Polysaccharide-based amorphous solid dispersions (ASDs) for improving solubility and bioavailability of drugs

Polysaccharide-based amorphous solid dispersions (ASDs) for improving solubility and bioavailability of drugs

10

Saleha Rehman*, Bushra Nabi*, Shavej Ahmad†, Sanjula Baboota*, Javed Ali* * Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard (Hamdard University), New Delhi, India, †Research and Development Centre, Sun Pharmaceutical Industries Ltd., Gurgaon, India

Abbreviations AFM AGU AMG API ASD BCS CAP CMC CMCAB DS DSC EC FTIR GIT GRAS HEC HPC HPMC HPMCAS IVIVC LBG LCST MC MGG MGK MHG MLBG MXG

atomic force microscopy anhydro-d-glucopyranose units aegel marmelos gum active pharmaceutical ingredient amorphous solid dispersion Biopharmaceutics Classification System cellulose acetate phthalate carboxymethylcellulose carboxymethyl cellulose acetate butyrate degree of substitution differential scanning calorimetry ethylcellulose Fourier transform infrared gastrointestinal tract generally recognized as safe hydroxyethyl cellulose hydroxypropyl cellulose hydroxypropylmethylcellulose hydroxypropylmethylcellulose acetate succinate/hypromellose acetate succinate in vitro in vivo correlation locust bean gum lower critical solution temperature methylcellulose modified guar gum modified karaya gum modified hupu gum modified locust bean gum modified xanthan gum

Polysaccharide Carriers for Drug Delivery. https://doi.org/10.1016/B978-0-08-102553-6.00010-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

272

NaCMC NDDS NMR PEG PVP PVP-VA SA SD XPRD

Polysaccharide Carriers for Drug Delivery

sodium carboxymethylcellulose novel drug delivery system nuclear magnetic resonance polyethylene glycol polyvinylpyrrolidone polyvidone-vinylacetate sodium alginate solid dispersion X-ray powder diffraction data

10.1 Introduction In recent years, the pharmaceutical industry has been increasingly populated with a high percentage of lipophilic compounds which possess extremely low aqueous solubility [1]. This came about because of combinatorial chemistry and high throughput screening in the pharmaceutical field with an aim to produce compounds with good pharmacological activity. However, ~40% of such drug candidates were associated with poor water solubility and subsequently less bioavailability [2, 3]. Previously these compounds were neglected and rejected at their initial stage without any further research being carried out on them. However, with the introduction and utilization of modern technologies, more focus was given to such compounds to resolve their problem of low solubility [4]. From then on, new strategies have kept emerging to formulate such problematic compounds into orally bioavailable and therapeutically effective drugs. Poor solubility of the drug in an aqueous medium is an issue which cannot be ignored and is definitely not going to disappear in the foreseeable future. It remains a critical factor if the molecule is to survive the pharmaceutical development process [5]. According to the Biopharmaceutics Classification System (BCS), poor solubility of a drug is the highest dose strength that cannot be dissolved in 250 mL water in the pH range of 1–7. On the other hand, drugs belonging to BCS Class IV have both poor solubility and poor permeability across the gastrointestinal tract (GIT) [6, 7]. An active pharmaceutical ingredient (API), if poorly soluble in water, remains undissolved in the GIT and is eventually excreted. The API thereby failing to reach its molecular target in the body results in low bioavailability [5]. Apart from this, increase in dose, large variations in blood concentration, and large interand intrasubject variations are the other outcomes observed with drugs with poor solubility [2]. Currently various techniques and approaches which are employed to tackle the problem of low solubility and to prepare effective and marketable drugs as shown in Fig. 10.1. The selection of the method is based on the physicochemical properties of the drug and the carrier and their expected use [6, 8]. Among all these techniques, solid dispersion has gained interest in recent years and is widely used for solubility enhancement of drugs following oral administration.

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Fig. 10.1  Approaches for improving solubility and bioavailability.

10.2 Solid dispersion Solid dispersion (SD) as defined by Chiou and Riegelman is the “dispersion of one or more active ingredient in an inert carrier at the solid state, prepared by the melting, the solvent, or the melting solvent method” [9]. This strategy of formulating poorly soluble compounds into SDs plays a significant role in handling dissolution-rate-limited oral absorption which is vital for achieving maximum oral bioavailability. Additionally, this methodology has been successfully implemented in developing formulations with high drug loading or drugs with high tendency to crystallize [10]. The physical state

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of the prepared SDs is dependent on the critical factors which include the physicochemical properties of the drug and the carrier, the interactions between them, and the method of preparation. SD is one such promising formulation strategy which is efficient, cost effective, reliable, and industrially scalable. It offers advantages such as reduced particle size, improved wettability, high porosity, and enhanced solubility [11]. The feasibility of oral administration of SDs paves the way for their easy administration which results in high patient compliance. The oral route is the most preferred route of drug administration but presents several bottlenecks such as first pass metabolism, permeation across the gut membrane, and lastly the dissolution in gastrointestinal fluids [12]. The SD technology by enhancing the solubility improves this dissolution behavior, consequently resulting in optimum therapeutic level. Formulating a drug into SD can result in dissolution enhancement of as high as 400-fold to less than twofold [13]. Ideally in SD, the main reason postulated for the significant improvement in solubility and dissolution is the reduction in drug particle size which thereby increases the surface area which comes into contact with the surrounding dissolution medium [14]. It is obligatory for the drug particles to be present in the submicron range to observe a dramatic rise in solubility. Moreover, the carriers employed in SD have a solubilizing effect in addition to increasing the wettability and dispersibility of the drug in the dissolution media. This will help in impeding particle agglomeration which, if it occurs, will slow down the dissolution process [15]. The dissolution state is supposed to be a supersaturated state, which is generated because of the enhanced dissolution rate of the amorphous, molecularly dispersed drug. This results in improved solubility, dissolution, and consequently enhanced bioavailability [16].

10.2.1 Mechanism of drug release from solid dispersion 10.2.1.1 For immediate release SDs There are two types of release mechanisms which are followed: drug controlled release and carrier controlled release. The SDs, when dispersed in water, involve rapid uptake of water by the hydrophilic carriers which then form a concentrated highly viscous carrier layer. If the drug is insoluble or sparingly soluble in the carrier layer, the drug is released intact which directly comes into contact with water. The dissolution profile will then depend on the properties of the drug particles (polymorphic state, particle size, drug solubility) therefore it is called drug controlled release. On the other hand, if the drug dissolves in this layer, its release across the layer will be hampered and it will require diffusion of the carrier into the bulk phase for it to be released, the rate-limiting step being the diffusion of carrier, hence known as carrier controlled release [17, 18].

10.2.1.2 For controlled release SDs The controlled release SDs also involve two mechanisms for the drug release: diffusion and erosion. These mechanisms depend on the characteristics of polymers and the miscibility of the drug and carrier. The former mechanism involves proper dispersion

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of drugs and carriers in the internal structure of SDs. However, if the drug and carriers exist as separate particles, they will follow the erosion mechanism for drug release. Yet, some drugs might follow both the mechanisms simultaneously for drug release [17].

10.2.2 Methods of manufacturing The manufacturing methods for SDs are fundamentally categorized into three methods: melt, solvent evaporation, and solvent melting method, which are further subcategorized as shown in Fig. 10.2.

10.2.3 Advantages and disadvantages of solid dispersion Formulating solid dispersion of poorly soluble drug offers various advantages which consequently increases its solubility and bioavailability. Micronization, increased drug wettability, higher degree of porosity, oral administration, simple, and cost effective method are some of the major advantages associated with SD [19–21]. However, the methodology is accompanied by several drawbacks, due to which the SD technique has failed to transfer enough products to commercialization. Some of these problems include thermal instability of drugs and carriers, toxic solvent residue, recrystallization, phase separation, crystal growth, processing glitches and lastly lack of in vitro in vivo correlation (IVIVC) [17, 20, 22].

Fig. 10.2  Manufacturing methods of solid dispersion.

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10.2.4 Classification of solid dispersion 10.2.4.1 Based on the composition The most recent classification by Vo and associates classified SDs into four generations as shown in Table  10.1. Concisely, first generation SDs generate crystalline dispersions where one molecule of a crystalline carrier replaces one molecule of crystalline drug. The second and third generation includes amorphous SDs prepared using polymeric carriers in the former and surfactants in the latter. The fourth generation includes the controlled release SDs for the drugs with short half-life [17, 23].

10.2.4.2 Based on physicochemical classification The physicochemical classification of SDs as introduced by Chiou and Riegelman [9] is given in Table 10.2. Based on the physical state of the carrier, whether crystalline or amorphous, SDs are classified into crystalline and amorphous. The crystalline SDs involve an intimately blended physical mixture of crystalline drug with a crystalline carrier, forming a eutectic or monotectic mixture. Their preparation involves fused melting of the two components followed by their rapid solidification obtaining a physical mixture of very fine Table 10.1  Classification of solid dispersion S. no.

Classification

Properties

1

First generation

2

Second generation

3

Third generation

4

Fourth generation

Crystalline drug dispersed in a crystalline carrier forming eutectic/monotectic mixture More thermodynamically stable therefore dissociate to a lesser extent Show improvement in dissolution rate compared to the pure drug Contains amorphous carrier mostly polymers Subdivided into solid solution and solid suspension Drug is present in supersaturated state due to forced solubilization in the carrier (leading to precipitation) Less stable Better dissolution profile compared to the first generation owing to faster dissolution rate Contains surface active agent or self emulsifiers Overcome problems of precipitation and recrystallization Increased stability Improved dissolution profile compared to second generation due to faster dissolution rate and lower precipitation rate and extent in supersaturated state Contains drugs with short half-life Controlled release SDs are formed Improved dissolution profile in a controlled or zeroorder manner

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Table 10.2  Types of solid dispersion S. no.

SD type

Matrix

Drug

1. 2.

