Handbook of Polymers for Pharmaceutical Technologies, Structure and Chemistry

Vijay Kumar Thakur, Manju Kumari Thakur

• Publisher: Wiley-Scrivener
• Year: 2015
• ISBN:
  9781119041351
• Edition: 1
• Topic: Technologie et ingénierie
• Subtopic: Ingénierie de la chimie et de la biochimie

Polymers are one of the most fascinating materials of the present era finding their applications in almost every aspects of life. Polymers are either directly available in nature or are chemically synthesized and used depending upon the targeted applications.Advances in polymer science and the introduction of new polymers have resulted in the significant development of polymers with unique properties. Different kinds of polymers have been and will be one of the key in several applications in many of the advanced pharmaceutical research being carried out over the globe.

This 4-partset of books contains precisely referenced chapters, emphasizing different kinds of polymers with basic fundamentals and practicality for application in diverse pharmaceutical technologies. The volumes aim at explaining basics of polymers based materials from different resources and their chemistry along with practical applications which present a future direction in the pharmaceutical industry. Each volume offer deep insight into the subject being treated.

Volume 1: Structure and Chemistry
Volume 2: Processing and Applications
Volume 3: Biodegradable Polymers
Volume 4: Bioactive and Compatible Synthetic/Hybrid Polymers

Chapter 1

Gellan as Novel Pharmaceutical Excipient

Priya Vashisth, Harmeet Singh, Parul A. Pruthi and Vikas Pruthi*

Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, India

*Corresponding author. [email protected]

Abstract

An excipient provides an effective therapeutic way for convenient and precise dispensation of medicine(s)/drug(s) to the desired site in order to achieve a long-lasting outcome during the period of treatment. Therefore, the techniques for delivering the drugs over a prolonged period of time, with a sustained release profile, have been constantly investigated. This article endeavors to provide an insight about the structural and physiochemical properties of gellan, with the intention of exploring the biological applications of gellan in the pharmaceutical sector. Gellan is a natural linear anionic natural polysaccharide which is commonly used in the food and cosmetic industries. The biodegradability, nontoxicity and wide applicability of gellan make it a suitable candidate for the pharmaceutical industry. The gellan excipients alone or in combination with other biopolymers have been investigated for a wide range of biopharmaceutical applications such as mucoadhesion, granulation, gene therapy and wound healing. Recent applications of gellan include its usage as pharmaceutical excipient in ophthalmic, nasal, buccal, periodontal, gastrointestinal, colon-targeted and vaginal drug delivery. Gellan has also been proven as a potential candidate for tablet coatings in order to produce a sustained release dosage system with improved drug dissolution.

Keywords: Gellan, mucoadhesion, microcapsules, nanoparticles, nanohydrogels, drug delivery

1.1 Introduction

An excipient is an inactive substance that is used along with the active agent or medicine(s) in order to provide a convenient and precise dispensation of it from the designed dosage formulations. Conventionally, excipients were only used as vehicles for giving the required weight and volume for the appropriate administration of the active ingredient, i.e., drug [1]. Whereas, the pharmaceutical role of excipients in a modern context is defined as dosage forms which play multifunctional roles such as enhanced drug stability, drug solubility/absorption, bioavailability and sustained release performance for better acceptability in patients. However, despite all these claims, a meticulous knowledge about the physical and chemical properties as well as information regarding the safety, management and regulatory status of the excipient materials are crucial, as they can no longer be totally considered as inactive ingredients. Thus, the design of novel and effective drug delivery systems has given rise to an increased number of excipients that are based on natural polymers.

The growing applications of natural polymers in pharmaceutical industry mainly relies on their abundance in nature, biodegradability, non-toxicity and their cost effectiveness as compared to synthetic polymers [2].

