6 carbons on acetylated or deacetylated units. Graft ing in chitosan can endow some interesting characteristics such as mucoadhesivity, biocompatibility and biodegradability.


Biomass Derived and Biomass Inspired Polymers in Pharmaceutical Applications

Th e exploitation of renewable, non-fossil-based resources and their development and transformation in high quality and high value products using advanced biorefi nery processes is becoming a standard venture of our times in which the decline of the fos-sil-based resources is faced, and, more immediately, the disadvantages of their use is becoming apparent [1–4]. Th anks to the increasing knowledge regarding biochemical processes in plants and simpler organisms, biotechnological approaches for the pro-duction of chemicals, including polymers, has emerged as a possibility to signifi cantly reduce the use of fossil-based resources [5]. Additionally, ever new reports highlighting an ever increasing degree of environmental pollution by non-degradable, or only very slowly degradable, man-made materials highlight the fact that rather drastic changes and changes of paradigms are necessary in order to prevent future economic and  ecologic collapses [6]. In the fi eld of medicinal and pharmacological applications, bio-mass-based materials have always been used. Direct consumption of plant components such as leafs or roots, or extracts from plants were used for curing maladies, while other components such as branches were used for stabilizing, e.g., as walking aid, etc. While plant extracts are still used nowadays in more or less the traditional form, biomass-derived materials that do not necessarily have a direct pharmaceutical or medicinal eff ect are used in diff erent ways and oft en are tailored for specifi c applications. Not only forest biomass is used, but also marine biomass [1,2]; nowadays, mankind does not have to rely only on the use of this biomass as it naturally comes, but thanks to the still insuffi  cient, but ever-increasing - understanding of chemical and biological pro-cesses in nature in general, and in more complex organisms like animals and humans, it is possible to use natural materials and to fi ne-tune them according to specifi c needs [7,8]. As soon as the original biomass is treated, however, one of the most important naturally added benefi ts of biomass, its biological degradability, is potentially aff ected [9]. In some cases, a reduced biological degradability can be a desired eff ect within a treatment—in fact, rendering an active small molecule isolated from a natural source like a sponge, less prone to enzymatic transformation and thus ultimately degrada-tion is an important venture. In other cases, such a decrease in biological degradability, especially if unintended, can pose a burden and render the initial use of a biomass-derived component meaningless. A rather profound knowledge regarding the biode-gradability is essential in either case, and this knowledge, in fact, can also be used to construct artifi cial polymers that can be biologically degraded—starting both from dif-ferent renewable, or from classical fossil-based resources [10–12]. Th e use of naturally occurring polymers that are biologically degradable, and the intelligent construction of artifi cial polymers that exhibit comparable biological degradation features, add up to an amazing variety of application-driven research in various fi elds [13]. Besides, exist-ing polymer blends are being modifi ed in order to introduce biodegradability features while maintaining the product performances [12], or natural polymers are modifi ed to achieve desired performances [14–16]. In the following literature survey, general fea-tures of important in-vivo-degradable polymers are highlighted, especially with respect to their use in pharmaceutical and selected medicinal applications. Biomass-derived and biomass-based polymers are then presented in detail, that are used in pharmaceuti-cal and selected medicinal applications due to their benefi cial features emerging from their in-vivo degradability, i.e., both biodegradability within the organism these poly-mers enter as part of a treatment, and biodegradability outside a specifi c organism. Th e latter point is addressed specifi cally in order to highlight the diffi  culties that arise from the short-term pharmaceutically and medicinally attractive, but long-term environ-mentally problematic interferences with processes involved in the biological degrada-tion process. Origins, fi elds of application and biodegradation mechanisms of diff erent biomass-derived and biomass-based or biomass-inspired polymers are systematically described. Over the last two to three decades, a huge amount of knowledge has been generated in the fi eld, and it is thus not possible to highlight every detail. Neither all fi elds of application could be listed in detail, but the following paragraphs will focus on the polymers as such, since the fi elds of applications have been described in other des-ignated literature. A comparative analysis and the attempt to identify emerging trends in the fi eld conclude this chapter. 

Modification of Cyclodextrin for Improvement of Complexation and Formulation Properties

In the concept of pharmaceutical drug delivery, addition of carrier components as addi-tives in conventional dosage forms has been practiced since time immemorial. In the ester years, most of them were strategically incorporated based on outcomes of optimi-zation experiments. In sequential developments these additives were designed or modi-fi ed as per the need of the hour; for instance, various forms of controlled, sustained and delayed release oral medication were developed to increase the duration of administra-tion. Use of carrier system was oft en limited to oral deliveries which essentially may not be biodegradable owing to their elimination in faeces. In the concurrent approach to formulate controlled release formulations for parentral delivery, biodegradation cri-terion was essential to avoid accumulation of carrier molecules aft er administration in systemic circulation. As a result, experimentation on biodegradable polymers gained signifi cant attention in pharmaceutical oral and parentral drug delivery. 
For reasons that are obviously related to high abundance and cost eff ectiveness, bio-degradable polymers from natural sources have gained much higher preference, out of which gelatin, albumin, chitosan, cyclodextrins (CDs), etc., have become polymers of great pharmaceutical interest. Although synthetic polymers, such as PLGA, PCL, poly-anhydrides, poly-phosphagenes, etc., have been formulated in several formulations, semisynthetic approaches have still been a boon for optimizing formulation properties. Chemical and physical modifi cations having implication in various novel formulations with environment- or stimulus-sensitive or other novel release behaviors. In a recent review we have discussed the scope of these modifi cations with special reference to poly-orthoester PCL [1]. Here in this chapter we have reviewed another extensively used carrier molecule CD and its various modifi cations that have been used in mar-keted pharmaceutical formulations in native or modifi ed form since 1976.

   


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