Eutectic mixtures Solid solution (a) Continuous solid solutions (b) Discontinuous solid solutions (c) Substitutional solid solutions (d) Interstitial solids solutions Amorphous precipitations in a crystalline carrier Glass solution Glass suspension Glass suspension

Crystalline

Crystalline

Crystalline Crystalline Crystalline Crystalline Crystalline

Molecularly dispersed Molecularly dispersed Molecularly dispersed Molecularly dispersed Amorphous

Amorphous Amorphous Amorphous

Molecularly dispersed Crystalline Amorphous

3. 4. 5. 6.

crystals [24]. The SDs prepared by this method show improvement in dissolution rate compared to the pure drug, and are thermodynamically more stable, and therefore dissociate to a lesser extent. The problem associated with this method is the time-­consuming generation of phase diagrams to obtain the optimum drug-polymer composition for producing a eutectic mixture [15]. Another crystalline SD is the solid solution in which the two components crystallize together in a homogeneous one-phase system. They are further subclassified based on their miscibility (continuous and discontinuous) and depending on the way the solvate molecules are distributed in the solvent (substitutional and interstitial). The increase in dissolution rate by solid solutions is attributed to the reduction in particle size of the drug to its molecular size [25]. The amorphous precipitation in a crystalline carrier differs from the simple eutectic mixture in the fact that the drug in the former is precipitated out in the amorphous form as opposed to the crystalline form in the latter. The reason is that the drug which has a strong tendency of supercooling solidifies in the amorphous form. An example is sulfathiazole in crystalline urea [2]. The amorphous SDs, on the other hand, are further subclassified into amorphous solid solutions (glass solutions) and amorphous solid suspensions. In amorphous solid solutions, the drug and amorphous carrier are completely miscible i.e. the drug is molecularly dispersed into a polymeric matrix, thus forming a molecularly homogenous mixture. Contrariwise, the amorphous solid suspensions consists of two separate phases, containing precipitated particles suspended in the carrier. Examples of carriers used in glass solution and suspensions include citric acid, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), cellulose derivatives, sugars, urea, and various other polysaccharides [26, 27].

10.3 Amorphous solid dispersions Formulating ASDs of poorly soluble drugs is an interesting approach which provides an upsurge in their bioavailability by improving their rate and extent of dissolution [23]. ASDs, particularly amorphous solid solution, are becoming popular amongst

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formulation scientists as the exhibit better dissolution profile in comparison to the corresponding SDs containing crystalline drugs [26, 28]. ASDs involve intimate mixing of poorly water-soluble drugs with hydrophilic carriers at molecular level which leads to particle size reduction, increased wettability, and dispersibility thereby affording improved drug release profile. The improved drug release is due to the higher apparent solubility shown by the high-energy level amorphous materials as compared to their crystalline equivalents [8]. Furthermore, ASDs are characterized by the absence of distinct intermolecular arrangement and hence thermodynamic stability. Therefore, the first step for the molecular dissolution of amorphous drugs which requires breaking of the crystal lattice is of a very short duration and lower energy is required to promote dissolution [8, 29]. Additionally, the ability of ASDs to maintain the drug in the supersaturation state in GIT increases the driving force for absorption as opposed to the other solubility enhancement techniques where the drug absorption does not occur via the GI epithelial membrane [30]. In ASDs, the concerted effects of thermodynamic and kinetic forces are the factors responsible for their enhanced bioavailability. Thermodynamic factors have less of a role to play as the drug is present in amorphous form, therefore, the energy barriers required for breaking the crystal lattice are very few. Kinetically, the carrier encumbers the conversion of the amorphous drug back to crystalline. The carrier interacts with the drug molecules forming bonds and posing steric hindrance in order to keep these molecules apart. The surface area is hence maximized, which also acts as a crystallization inhibitor, assisting in extensive and faster dissolution. Moreover, in cases where complete dissolution is not achieved, absorption can be still be enhanced by maintaining the supersaturated state during its GIT transit time. The improvement in wetting is also achieved owing to the rapid water influx into the dispersion by the water-soluble polymer. The formation of micelles, microparticles or nanoparticles in the GIT leads to increased permeation rate. All these factors are collectively responsible for improving the dissolution kinetics [31, 32].

10.3.1 Methods of preparation The methods which are intended for use in preparation of ASDs include solvent evaporation and melting methods which have proved useful at laboratorial as well as industrial scales. The mechanical methods such as ball milling or grinding have also been used but the degree of amorphisation they offer is very low and therefore they find limited applicability [21]. The two most widely used methods for preparing ASDs include spray drying and hot melt extrusion method. Besides these two methods, co-­ precipitation can also be utilized for preparing ASD which involves precipitating micro-particles of the drug and the carrier from a co-solvent into a common nonsolvent. However, the spray drying method is the most commonly used method when ASDs are to be prepared on a large scale. This process, in comparison to other solvent evaporation methods, has higher likelihoods for the preparation of amorphous SDs due to the comparatively faster solvent evaporation. The process requires an intimate mixing between drug and polymers due to the predissolution of these in the solvent or co-­solvent. The solution is subjected to atomization using a nozzle and the solvent

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is consequently evaporated which gives no time for the drugs to recrystallize thus contributing to the amorphous state of the solid dispersion. The solid dispersion is collected as a dry powder which is then further dried to achieve acceptable residual solvent levels. Sporanox (Itraconazole) is a popular example of this process [23, 32, 33]. The second method, i.e. hot melt extrusion, involves melting of the drug and excipients after they are introduced into a heated barrel via a hopper. The rotating screw fixed inside the barrel allows rigorous mixing of the melted blend. After homogenization and extrusion, it is then solidified when it moves towards the die and can be reshaped into tablets, granules, or pellets. The physical structure of the solid dispersion so obtained is estimated by the amount of heat provided, the rate of cooling, and the amount of shear force applied while mixing [23]. This method is the favored choice owing to the favorable properties of the powder obtained by using this technology. The absence of organic solvents, suitability of increasing batch size, and easy scale-up are some of the advantages associated with this method [34]. However, the limitation with this method is that the drug and the carrier both should possess thermal stability against degradation.

10.3.2 Pros and cons ASD technology is one of the most promising strategies for improving solubility and oral bioavailability of poorly water-soluble drugs. ASDs, as opposed to the other solubilization methods, do not alter the equilibrium solubility of the drug; instead it maintains the supersaturation state [35]. Moreover, formulating ASD ensures homogenous distribution of the drug which leads to increase in dissolution rate and absorption thus contributing to more rapid onset of action. In addition, ASDs provide flexibility in dose escalation, one of its main benefits being the reduction in pill burden by 30%– 40%, permitting high drug loading in the carrier without phase separation. Lastly, the carriers used in ASDs come under the category of generally recognized as safe (GRAS) thus displaying wide acceptance and tolerance in toxicology studies. They have also proven their safety and efficacy in preclinical and clinical studies [34]. However, the technology is accompanied by some shortcomings, principally its physical instability. The tendency of the high-energy level amorphous drug present in SDs is to revert to the thermodynamically stable crystalline state [36]. This physical instability of SDs might lead to retardation in the dissolution rate over time. Therefore measures are taken for the prediction and enhancement of the physical stability of amorphous SDs [37, 38]. The phase instability impelled as a function of time and/or due to storage conditions have resulted in lesser ASD-based products which have entered the market [23]. The issue of physical instability has become a subject matter of concern, which led the researchers to thoroughly investigate the solid state properties as well as the physical chemistry of the ASDs. Since then, numerous analytical techniques have been employed for the solid-state analysis of the dispersions. Modulated differential scanning calorimetry (DSC), X-ray powder diffraction data (XRD), solid state nuclear magnetic resonance (NMR), atomic force microscopy (AFM), photothermal Fourier transform infrared (FTIR) microscopy, and nanothermal analysis are some of these techniques [39, 40].

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10.4 Amorphous carriers Since these carriers constitute the major part of the formulation, its contribution to the properties and behavior of SD is quite evident. The prime characteristic which a carrier must possess is being physiologically inert, nontoxic, and categorized as GRAS by USFDA. The selection of a suitable carrier is imperative for faster drug release in addition to maintenance of supersaturated amorphous state and inhibition of crystallization in the prepared SDs. The ideal polymer should have the property of maintaining the drug in an amorphous state not only during processing and manufacturing of SD but also during shipping and storage. It should possess the ability to dissolve rapidly, release the drug at the absorption site in the GIT, and enhance the permeation of drug through it [34]. A theoretical approach for the carrier selection is the solubility of the drug and carrier, which if the same accounts for their miscibility. However, this is not always true. The dissolution characteristics of the dispersed drug depends typically on the solubility of the carrier, exhibiting faster drug release from the water-soluble carrier and slower drug release from the water-insoluble carrier [29, 41]. Moreover, the carriers in SD play crucial role in providing stability to the amorphous drugs against nucleation and crystal growth which is an outcome of various mechanisms including antiplasticization effect, increase in nucleation activation energy, drug-carrier interaction, and reduction in drug molecular mobility [41, 42]. Furthermore, the carriers are required to inhibit the drug precipitation and maintain the supersaturated state. The drug precipitation can be diminished by enhancing the solution viscosity and by decelerating the crystallization kinetics [43]. In addition, with respect to manufacturing ASDs by hot melt extrusion, the melting point of the carrier should not be much higher than that of the drug and the thermal stability and thermoplasticity at melting temperature should be taken into account. For the preparation of ASDs by solvent evaporation method, the solubility in organic solvents is an essential criterion for carrier selection [44]. Additionally, the physicochemical properties of the carrier also have a great impact on the prepared SD. The molecular weight of the amorphous carriers significantly affects the dissolution rate of the drug which increases with increase in molecular weight. The viscosity increases with the increase in molecular weight of the carrier which hinders the solubilized drug molecules to diffuse into the bulk solution, favorable in maintaining the drug in supersaturation state [45]. In addition, the drug/carrier ratio also influences the dissolution rate of ASDs which decreases with the decrease in carrier content. The drug is destabilized and the concentration exceeds the solubility in the carrier leading to the formation of drug crystals. However, in cases involving elevated temperature and relative humidity, increased drug content also imparts instability to the prepared dispersion [41]. Moreover, the carriers should be less hygroscopic as they lead to crystallization and hence destabilization if they uptake moisture [46]. The conformation of the carrier also has a huge impact on Tg, supersaturation maintenance, and drug-carrier interaction [47]. Furthermore, high Tg is a prerequisite for sufficient kinetic stabilization in ASDs as the molecular mobility becomes negligible 50°C below Tg [48]. Also, the presence of certain functional groups (particularly hydrogen donors or acceptors) on

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the carrier resulting in interactions between the drug and carrier lead to increased drug solubility as well as inhibition of drug crystallization [49]. Classifying based on origin, the carriers for preparation of ASD are synthetic polymers and natural-based polymers. The synthetic polymers such as vinylpyrrolidone polymers, polymethacrylates (Eudragit L, S, EPO), poloxamers, soluplus, polyethylene glycol (PEG) derivatives, etc. have demonstrated great potential in the dissolution and bioavailability enhancement of poorly soluble drugs. However, they are accompanied by several disadvantages which limits their usage, the most important being the toxic effects produced by their by-products. Contrariwise, the natural ­product-based polymers such as carbohydrates, sugars, cellulose derivatives, various gums, urea, starch, chitosan etc. possess minimum side effects and have been exploited widely as carriers in ASD preparation [41].