Gellan is a natural biocompatible polysaccharide which is obtained as a fermentative product from a pure culture of nonpathogenic microbial strain [3,4]. It has been successfully employed in solid, liquid and semi-solid dosage formulations. It has found enormous applications as gelling agent, thickening agent, stabilizer and foaming agent, which are precisely useful in the designing of improved drug delivery systems [5]. Gellan does not affect the chemical structure of formulated drug and get degraded by natural biological processes within the body. These properties of gellan circumvent the need for removal of the drug delivery system from the body after its action has been accomplished. Additionally, as an excipient, it helps to maintain a steady-state plasma concentration of drug at the desired site during the entire period of treatment, and also reduces the adverse effects of the drug by releasing the drug in a well-controlled manner. As compared to other polysaccharides, gellan exhibits better thermal stability, acid reliability, adjustable gel elasticity and high transparency, and is therefore a preferred candidate for the food and pharmaceutical industries [6]. Here, in this article, our emphasis is on gellan-based materials, and their chemical modification, with the intention of exploring the biological applications of gellan as pharmaceutical formulations such as drug release modernizers, gelling agents, implants, films, beads, microparticles, nanoparticles, injectable systems and granulating systems, as well as mucoadhesive formulations.

1.2 Structural Properties of Gellan

The purpose of analyzing the structural features of gellan is to understand the influence of chemical modifications on its physiochemical properties. Structurally, gellan is a linear, anionic polymer which is composed of tetrasaccharide repeating-units, comprising two molecules of monosaccharide β-D-glucose, one molecule of β-D-glucoronic acid and one molecule of α-L-rhamnose linked together in a linear fashion [4]. The percentage of the three main constituents of gellan is reported as approximately 60% for glucose, 20% for rhamnose and 20% for glucuronic acid [6]. The native form of gellan is found to be esterified with L-glycerate and O-acetate at 2 and 6 positions of the D-glucose. However, the commercially available Gelrite^® is the de-esterified form of gellan [7].

The detailed structural analysis of gellan has been performed using X-ray diffraction technique by Chandrasekaran and Radha. The X-ray diffraction study on Li⁺ gellan revealed that it possesses an extended double helical molecular structure formed by intertwining of threefold left-handed helical chains of pitch 56.4 Å in a parallel fashion [8]. This helical structure is stabilized by means of interchain hydrogen bond between the hydroxymethyl groups of 4-linked glucosyl units in one chain and carboxylate group in the other chain [9]. The X-ray diffraction analysis of the K⁺ salt also showed the K⁺ ion is linked with the carboxylate group of gellan and surrounded by six ligands to attain a strongly anchored octahedral coordination which is responsible for the stability of double helical gellan structure.

Recently, atomic force microscopy (AFM) and dynamic viscoelasticity measurements have been employed for investigating the detailed chemical structure of Na⁺-gellan. The study revealed that gellan is composed of a continuous network of structures that is mainly developed through the inter-helical associations of end-to-end type rather than the associations of side-by-side type. The presence of cations (K⁺ ions) is found to be a necessary component for the development of these types of continuous network structures. The study further confirmed the fibrous model of gellan gelation instead of the conventional model which presumed that joining of the adjacent junction zones leads to formation of disordered flexible polymer chains [10,11].

On the basis of o-acetyl substitution of the polysaccharide chain, gellan can be categorized into two basic forms: (i) high acyl form and (ii) low acyl form (Figure 1.1). Both forms exhibit different characteristic properties (Table 1.1). The acyl substitution of gellan chain shows an intense effect on its gelling characteristics. The high acyl form of gellan produces soft, elastic and non-brittle gels, whereas the low acyl form yielded steady, non-elastic and brittle gels [12].

Figure 1.1 Chemical structure of repeating units of gellan.

Table 1.1 Comparison of the physical properties of high-acyl and low-acyl gellan.