10.5 Polysaccharide carriers used in ASD Most of the natural polymers are polysaccharide-based carriers which are found to be extremely safe and effective when employed as carriers in ASD. These carriers are alleged to be absorbed minimally and their side-products after chemical or enzymatic breakdown do not pose any threat in the human body. Their utility in oral drug delivery applications, particularly for ASDs, has been well established in the literature owing to their nontoxic and biologically inert nature. High Tg of these polymers is strongly favored which provides stability to the prepared dispersions at high temperatures for a longer period. They offer the advantage of being water-soluble, one of the prerequisites for the development of ASDs of hydrophobic drugs. Additionally, they possess good compatibility and do not hinder drugs from reaching the systemic circulation. These carriers possess functional groups, which interact with the active moieties, most of them forming hydrogen bonds which thus improve the miscibility and solubility and avoid phase separation. Besides their exploitation in SDs, many of these polysaccharide-based carriers are also utilized for targeted and controlled release in order to avoid side-effects or toxicity to other organs as well as providing therapeutic relief for a longer duration [41, 50]. Some of these polysaccharides employed in the preparation of ASD for enhancing solubility and bioavailability have been discussed further.

10.5.1 Cellulose derivatives The most abundant naturally occurring biopolymer is cellulose, produced mainly by plants. It is the main structural component present in herbal cells and tissues [51]. It is also found in the cell walls of bacteria (Cyanobacteria), prokaryotes (Rhizobium, Acetobacter) and eukaryotes (angiosperms, gymnosperms, ferns, mosses, fungi, amoebae, freshwater, marine and green algae) [52]. Cellulose has been used for years in a diverse range of applications which include paper, coatings, packing, composites, paper, netting, upholstery, clothes, cosmetics, and pharmaceuticals etc.

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Chemically, cellulose comprises long chains of anhydro-d-glucopyranose units (AGU) to which three-hydroxyl groups per AGU are attached with the exception of the terminal ends. The cellulose molecule usually exists in 2 allomorphs: cellulose I, in which the glucan chains are oriented in a parallel manner whereas it is antiparallel in the case of cellulose II. The majority of plants possess cellulose I and algae and some bacteria possess cellulose in the form of cellulose II [53]. The hydroxyl groups are responsible for the intermolecular and intramolecular hydrogen bonding between each of the AGU chains. The strong H-bonding in cellulose molecule consequently leads to its low solubility in water and most of the organic solvents [54]. The cellulose is therefore chemically modified to yield various cellulose derivatives (or cellulosics) (as given in Table 10.3) which are strong, biocompatible, reproducible, recyclable, and most importantly soluble (both in aqueous and organic solvents) [51, 55, 56]. The most commonly employed chemical modification includes esterification and etherification at the hydroxyl groups. Other modifications include ionic and radical addition, acetylation, oxidation deoxyhalogenation, and reaction with organometallic compounds. These modifications break the H-bonding originally present in the cellulose molecule thus rendering it more soluble. These derivatives having different mechanical and pharmaceutical properties can be further tailored to suit their different biomedical applications in the industry [57]. Table 10.3  Classification of cellulose derivatives Cellulose derivatives

Single substituent

Mixed

Cellulose ethers

Methylcellulose (MC) Ethylcellulose (EC) Hydroxyethylcellulose (HEC) Hydroxypropylcellulose (HPC) Sodium carboxymethylcellulose (NaCMC)

Cellulose esters

Cellulose nitrate (CN) Cellulose acetate (CA) Cellulose triacetate (CTA) Hydroxypropylmethylcellulose acetate succinate (HPMCAS) Hydroxypropylcellulose acetate (HPCA) Crosslinked sodium carboxymethylcellulose (croscarmellose sodium) Hydroxyethylcellulose grafted with alkyl C12-C24 chains (g-HEC)

Methylethylcellulose (MEC) Methylhydroxyethylcellulose (MHEC) Hydroxypropylmethylcellulose (HPMC) Ethylhydroxyethylcellulose (EHEC) Sodium carboxymethylhydroxyethylcellulose (NaCMHEC) Carboxymethylethylcellulose (CMEC) Cellulose acetate butyrate (CAB) Cellulose acetate propionate (CAPr) Cellulose acetate phthalate (CAP) –

Ether esters

Crosslinked derivatives Grafted derivatives

–

–

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Moreover, the cellulose ethers and esters are found to be exceptionally safe, owing to their high molecular weights and other physicochemical properties which hinder their absorption from the GIT. Their by-products (if hydrolyzed) are also endogenous or dietary making them safe for drug delivery applications [58]. Presently, the pharmaceutical industry is flooded with cellulose derivatives occupying the major share of pharmaceutical excipients. They have been used as tablet-binding agents, granulating agents, coating agents, gelling agents, disintegrants, compressibility enhancers, fillers, solubilizers, stabilizers, thickeners, extended and controlled release agents, for taste masking, osmotic drug delivery systems, bioadhesives, and mucoadhesives [59]. Some of these important cellulose derivatives utilized as carriers in SD are discussed below.

10.5.1.1 Methylcellulose Methylcellulose (MC) is one of the most common types of cellulose, which is extensively employed in the pharmaceutical industry. It is produced by replacement of hydroxyl groups at C-2, C-3 and/or C-6 positions of AGU by methyl (CH3) groups. MC is available in several grades having molecular weight ranging from 10,000 to 220,000 Da and degree of polymerization in the range of 50 to 1000 [60]. In addition to being inert, odorless, and tasteless, it is insoluble in most of the organic solvents (except for MCs with degree of substitution DS > 2.5) but when it comes in contact with water, it absorbs water, swells, and produces a clear to opalescent viscous solution (DS =1.3–2.5) [61]. Their viscosity does not change with change in pH and they remain stable over a wide range of pH 2–12. However, with increase in temperature above 29±2°C, the viscosity of MC increases remarkably resulting in the formation of a thermoreversible gel [62]. MC therefore is classified as a lower critical solution temperature (LCST) polymer [61]. MC is used for treating constipation, hemorrhoids, diverticulosis, irritable bowel syndrome, and dry eyes. They serve as an efficient water retention agent and are administered in powder form which is not digestible in the body. They do not cause any allergic reaction since they consist of an interesting dietary fiber. The pharmaceutical uses of MC comprises of an emulsifying agent, suspending agent, capsule disintegrants, binders, controlled release agents and viscosity enhancer in oral and topical formulations [63, 64]. Hirasawa et  al. exhibited potential of MC for improvement in dissolution and bioavailability by preparing tablets of Nilvadipine based on SD technology using MC as the carrier. The tablets were reported to exhibit higher solubility and dissolution rate and indicated good physical stability during storage [65]. However, much less research has been carried out on MC pertaining to solubility enhancement as newer forms have been developed giving better outcomes.

10.5.1.2 Ethylcellulose Ethylcellulose (EC) is one of the few cellulose ethers which are hydrophobic in nature i.e. insoluble in water but soluble in many polar organic solvents. The replacement of hydroxyl groups of AGU by ethyl ether (OCH2CH3) groups result in the formation of EC. It is a nonionic polymer, which is odorless, tasteless and not

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affected by the change in pH [60, 63]. EC is often used in the pharmaceutical industry as a binding, coating, granulating, flavoring, thickening, extended, and sustained release agent [51]. The extended release property of EC is attributed to the formation of a viscose gel around the tablet which hinders the free release of the drug from the formulation [66]. EC has several applications in modified release dosage forms, however, it is used in conjunction with water soluble polymers like MC and HPMC (hydroxypropylmethylcellulose) in aqueous coating of liquids [67]. EC has also been used as a carrier for preparing SD of Dimenhydrinate and Indomethacin for its solubility and dissolution enhancement, although it is not widely utilized for this technology [68, 69].

10.5.1.3 Hydroxyalkyl cellulose Hydroxyalkyl celluloses such as hydroxyethyl and hydroxypropyl cellulose are cellulose ethers synthesized by replacing deprotonated hydroxyl groups in AGU with hydroxyethyl/hydroxypropyl groups by reacting it with ethylene oxide/propylene o­ xide [70]. The ring opening reaction of epoxides generates a new hydroxyl group at the terminal end, distant from the main cellulose chain which is more reactive and can be further modified. However, so far, the hydroxyalkyl cellulose derivatives available in the commercial market are very few owing to the harsh conditions used in the alkaline etherification procedures [71]. Therefore there is a need of developing new and more efficient methodologies for their synthesis taking into consideration the high urge of sustainable biomaterials. Hydroxypropyl cellulose (HPC) is a nonionic water-soluble polymer which is freely soluble in water below 38°C but precipitate in hot water (40–45°C). It is a pH insensitive cellulose derivative with DS of 3.0. HPC is widely employed as a food additive, thickening, stabilizing, binding, and disintegrating agent in the pharmaceutical industry. It is also known to be used as a carrier in ASDs and the drug release from these dispersions are primarily dependent on the molecular weight of HPC which ranges from 37,000 (Type SSL) to 150,000 (Type H) [72]. The release rate of flurbiprofen was found to improve with low molecular weight HPCs and with increased proportion of HPC in SD [73]. The high Tg of the polymer is another factor responsible for stabilizing the prepared formulations by restricting the drug recrystallization. In addition, both the hydrophobic and hydrophilic moieties of HPC are required for maintaining the drug in a supersaturated state which provides optimum dissolution rate to ASDs [74]. The improvement in solubility using HPC has been investigated on nifedipine which showed promising results [75]. In a study involving preparation of dispersions of fenofibrate using spray-drying technique, HPC was compared with Eudragit E-100 and Solutol HS15 for improvement in dissolution. However, Eudragit E-100 was found to exhibit faster dissolution efficiency than the other two polymers but HPC also showed favorable results in augmenting the dissolution profile of fenofibrate [76]. The polymer HPC has also been used in combination with EC to control the release of the water-soluble drug oxprenolol hydrochloride. The mechanism involving this is that HPC swells in water and is then trapped in water-insoluble EC which is responsible for the slow release of drug [51].

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Percent drug dissolved

8 HPC-SSL 6

PVP-VA Pure drug

4 2

0 0

60

120

180

240

300

Time (min)

Fig. 10.3  Dissolution profile of felodipine and its solid dispersions. Reproduced with permission from Sarode AL, Malekar SA, Cote C, Worthen DR. Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydr Polym 2014;12:518.

The low viscosity grade of HPC (HPC-SSL) has also been effectively utilized as a carrier in ASD. Research was done using HPC-SSL for investigating its potential in stabilizing the ASDs of felodipine, a poorly water-soluble drug. The effect was compared with vinyl acetate-substituted, polyvidone-vinylacetate (PVP-VA) and the results demonstrated that HPC-SSL was successful in providing stability to the felodipine ASDs when they are stored at lower or room temperature with elevated humidity. The dissolution profile of felodipine as shown in Fig. 10.3 exhibited that HPC-SSL displayed higher dissolution rate than PVP-VA [77]. Hydroxyethyl cellulose (HEC) is partially substituted polyhydroxylethyl ether of cellulose. Like EC, it is also nonionic water-soluble cellulose ether which readily disperses in water but is insoluble in organic solvents. HPC is available in many grades differing in their viscosity which depends on DS and molecular weight [63]. The polymer finds its use as a matrix for modified release tablet, as a film former, stabilizer, thickener, and suspending agent for oral and topical drug delivery. HEC is primarily used as a gel in topical formulations owing to its nonionic and water-soluble property [60]. Although the research pertaining to its use in ASD is limited, the recent research involved preparation of ASDs of etoricoxib using three water-soluble polymers—polyvinyl alcohol, PVP, and HEC—and further evaluating the kinetic solubility advantage of these prepared ASDs. The study confirmed the potential of HEC to maintain supersaturation state and imparting stability to the prepared formulation [78]. Therefore the hydroxyalkyl cellulose demands further research in the area of solubility and bioavailability enhancement of poorly water-soluble drugs.

10.5.1.4 Sodium carboxymethylcellulose Sodium carboxymethylcellulose (NaCMC) is a white, odorless, tasteless, and granular powder which is polyanionic in nature [79]. It is a product formed by substituting the

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H atoms of the hydroxyl groups of AGU by CH2CO2Na with the DS ranging from 0 to 3 [80]. NaCMC is the most important industrial derivative as well as the most exploited commercial salt of carboxymethylcellulose in comparison to its other salts (potassium, calcium, ammonium etc.). Due to its ability to easily dissolve/disperse in water, it forms highly viscous solutions which are used as a thickening or suspending agent. Moreover, their swelling behavior is observed at high pH which finds its applicability in formulating pH sensitive drug delivery of aspirin, diclofenac etc. The polymer retards the drug release at low pH values in the stomach thereby releasing the drug at high pH values in the intestine [80, 81]. NaCMC has found wide applications in the food, textile, paper, and cosmetic industry. In the pharmaceutical industry, NaCMC has been employed as a binding, emulsifying, film forming, coating, and stabilizing agent. It has been extensively used as a constituent of vehicles used for formulating oral suspension. The viscosity increasing properties have also been employed for topical formulations including gel, emulsions etc. [82]. Further, the use of NaCMC as a carrier in SD for solubility enhancement of poorly soluble drugs is well known. The latest research signifying the potential of NaCMC in augmenting dissolution and bioavailability involved the preparation of SD of Cefdinir using spray-drying method. The in vivo bioavailability was found to be increased 6.77-fold using this method [83]. The SD of Tacrolimus prepared using NaCMC and sodium lauryl sulfate reported a 2000-fold increase in the solubility and a 10-fold increase in dissolution in comparison to the tacrolimus powder [84]. In another study, the effect of NaCMC on aqueous solubility of a nonsteroidal antiinflammatory agent, flurbiprofen was investigated, where it was reported to deliver the poorly water-soluble drug flurbiprofen with enhanced solubility and bioavailability [85]. Similarly, numerous other research studies demonstrated NaCMC to be a promising vehicle in providing better dissolution and bioavailability profile for poorly ­water-soluble drugs [86–88].

10.5.1.5 Hydroxypropylmethylcellulose The most common mixed ether cellulose derivative employed in the pharmaceutical industry is Hydroxypropylmethylcellulose (HPMC). It is a water soluble nonionic polymer with molecular weight ranging from 10,000 to 150,000. It is prepared by derivatizing 16.5%–30% of the hydroxyl groups by methyl groups and 4%–32% with hydroxypropyl groups [89, 90]. HPMC acts as a binding, thickening, emulsifying, ­viscosity-controlling agent and has the ability of water retention in pharmaceuticals and personal care products. It has been used in the preparation of controlled and sustained release dosage forms where it forms a gel on coming in contact with water, following the two mechanisms for the drug release: drug diffusion through the gel layer and drug release by membrane erosion [51]. Furthermore it has been extensively employed in ASDs for improvement in solubility and is the sole pH-independent cellulose derivative utilized for the same. HPMC is reported to form a solid solution with poorly water-soluble crystalline drugs. Earlier research involving HPMC in augmenting the solubility of nifedipine [91], ER-34122 (5lipoxygenase/cyclooxygenase inhibitor) [92], and Itraconazole [93] has been r­eported.

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The polymer exhibited highest supersaturation level in the dissolution studies in comparison to the other polymers involved in the research. Since then, numerous studies have been done which unfolded the potential of HPMC in solubility enhancement, inhibition of crystallization, as well as maintaining the supersaturated state. Xie and Taylor investigated the crystallization inhibitory properties of HPMC when incorporated in the SD of Celecoxib in order to attain an improved drug release [94]. Further, Vora and his associates investigated the maintenance of supersaturation state by HPMC as the drug traverses from acidic to neutral pH. They prepared SD of dipyridamole using three molecular weight grades of HPMC (HPMC E5, E15 and E50) and found that HPMC E50 was the best polymer in inhibiting the precipitation and extending the supersaturation. However, the solubility and dissolution improvement was reported with all three grades [95]. Adibkia and coworkers prepared and characterized solid dispersion of naproxen using HPMC E4M. The maximum drug release owing to the hydrophilicity and gel forming capacity of HPMC was obtained at drug/carrier ratio of 1:2 as shown in Fig. 10.4. The dissolution was also greatly affected by the pH of the dissolution media being higher at pH 7.4 than at pH 3.0 due to increased ionization at high pH leading to improved solubility [96]. The increase in solubility and drug release was also obtained when HPMC was used as a carrier to prepare the SDs of Itroconazole [97] and Cefdinir [83].

10.5.1.6 Cellulose acetate phthalate Cellulose acetate phthalate (CAP) is a cellulose ester containing acetyl (21.5%–26%) and phthalyl or o-carboxybenzoyl (30%–36%) groups. It is synthesized by reacting phthalic anhydride and partial acetate ester of cellulose. CAP is mainly employed as an

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Fig. 10.4  Dissolution profile of pure naproxen, physical mixtures, and solid dispersions in (A) pH 3.0 and (B) pH 7.4. Reproduced with permission from Adibkia K, Barzegar-Jalali M, Maheri-Esfanjani H, Ghanbarzadeh S, Shokri J, Sabzevari A, Javadzadeh Y. Physicochemical characterization of naproxen solid dispersions prepared via spray drying technology. Powder Technol 2013;246:452–453.

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enteric coating agent in delayed-release dosage forms which confers gastro-­resistance and it readily dissolves in a neutral or mildly acidic intestinal environment [98]. The polymer is insoluble at low pH and dissolves/swells at neutral to high pH. Due to its distinctive properties such as high Tg value, ability to ionize at low pH, and as a concentration enhancer, it was evaluated for its potential as a carrier in ASDs. A study involving CAP/Itraconazole matrix revealed twofold improvement in its oral bioavailability in comparison to the marketed formulation of Itraconazole (SPORANOX) in rat models. The improvement in bioavailability was due to the enhanced intestinal targeting and increased extent of supersaturation exhibited by CAP [99]. Recently, CAP displayed significant results when evaluated in comparison to other cellulosics for increasing the solubility of Lopinavir [100]. However, the polymer lacks sufficient research pertaining to its use in ASDs for solubility enhancement.