	High Acyl Gellan	Low Acyl Gellan
Molecular Weight	1–2 × 10^6 Daltons	2–3 × 10^5 Daltons
Solubility	Hot water	Hot/ or cold water
Setting Temperature	70°–80°C (158°–176°F)	30°–50°C (86°–122°F)
Thermo-reversibility	Thermo-reversible	Thermo stable

1.3 Physiochemical Properties of Gellan

Gellan exhibits high gel strength, an excellent stability, process flexibility and tolerance, high clarity and an outstanding active reagent release property. The physiochemical properties of gellan are listed in Table 1.2 [13–15].

Table 1.2 Physiochemical properties of gellan.

Color	Off White
Molecular weight	>70,000 with 95% above 500 000
Bulk density	Approximately 836 kg/m3
Solubility	in water; insoluble in ethanol
pH (1% solution)	Neutral
Gel strength	≥850 g/cm2
Specific gravity	<1
Stability	Stable at room temperature
Moisture content	98.6%wb or 67.6% db
Loss on drying	≤15.0% (105°, 2 1/2 h)
Nitrogen	≤3%
Isopropyl alcohol	≤750 mg/kg
Microbiological criteria	Bacterium count: ≤10,000 cfu/g E. coli: Negative by test Salmonella: Negative by test Yeasts and molds: <400 cfu/g

1.3.1 Gelling Features and Texture Properties

Gellan is a polysaccharide which has a characteristic property of temperature-dependent and cation-induced gelation. Gellan abruptly undergo sol-gel transitions (phase transition) and forms gels on heating and cooling of its solutions in the presence of cations (Figure 1.2). These gels are transparent and resistant to a wide range of heat and pH [16]. Light scattering analysis demonstrated that the gelation behavior of gellan involves two separate thermo-reversible steps: (i) at low temperature/or on cooling gellan converted in an ordered double helix from two single chains, and (ii) on high temperature/or heating it changes from a double helix to two single-stranded polysaccharide chains [17,18]. Rheological studies have indicated that at low temperature, gelling of gellan occurs due to the coil-to-helix transition [19]. The mechanism lying behind the gelation of gellan includes the synthesis of junctions in double-helix and the aggregation of these junctions to develop a three-dimensional network in the presence of cations and water [20]. Since gellan is a polyelectrolyte, the presence of divalent or monovalent cations markedly influences the texture and properties of gellan gel. The presence of cations has always been found to promote the gelation process by producing a shelding effect over the helices, thereby enhancing the probability of hydrogen bond formation by inter-helical interaction. One of the mechanisms explain by Gunning et al. showed the development of distinct junction zones on the helical polymer chains and the presence of mutual interactions (inter-helical associations) between the connecting adjacent junction zones [21]. These junction zones are thought to be stabilized by cation binding. The addition of salt solution significantly increases the number of bridges at a junction zone, and thus improves the elastic modulus and gelling properties of gellan. Another investigation explaining the gelation process in gellan has been accomplished using atomic force microscopy (AFM) technique. It supports the fibrous model of gellan gelation, which states that in the presence of cations, some primary fibers form during the process of coil to helix transition. This process is followed by the aggregation of primary fibers into thicker branched fibers which results in the enhanced elastic behavior [22].

Figure 1.2 Schematic model representing the gelation mechanism for gellan.

1.3.2 Rheology

Rheological assessments are appropriate tools in order to attain the organizational information about the macromolecules in a certain medium. The rheological properties of gellan solutions in the presence and absence of salt were reported by Miyoshi et al. [19]. They evaluated the steady shear viscosities and oscillatory measurements for gellan solution. The data obtained from this study suggested that in the absence of salt, gellan solution followed a shear-thinning behavior and its conformation changes from a compact coiled structure to a helical structure (the helical structure compared to coiled structural conformation can be more easily oriented with the shear flow). At low shear rates, the range of Newtonian plateau was found to become gradually narrower because of the development of an ordered structure of gellan in the solution. Whereas, in the presence of a sufficient concentration of cations, gellan associates in highly ordered structure and tends to form weak gel, which significantly followed a...