10.5.1.7 Carboxymethyl cellulose acetate butyrate Carboxymethyl cellulose acetate butyrate (CMCAB) is a hydrophobic ester derivative of water-soluble, anionic cellulose ether, carboxymethylcellulose (CMC) [101]. The DS of CMCAB polymers varies depending on the feed ratios and reaction conditions with different DS values for each of carboxymethyl (0.29–0.35), butyryl (1.37–1.64), and acetyl (0.30–0.55) groups. The synthesis of CMCAB is done by the esterification of NaCMC with acetic and butyric anhydrides. It is a thermoplastic polymer with high molecular weight and high Tg [102]. Being a nonpolar compound, it is insoluble in water but soluble in common organic solvents such as ketones, alcohols, esters, and ethers. However, CMCAB swells in water when it is partially ionized [103]. The use of CMCAB in oral drug delivery employs two very effective methods as described by Posey-Dowty and associates. The first, being the easiest one, involved preparing physical blends of ibuprofen with CMCAB by direct compression which resulted in extended drug release at zero-order at pH 6.8 [103]. The second method, being more effective, involved preparation of ASD of a poorly water-soluble drug (Fexofenadine HCl) which resulted in enhancement of its solubility [104]. The ASDs of poorly water-soluble drugs prepared using CMCAB produce stable supersaturated solution with zero-order release profile [105]. The potential of CMCAB for increasing solubility in ASDs were also evaluated in quercetin [106], curcumin [107], naringenin [105], ellagic acid [108], and resveratrol [109]. CMCAB has also recently been employed in novel techniques involving preparation of nanoparticles of cellulose acetate-based SD matrices. The ASD of p­ olymer-drug nanoparticles of ritonavir (RTV) and efavirenz (EFV) was prepared using flash ­nano-precipitation method. CMCAB showed best results among other polymers employed in this research (cellulose acetate propionate 504-0.2 adipate 0.33, cellulose acetate propionate adipate 0.85, and cellulose acetate 320S sebacate). There was a 10- to 20-fold improvement in the solubility of RTV and EFV using these cellulose derivatives [110]. An earlier similar study has been reported involving preparation of CMCAB nanoparticles containing acyclovir [111]. Thus CMCAB is a carboxylated cellulose derivative strongly recommended for use in ASD due to its unique properties

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of high Tg, low toxicity, impeding crystallization, maintaining supersaturation, and imparting pH controlled drug release [112].

10.5.1.8 Hydroxypropylmethylcellulose acetate succinate HPMCAS is known to be a premier polymer excipient available in the industry due to its high Tg value (133°C), benign toxicity profile, maintaining supersaturation state, and hampering crystal growth. The synthesis of HPMCAS is very complicated and requires critical control of the five substituents, i.e. methoxyl, hydroxypropyl, acetate, and succinate [113]. Due to these hydrophobic (methoxyl and acetate) and hydrophilic (hydroxypropyl and succinate) groups attached on the AGU chain, HPMCAS behaves as an amphiphilic polymer which facilitates strong interaction with hydrophobic drugs, thus leading to the formation of stable dispersions in water. The high Tg of the HPMCAS-based dispersions is also one of the reasons for the formation of physically stable dispersions having shelf lives of more than 2 years under standard storage conditions [114]. In addition, HPMCAS being less hygroscopic does not allow moisture uptake thus contributing stability to the formulation in which it is incorporated. HPMCAS is an enteric polymer and its dissolution behavior can be controlled by controlling the number of acetyl and succinoyl groups attached at the AGU chain. Thus the amorphous dispersion of HPMCAS with poorly soluble drugs was found to release the drug at the pH of the small intestine and showed no release at the pH of the stomach [16]. Hydroxypropylmethylcellulose acetate succinate or Hypromellose acetate succinate (HPMCAS) was initially developed as a cellulosic enteric coating agent in 1984. In addition, it also proved its efficacy as a carrier in the preparation of SDs [115]. HPMCAS was first patented by Shin-Etsu in 1987 and its use as a carrier in ASD was developed and patented by Pfizer Inc. in alliance with Bend Research. The mere admixture of HPMCAS with the basic or zwitterionic drugs was reported to improve the solubility ~1.5-fold [116]. In a study, the effect of polymer type on the solubility and dissolution enhancement of ASDs containing felodipine was studied, where HPMCAS outperformed other polymers (HPMC & PVP) in maintaining the supersaturated state subsequent to the dissolution of amorphous solids. In addition, it was found to impede crystallization thus reducing the growth of felodipine crystals and contributing to its enhanced dissolution [117]. Li et  al. demonstrated the solubilizing potential of HPMCAS in several studies and compared it with other carriers. In one such study, fast and complete drug release was obtained for ASDs containing curcumin:HPMCAS at 1:9 as shown in Fig.  10.5. The dispersions were also found to inhibit crystallization and protect curcumin against chemical degradation, thereby yielding stable dispersions [107]. HPMCAS was able to achieve high solubility and bioavailability in quercetin [106], ellagic acid [108], naringenin [105], and resveratrol [109] and was found more effective than other polymers in inhibiting crystallization and maintaining a supersaturated state. Recently, ASD of quercetin was prepared using cellulose ester, HPMCAS to improve its aqueous solubility, provide stability against crystallization, and impart pH-triggered release [118]. Similar effects were observed in progesterone [35], nifedipine [119], celecoxib [94], and danazol [120].

Polysaccharide Carriers for Drug Delivery

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Fig. 10.5  Dissolution profile of curcumin/HPMCAS solid dispersions in pH 6.8 buffer. Reproduced with permission from Li B, Konecke S, Wegiel LA, Taylor LS, Edgar KJ. Both solubility and chemical stability of curcumin are enhanced by solid dispersion in cellulose derivative matrices. Carbohydr Polym 2013;98(1):1114.

10.5.2 Natural gums The natural carriers have always evoked tremendous interest of the researchers due to their being nontoxic, biocompatible, biodegradable, cost-effective, chemically inert, and available in abundance. Moreover, they can be tailored easily to obtain the material of desired properties thus giving tough competition to the available synthetic excipients [121]. The orientation of the pharmaceutical industry as well as the increase in patients’ interest towards these natural agents has led to the improvement in their methods of extraction and purification to give higher yield. The investigations on the natural carriers majorly center around polysaccharides. Natural gums (polysaccharides) have gained interest in recent years and have been investigated for drug delivery applications and in the biomedical field. Moreover, they are devoid of any toxicity and thus have been categorized as GRAS by USFDA [122]. India has been a rich source of these gums among the Asian countries because of its environmental and geographical position [123]. The gums have diverse application in the pharmaceutical industry as a tablet binder, disintegrant, emulsifying agent, suspending agent, targeting, and for immediate and sustained-release preparation [124, 125]. Moreover, many natural gums have found their use in formulation of solid dispersion for solubility enhancement of poorly soluble drugs [126]. They have been investigated by many researchers and have shown promising results in modifying drug release from the formulations [127]. The natural gums are also associated with disadvantages such as microbial contamination, batch to batch variation, uncontrolled rate of hydration, and reduced viscosity on storage which demands modification of existing natural agents for their successful incorporation in novel drug delivery systems (NDDS) [124]. In addition, they readily dissolve in water and swell forming a viscous gel layer around the dosage form leading to its sustained release. Due to these inherent limitations and undesired properties, the gums are modified by heating at a specific temperature for a definite period and then sieved

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and stored at 25° C. This step reduces the viscosity and increases the water retention capacity of the gums causing minimal changes in their swelling behavior [128]. Thus there is huge scope for research on these gums for exploiting them for largescale manufacturing of different drug delivery systems in the pharma industry.

10.5.2.1 Neem gum The use of neem (Azadirachta indica Family: Meliaceae) in Ayurvedic medicine dates back 4000  years and it is considered as a wonder tree in India, offering treatments for almost every ailment [129]. Azadirachtin and nimbin are the main constituents of neem gum. Neem gum is composed of mannose, galactose, arabinose, glucosamine, glucose, fucose, and xylose [123]. Several compounds have been isolated from different parts of the tree, used for antifungal, antimalarial, antibacterial, antiviral, antitumor, antiinflammatory, antipyretic, analgesic, antiulcer, antiglycemic, and antifertility activity [130]. Besides its medicinal uses, neem gum has certain pharmaceutical applications. Previous studies have shown the use of neem gum as a directly compressible excipient [131], tablet binder [132], suspending agent [133], thickening agent [134], sustained release agent, and film coating agent [135]. Recently, the applicability of neem gum as a solubility-enhancing agent has been discovered; however, very little research has been done in this area. Neem gum has a very low viscosity which makes it suitable as a solubilizer. Rodde and coworkers have prepared solid dispersion of Atorvastatin using neem gum as a hydrophilic carrier. The results exhibited an increase in solubility (~85.8%) of the drug with increase in gum concentration (drug: polymer=1:9). The in vitro, ex vivo and in vivo studies further confirmed the potential of neem gum in enhancing the solubility and bioavailability of Atorvastatin [136]. A similar study utilized neem gum as a prospective carrier for bioavailability enhancement of the poorly soluble drug Aceclofenac, achieving enhanced dissolution profile. The in vivo pharmacodynamic studies exhibited improved analgesic potential of the solid dispersion-based tablet formulation when compared to that of the pure drug and the marketed formulation [137]. Hence, more exhaustive research and thorough investigations are a prerequisite for neem gum to be established as a solubility enhancing agent.

10.5.2.2 Locust bean gum Locust bean gum (LBG) is also known as carob gum or carubin, is a galactomannan vegetable gum obtained by removing and processing of endosperm of the pods of the tree Ceratonia silique (Family: Leguminosae/Fabaceae) [122]. It is a high molecular weight polysaccharide consisting of 80% d-galacto-d-mannoglycan (mannose:galactose=4:1) and the rest 20% consisting of proteins cellulose and impurities [138, 139]. USFDA has categorized LBG as GRAS and has defined 74.25 mg as the approved limit for its use. LBG is partially soluble in water at room temperature; therefore in order to attain maximum viscosity, hydration, and solubilization, modified LBG (MLBG) is prepared by heating at above 85° C for 10 min [140, 141]. LBG has been widely used as an excipient in the pharmaceutical industry owing to its gelling, thickening, and stabilizing property [142]. It is also employed as a

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­superdisintegrant [141], emulsifying, binding, granulating agent [125], mucoadhesive, coating agent [143], and for the controlled and sustained delivery of the drugs [144]. The extensive use of LBG has been credited to its high swelling behavior, high water retention capability, chemical compatibility, binding, and digestible nature [128]. MLBG has been used as a carrier for the solubility enhancement of lovastatin using solid dispersion method. The results revealed enhanced solubility and improved dissolution which was found to be dependent on LBG concentration and method of preparation. Further the in vivo study confirmed a significant reduction in HMG Co-A (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase activity [128]. In another study involving preparation of solid dispersion of loratadine using MLBG as a carrier, enhanced solubility and dissolution was achieved owing to the synergistic effect of reduced crystallinity, reduced drug particle size and improved wettability [145]. MLBG also enhanced the solubility of glibenclamide (from 26 to 97 μg/mL) on the same principle and the in vivo studies exhibited better activity in alloxan induced diabetic rat model. Similar studies were conducted which demonstrated the superior potential of MLBG in the biopharmaceutical field for solubility enhancement [146–149].

10.5.2.3 Karaya gum Karaya gum is a dried gummy exudate which is obtained from a large bushy tree (30 ft.) Sterculia urens (Family: Sterculiaceae) which is native to India. The gum is an acid polysaccharide which includes d-galactose, d-glucouronic acid, l-rhamnose, xylose residues, and acetyl groups as its main constituents [122]. Karaya gum is categorized as GRAS by USFDA and has been widely used as a food additive [150, 151]. In addition, the use of this gum as a laxative is evident from the literature [152]. It has been employed as a mucoadhesive, emulsifying agent, suspending agent, and sustained release agent [153]. The prior investigations have also indicated its use as a disintegrant and hence it can be used as an alternative to synthetic superdisintegrants owing to its abundant availability, biocompatibility, and low cost. The varied uses of this gum are due to its high water retention capacity, viscosity, and swelling behavior, antimicrobial property, and abundant availability [140]. The use of karaya gum as a tablet binder and as a disintegrant has been limited by its high viscosity which led to modifications in the gum. Modified karaya gum (MGK) has been prepared by heating at 120°C for 2 h to modify its viscosity and for its better processing and handling during the preparation of solid mixtures. However, the swelling behavior of MGK has not been compromised and is found comparable to unmodified karaya gum. Some researchers have also indicated the potential of MGK in dissolution enhancement of poorly soluble drugs. In a research study involving preparation of solid dispersion of Nimodipine using MGK as the carrier, the superiority of MGK over unmodified gum was demonstrated. MGK was found to be a potential carrier in dissolution rate enhancement of nimodipine as shown in Fig. 10.6 [154]. They later conducted in vivo study which also confirmed the efficiency of MGK as a solubility and bioavailability enhancing agent [155]. In another study, which involved preparation of solid mixtures of Nimesulide with MGK by physical mixing, kneading, and solid dispersion techniques, solid dispersion exhibited the most promising results

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Fig. 10.6  Dissolution profile of nimodipine and its solid dispersions. Reproduced with permission from Murali Mohan Babu GV, Prasad CDS, Ramana Murthy KV. Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly watersoluble drug nimodipine. Int J Pharm 2002;234(1–2):12.

in solubility enhancement of nimesulide [156]. MGK also enhanced the dissolution rate of glimepiride and was found to overcome the high viscosity issues observed with karaya gum [157]. Several other studies have been done in the past involving preparation of solid dispersion with MGK confirming its potential as a carrier for solubility and bioavailability enhancement [150, 158].

10.5.2.4 Guar gum Guar gum, also known as cluster bean or guaran, is a galactomannan extracted from the endosperm of the seeds of Cyamompsis tetragaonolobus (Family: Leguminoseae). It is high molecular weight polysaccharide consisting of a linear chain of galactose and mannose residues (mannose:galactose=2:1) [159, 160]. Therapeutically guar gum has been utilized as a bulk-forming laxative, in peptic-ulcers, as an adjunct in treatment of Type II diabetics and as an appetite depressant [125]. The pharmaceutical uses of guar gum encompass tablet binding, disintegrating, stabilizing, thickening, emulsifying, as a sustained release agent, and for colon targeted drug delivery [161–163]. For their use in pharmaceutical industry they are modified by heating at 125–130°C for 2–3 h. The viscosity of the modified guar gum (MGG) was found to be reduced by ~3 times without any change in the swelling and water retention capacity, thus paving the way for their use in solubility enhancement. Solid dispersion of licofelone was prepared by using guar gum and MGG at a ratio of 1:6 (drug:gum). The results clearly

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indicated the efficacy of MGG in enhancing the solubility of licofelone. The reason was the swelling property of the gum which increased the surface of carrier coming into contact with the dissolution medium resulting in enhanced dissolution rate [164]. Another study involved the preparation of solid dispersion of gliclazide using guar gum as the carrier which resulted in 96.79% release within 60 min [165]. Maximum solubility and in vitro dissolution were attained when solid dispersion of cefixime was prepared using MGG as the carrier by using solvent evaporation method [166]. The ability of guar gum to enhance the dissolution rate of poorly soluble drugs has been widely studied thus establishing it as a prospective solubilizer [167–169].

10.5.2.5 Hupu gum Hupu gum or kondagogu gum is a dried gummy exudate obtained from Cochlospermum gossypium (Family: Cochlospermaceae/Bixaceae). It is an anionic polysaccharide belonging to the class of substituted rhamnogalacturonans which consist of rhamnose, glucuronic acid, galacturonic acid, galactopyranose, glucose, galactose, fructose, mannose, and arabinose with sugar linkages [170]. The gum is modified to reduce the viscosity, increase water-holding capacity and improve mucoadhesiveness by the process of carboxymethylation or heating at 140°C for 2 h [171]. The utilization of hupu gum in the field of pharmaceutics include solubility enhancement, colon targeting, as an emulsifying agent, and for controlled and sustained drug release [172–175]. The ability of the gum to swell to a considerable size proves to be favorable for improving the solubility of a poorly water-soluble drug. A study was conducted to improve the dissolution profile of an antidiabetic drug, pioglitazone HCl, using hupu gum and modified hupu gum (MHG) as carriers using solid dispersion methodology. The unmodified gum was found to form lumps with the drug thereby decreasing dissolution whereas the solid dispersion formed using MHG as the carrier resulted in easily dispersed particles. Thus MHG proved its efficacy in enhancing the solubility of pioglitazone HCl over that of unmodified hupu gum [176]. Thereafter, studies were conducted involving preparation of solid dispersion of the drugs using different carriers including hupu gum and comparing their potencies in solubility enhancement [165, 169, 177]. Hupu gum showed promising results but needs further exploration for it to be established as a potential solubilizer.

10.5.2.6 Xanthan gum Xanthan gum is an anionic, high molecular weight polysaccharide produced by the bacterium Xanthomonas campestris. It consists of a backbone made of glucose with mannose and glucose units [122, 172]. The pharmaceutical uses of xanthan gum include sustained and controlled drug release [178], as a suspending agent [179], and for colon-specific drug delivery [180]. Xanthan gum is modified to reduce its viscosity by heating at a temperature of 120°C. Modified xanthan gum (MXG) was found to possess less viscosity, comparable swelling index, and increased water retention capacity which proves to be advantageous for enhancement in dissolution [172]. The enhancement of dissolution profile of valsartan was achieved when it was formulated as solid dispersion using MXG as

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carrier. The solubility studies demonstrated that drug solubility increased with the increase in concentration of polymer [169]. In a study, MXG increased the percent drug release from 40% to 70% owing to the enhanced wettability and dispersibility of gliclazide in the surrounding dissolution medium [165]. Similar results were obtained when simvastatin [181] and pioglitazone HCl [182] was formulated as solid dispersion using MXG. Xanthan gum requires further studies to confirm its applicability in the formulation technology.

10.5.2.7 Tamarind gum Tamarind gum is a biodegradable polysaccharide obtained from the endosperm of the kernels of Tamarindus indica (Family: Leguminosae). The gum constitutes 65% of the total seed components [183]. It is a galactoxyloglucan consisting of a backbone of d-(1-4)-galactopyranosyl unit which is substituted with side chains of xylose and galactose linked to glucose. This polysaccharide is a monomer of glucosyl:xylosyl:galactosyl in the ratio of 3:2:1 [123]. Being under the GRAS category, it has been widely utilized as a tablet binder, disintegrant [184], emulsifier [185], suspending agent [186], gelling agent [183], and for colon targeting [187, 188]. The gum possesses mucoadhesive properties due to which it has been used in the past as a controlled release excipient for drug delivery through nasal mucosa [189]. Owing to its viscosity and swelling behavior it has been employed for increasing the solubility of Aceclofenac, Atorvastatin and Irbesartan [190]. The combination of tamarind gum with xanthan gum has yielded promising results for solubility enhancement of BCS Class II drugs [125]. However, there is scope for more research for exploration of solubility enhancement potential of tamarind gum.

10.5.2.8 Mango gum Mango gum is isolated from the barks of Mangifera indica (Family: Anacardiaceae). It is a dried gummy exudate polysaccharide obtained from the incised trunk which is rich in mangiferin, protocatechuic acid, γ-aminobutyric acid, catechin, indicoside A and B, manghopanal, mangocoumarin, manglupenone, mangsterol, and mangiferolic acid methyl ester. Mango gum has inherent antidiabetic, antiviral, antiparasitic, antidiarrhoeal, antitumour, antispasmodial, antifungal, antibacterial, and immunomodulatory activity [121]. However, the pharmaceutical applications of mango gum include its use as a tablet binder [191], disintegrant [192], and for sustained release [193]. Although mango peel pectin has been utilized as a carrier for enhancing the dissolution rate of a poorly water-soluble drug, Aceclofenac, the exploitation of mango gum for solubility enhancement is still pending [194].

10.5.2.9 Aegel marmelos gum Aegel marmelos gum (AMG) is obtained from the fruits of Aegle marmelos belonging to family Rutaceae. The gum is rich in d-galactose, l-Rhamnose, l-arabinose and d-galacturonic acid. The medicinal uses of AMG include reducing glutathione concentration in the liver, stomach, intestine, and kidney, decreasing lipid peroxidation,

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plasma insulin, and liver glycogen level [140]. In addition to augmenting the solubility of poorly soluble drugs, AMG has been utilized as a tablet binder and as a mucoadhesive agent [140, 195]. The solubility enhancing property of AMG has been studied in two separate research studies, which involved preparation of solid dispersion of aceclofenac and atorvastatin. The solubility of aceclofenac was found to markedly increase from 0.0816 to 15.65 mg/mL with the increase in concentration of AMG [196]. Similarly, solid dispersion of atorvastatin with AMG resulted in a twofold increase in its solubility [197]. Therefore AMG can be utilized as a prospective natural carrier for solubility enhancement.

10.5.3 Sugar and urea Sugars are the first generation carriers which were earlier used in the preparation of SD but now have very limited use. Although they possess advantages such as very high water-solubility, very little to no toxicity, and easy availability, which makes them a suitable carrier, their disadvantages such as high melting point, low solubility in organic solvents, and hygroscopic nature outweigh these advantages thus leading to rare use in SD [89, 198]. Moreover, the SDs which resulted using these carriers were found to be crystalline in nature exhibiting a slow drug release as opposed to the rapid drug release by ASDs. Mannitol, having a high melting point of 165–168°C and decomposition at above 250°C can be used to prepare SD by hot melt method in some cases. A research study involved preparation of SD of celecoxib using mannitol by physical trituration, solvent evaporation, and melt methods. The results reported highest increment in solubility in SD prepared by melt/fusion method at 1:5 drug:mannitol ratio. However, the results were insufficient to indicate whether the prepared SD was amorphous or crystalline [14]. A recent study utilized various sugar carriers like d-mannitol, d-fructose, d-­dextrose and d-maltose for the solubility enhancement of clotrimazole by the SD approach. The results indicated improvement in solubility, dissolution, and antifungal activity of clotrimazole. The solubility was increased 806-fold as compared with the plain drug using saturated solution of mannitol. This study inferred that the sugar alcohols like mannitol are suitable carriers for SD in comparison to the monosaccharide and disaccharide having aldehyde and ketone group [199]. Another study involved the preparation of SD of griseofulvin by roll mixing method using saccharides such as corn starch, maltose, and lactose as carriers. The dissolution was enhanced ~170-fold and griseofulvin in the roll mixture was found to be present in the amorphous state as detected by absence of drug peaks in XRD [200]. Some of the past research involving use of other sugar carriers such as xylitol [201], sorbitol [202], dextrose, sucrose [203], galactose [204], mannitol [205], trihalose [27], and isomalt [206] have been reported by researchers. All these carriers were found to report increase in solubility when employed as carriers in solid dispersions but do not find much application currently due to the availability of more effective synthetic polymers. Urea is the end product of human protein metabolism and is the first generation agent employed in SD. It is reported to exhibit no toxicity. Urea is found to have sufficient solubility in water and to exhibit good solubility in organic solvents. The earlier

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297

and perhaps the first study incorporating urea as the carrier in SD was that by Sekiguchi and Obi who reported better absorption in rabbits when sulphathiazile was given as a eutectic with urea [24]. Similarly, better dissolution was observed with solid dispersion of chloramphenicol [207] and ursodeoxycholic acid [208] using urea as the carrier. However, since then, the use of urea in SDs has become more or less obsolete due to the introduction of second and third generation carriers which were found more effective. Though there are few research studies done lately to support the use of urea as a carrier in SD, the most recent research was based on preparation of clarithromycin-urea solid dispersion by solvent evaporation, electrospraying, and freeze-drying method. Among all these, the SDs prepared by freeze-drying displayed best results in terms of improvement in solubility and bioavailability as shown in Fig. 10.7 [209]. Urea exhibited improvement in dissolution of cefuroxime axetil [210] and rofecoxib [211] as well when incorporated in their SDs.

10.5.4 Inutec SP1

Plasma Concentration (ng/ml)

Inutec SP1 is a polydisperse polysaccharide which is extracted from the roots of Cichorium intybus (Family: Asteraceae) consisting mainly of fructosyl fructose units and not necessarily one glucopyranose unit. It is obtained by reacting isocyanates and the polyfructose backbone using tertiary amine or a Lewis acid as the catalyst which introduces alkyl groups on its backbone [212]. The polymer depicts excellent surfactant properties (with both hydrophilic and lipophilic parts on the chain) which present an interesting approach for it to be utilized as a carrier in SDs [213]. Mooter and his coworkers introduced the new use of Inutec SP1 as a suitable carrier and evaluated its potential by incorporating it in SD of itroconazole, an antifungal

100

% Release

80 60

1:3 ratio 1:2 ratio

40

1:1 ratio

20

Clarithromycin

0

(A)

0

30

60 90 120 Time (min)

150

180

1000 900 800 700 600 500 400 300 200 100 0

(B)

Freeze drying (Drug:urea=1:3) Drug powder

0

2

4

6

8

10

12

Time (h)

Fig. 10.7  (A) Dissolution profiles of clarithromycin and its solid dispersions prepared by freeze drying method and (B) in vivo blood concentration of clarithromycin powder and solid dispersions prepared by freeze drying method. Reproduced with permission from Mohammadi G, Hemati V, Nikbakht M, Mirzaee S, Fattahi A, Ghanbari K, Adibkia K. In vitro and in vivo evaluation of clarithromycin–urea solid dispersions prepared by solvent evaporation, electrospraying and freeze drying methods. Powder Technol 2014;257:173.

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Fig. 10.8  Dissolution profile of itroconazole and its solid dispersions using (A) Inutec SP1, (B) Inutec SP1, and PVPVA 64. Reproduced with permission from (A) Van den Mooter G, Weuts I, De Ridder T, Blaton N. Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersion for poorly soluble drugs. Int J Pharm 2006;316(1–2):3. (B) Janssens S, Humbeeck JV, Van den Mooter G. Evaluation of the formulation of solid dispersions by co-spray drying itraconazole with Inutec SP1, a polymeric surfactant, in combination with PVPVA 64. Eur J Pharm Biopharm 2008;70(2):502.

BCS Class II drug. However, the SDs prepared were found to be crystalline in nature as revealed by DSC and XRD studies and despite this the dissolution was improved as compared to the pure drug [3]. However, in another research by Janssens and associates, the XRD studies of the solid dispersion of itroconazole reported amorphous content of the drug. In addition to inutec SP1, they incorporated PVP-VA 64 which kept the drug molecularly dispersed and led to an immense improvement in the degree of dissolution in comparison to earlier research as shown in Fig. 10.8 [214]. Later, a research study which involved evaluation and comparison of the solubilizing potential of inutec SP1 with PVP was done for the poorly soluble drugs such as diazepam, fenofibrate, ritonavir, and efavirenz. The results depicted the outstanding performance of inutec SP1 in increasing the solubility of the respective drugs. The prepared SDs were also found to possess good physical stability when tested for three months [215]. Moreover, besides being used as a carrier in SDs, inutec SP1 is employed successfully as a surfactant, emulsifying, stabilizing, and suspending agent because of its excellent surfactant properties, nontoxicity, and biodegradability [213].

10.5.5 Pectin Pectins are heterogeneous polysaccharides with a linear homo-galacturonic backbone alternating with two types of highly branched rhamno-galacturonans regions (RG-I & RG-II) [216, 217]. It is the methylated ester of polygalacturonic acid which makes up about 33% of the cell wall dry substance of higher plants. They find their main application in the food industry as gelling or thickening agents, particularly pectins

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derived from citrus peel and apple pomace under mildly acidic conditions. In the pharmaceutical industry, it is mainly employed as an excipient due to its nontoxic and nonirritating nature, abundant availability, and low production costs. Pectins are also used for colonic targeting drug delivery, controlled drug delivery, and as an immunostimulant [218, 219]. However, despite the several advantages offered by pectins, only one study reports the use of pectin in SDs. The pectin used in the study was extracted from mango peel and was used in the preparation of SDs of Aceclofenac. The findings revealed that with the increase in pectin content, the dissolution of the drug was significantly improved [194]. Therefore more research needs to be conducted on pectins pertaining to their use in SDs.

10.5.6 Corn starch Starch is synthesized by the plants in granular form and consists of linear amylose, branched amylopectin, and minor constituents including proteins, lipids, and minerals [220]. It is a nontoxic, biodegradable and renewable material and therefore has tremendous potential in the industry. On the other hand, the inherent properties of starch limit their direct industrial applicability, for which several physical, chemical, and enzymatic modifications are needed [221]. In addition, the use of corn starch as a carrier in SD is also very limited. In one study the solubility enhancement of Griseofulvin [200] was observed and another study used a mixture of corn starch and lactose to achieve improved dissolution for aceclofenac [222]. Recently, corn starch with varying ratios of amylose to amylopectin was used to study the thermodynamic interactions with the model drugs (acetaminophen and phenazone). Holt-melt extrusion method was used to prepare the SDs but the findings revealed that the drug in SD showed crystalline behavior [223].

10.5.7 Chitosan Chitin, a nitrogenous polysaccharide, is isolated from the exoskeleton of marine organisms (largely crabs and shrimps) which are crushed, washed, and treated with sodium hydroxide to obtain crude chitin [224]. Chitin has been widely used for lowering serum cholesterol and in hypertension and ophthalmic formulations. However, the practical use of chitin has declined owing to its semicrystalline structure with extensive hydrogen bonds and it being insoluble in most of the solvents [218]. Therefore its derivative chitosan was developed, which is a deacetylated product obtained from chitin and is a copolymer of β-(1→4)-linked 2-acetamido-2-deoxy-d-glucopyranose and 2-amino-2-deoxy-dglucopyranose [224]. The different grades of chitosan contain varying amounts of these two monosaccharides with molecular weight ranging from 50 to 2000 kDa, each differing in their viscosity and pKa values [225]. Chitosan is reported to be insoluble in water and organic solvents. However, it exhibits pH-dependent solubility, being soluble at pH 6.0 and insoluble above pH 7.0, therefore it cannot be used for biological applications which require a neutral environment. Hence, modifications of chitin/chitosan in the form of esterification, etherification, O-acetylation, cross-linking, and graft copolymerization can be done to introduce desired properties in the polymer [226].

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Chitosan is the second most abundant natural polysaccharide after cellulose and has attracted researchers’ interest owing to its nontoxic, biocompatible, biodegradable, bioadhesion, bioabsorbable, and renewable nature supplemented with its wide availability, flexibility in usage, and low cost. It has consequently emerged as one of the most promising polymers achieving the status of most desired polymer for use in therapeutic interventions [227, 228]. As reported firstly by Allan & Hardwiger in 1979, chitosan is believed to have an excellent antimicrobial activity. They demonstrated that chitosan possesses a wide spectrum of activity and a high killing rate against both gram-positive and gram-negative bacteria [229, 230]. A recent study investigated the antimicrobial and antioxidant properties of abietic acid-chitosan SDs. It suggested that abietic acid and chitosan displayed a synergistic effect at 1:1 ratio. In addition, increased antimicrobial and antioxidant activity was observed with the drug in its amorphous state [231]. Some authors have also reported the use of chitosan in enhancing solubility and consequently bioavailability of poorly soluble drugs. The solubilizing potential of chitosan was investigated by preparing ASD of telmisartan using chitosan as the carrier by different methods. The results advocated use of cogrinding method to achieve markedly improved dissolution, reduced particle size, and drug amorphization which increased with the increase in concentration of chitosan [232]. Mura et al. prepared binary solid dispersions of naproxen with chitosan and studied the effect of varying chitosan molecular weight, drug/chitosan (w/w) ratio, and preparation method on the dissolution rate of naproxen. The results revealed that the dispersions prepared by cogrinding method using low molecular weight chitosan (CS-Lw) and with drug:chitosan of 1:9 increased the dissolution rate 10-fold. The relative increase in dissolution efficiency for solid dispersions prepared by different methods using chitosan at low (CS-Lw) and medium (CS-Mw) molecular weight is depicted in Fig. 10.9 [233]. Earlier studies validated the potential of chitosan in enhancing the solubility and bioavailability of poorly soluble drugs [234–236].

10.5.8 Carrageenan Carrageenan is a natural heteropolysaccharide which is extracted from a species of red seaweed (Class: Rhodophyceae). The main sources are Eucheuma spinosum, Eucheuma cottonii, and Chondrus crispus. Chemically, carrageenan is a high molecular weight linear polysaccharide comprising of repeating galactose units. It is soluble in water and insoluble in most of the organic solvents. Carrageenan at very low concentrations in water forms a weak gel and is unstable in highly acidic conditions. The pharmaceutical uses of carrageenan comprise of suspending, stabilizing, thickening, and gelling agents. It is most commonly used for oral and topical drug delivery, dentrifices, wound cleaning, cosmetics, suppository bases, and in controlling humidity in industrial plants [237]. Carrageenan has been shown to possess solubilizing potential, however, only one study has been reported which depicted solubility enhancement of efavirenz by formulating its SD using carrageenan as a carrier [238, 239]. Therefore the polymer needs further exploration in this area to establish its solubilizing potential.

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rel. incr. DE 6 5 4 3 2 1 0

CS-Lw P.M.

COE

CS-Mw KN

GR

P.M. = Physical mixture COE = Co evaporation KN = Kneading GR = Cogrounded

Fig. 10.9  Relative increase in dissolution efficiency for 3:7 (w/w) products of naproxen with chitosan. Reproduced with permission from Mura P, Zerrouk N, Mennini N, Maestrelli F, Chemtob C. Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties. Eur J Pharm Sci 2003;19(1):73.

10.5.9 Alginate Sodium alginate (SA), the most available form of alginate, is a hydrophilic polysaccharide which is mainly isolated from the cell walls of brown seaweeds. Chemically it consists of guluronic acid and mannuronic acid arranged in an irregular pattern with reactive sites like hydroxyl and carbonyl groups present along the backbone [218, 240]. Alginate is nontoxic, biocompatible, and biodegradable and has been categorized as GRAS by FDA since 1982 [241]. Alginate has been invariably used in forming hydrogels, microparticles, and in drug delivery [218]. It has been employed in solid dispersion as an ester derivative for enhancing the solubility of poorly soluble drugs [242]. In another recent study, SA showed enhanced solubility and dissolution rate of telmisartan when employed as a carrier in its SD prepared by ball milling method as displayed in Fig. 10.10. The polymer has also been reported to inhibit the recrystallization of the drug [241]. The most recent research explored the potential of SA as a diphase SD carrier in enhancing solubility and solubility of two model drugs: indomethacin and lovastatin. SA was successful in providing stability and improving dissolution in comparison to HPMCAS-based systems [243]. As not much research has been done using SA as a carrier in SD due to limited molecular interaction between alginate and drugs, the area needs further exploration.

302

Polysaccharide Carriers for Drug Delivery 100

Dissolution efficiency (%)

*

*

80 60 40 20

s di

9 _1 :

M

ic ar

7 _1 :

SD

5 _1 :

SD

3 _1 :

SD

1 SD

_1 :

PM

SD

TE L

0

Fig. 10.10  Dissolution profiles of telmisartan and its solid dispersions. Reproduced with permission from Borba PAA, Pinotti M, de Campos CEM, Pezzini BR, Stulzer HK. Sodium alginate as a potential carrier in solid dispersion formulations to enhance dissolution rate and apparent water solubility of BCS II drugs. Carbohydr Polym 2016;137.

10.6 Marketed amorphous solid dispersions Solid dispersion has managed to attract the attention of researchers in the area of solubility enhancement but still the number of products reaching the stage of commercialization is relatively very few. However, most of the SDs available on the market contain polysaccharides as the carriers as shown in Table 10.4. The reason for the lesser availability of marketed formulations employing an SD approach can be primarily attributed to the scale-up problems, physicochemical instability in the manufacturing process, or during storage leading to crystallization and phase separation [5, 17, 244].

10.7 Concluding remarks The pharmaceutical development pipeline is comprised of a large number of drugs which are poorly water-soluble and present significant challenges to formulation scientists. Over the past few decades, ASD technology has emerged as a powerful solubility enhancing technology which stabilizes the drug in the amorphous form both in the dosage form as well as during the supersaturation state. This technique has been considered as a major advancement in the area where poor water-solubility is a concern. ASDs are accompanied by various benefits such as drug stabilization, enhanced drug release, and ease of administration by the patient compliant oral route. However, the physical instability and the processing difficulties observed with ASDs are the

Marketed product

Drug

Carrier

Manufacturer (year of approval)

Indication

Orkambi Noxafil

Lumacaftor/Ivacaftor Posaconazole

HPMCAS/SLS HPMCAS

Vertex Pharmaceuticals Inc. (2015) Merch Sharp & Dohme Ltd. (2014)

Kalydeco Zelboraf Incivek

Ivacaftor Vemurafenib Telaprevir

HPMCAS HPMCAS HPMCAS-M

Abbott Laboratories (2012) Roche (2011) Vertex Pharmaceuticals (2011)

Certican Onmel Zotress

Everolimus Itraconazole Everolimus

HPMC HPMC HPMC

Novartis (2010) Merz Pharma. Inc. (2010) Novartis (2010)

Intelence Crestor Afeditab CR Rezulin

Etravirine Rosuvastatin Nifedipin Troglitazone

HPMC HPMC HPMC/PEG HPMC

Tibotec (2008) Astra Zeneca (2003) Watson lab. (2002) Pfizer (1997)

Prograf Sporanox Nivadil Nimotop Isoptin SRE

Tacrolims Itraconazole Nivaldipine Nimodipine Verapamil

HPMC HPMC/PEG HPMC – HPC/HPMC

Astellas (1994) Janssen-Cilag (1992) Astellas (1989) Bayer (1988) Abbott (1987)

Cystic fibrosis Aspergillosis coccidioidomycosis Candidiasis mycoses Cystic fibrosis Certain types of melanoma Chronic hepatitis C genotype 1 infection Antineoplastic agent Onychomycosis Prophylaxis of organ rejection in adult patients HIV Hypolipidemic agent Hypertension Antihyperglycemic agent (withdrawn from US market) Immunosuppressant Onychomycosis Hypertension Hypertension Mild to moderate hypertension and coronary heart disease

ASDs for improving solubility and bioavailability of drugs

Table 10.4  Polysaccharide-based amorphous solid dispersions available in market

303

304

Polysaccharide Carriers for Drug Delivery

r­easons behind its limited product progression and exposure into the commercial market. Owing to present needs, significant upfront development is a prerequisite to produce stable ASDs. The noteworthy improvements in this field by researchers have finally paved the way for the use of amorphous products for solubility enhancement which were once avoided owing to their high-energy amorphous state. Consequently, ASDs enjoy superiority over other solubility enhancing formulation approaches because of their added advantages. ASDs have exhibited remarkable results using both synthetic and natural polymers. However, synthetic polymers do have a number of limitations, therefore natural polymers such as polysaccharides prove beneficial in ASD preparation. Some of these polymers are modified for better chemical stability and for minimizing processing issues to exploit their potential to the fullest. It is anticipated that these carriers with easy-to-tune structures will result in remarkably improved oral bioavailability. This chapter attempted to discuss the various polysaccharide carriers which are employed in the preparation of amorphous solid dispersions.

10.8 Future perspectives The enhancement of solubility and bioavailability of lipophilic drugs by formulating them into ASDs is challenging and a mostly unsettled frontier. Future development in this field demands use of novel polymers or their combinations coupled with thorough understanding at molecular level which can drive the use of this technology towards increase in solubility and bioavailability and most importantly for further modulation of pharmacokinetic profiles. The current need demands an exhaustive study of the interactions occurring at molecular level for the rational design of products based on amorphous solid dispersion. The physicochemical properties governed by the molecular and thermodynamic factors need to be properly addressed. The high energy amorphous state of the incorporated drug limits their commercial applicability by reverting them to crystalline forms. Therefore, better knowledge about the thermodynamics, glass transition temperature, crystallization, molecular mobility, and drug-polymer interactions is imperative for the rational design of amorphous solid dispersion products. Moreover, the solid-state stability and maintenance of a supersaturation state should also be critically focused upon in order to produce efficient ASDs with desirable properties. Irrespective of the underlying challenges, the area warrants collaboration between formulators, chemists, and biopharmaceutics scientists for fruitful implementation of the strategy in the pharmaceutical discovery and development phases.

Acknowledgment The authors acknowledge Jamia Hamdard, New Delhi, India for providing the “Jamia HamdardSilver Jubilee Research Fellowship-2017” (AS/Fellow/JH-5/2018).

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