Hydroxypropyl Methylcellulose

2.1.8 Hydroxypropyl Methylcellulose

By reducing the molar substitution of hydroxyl propyl group, the glass transition temperature of HPMC can be reduced to 40^oC. HPMC forms flexible and transparent films from aqueous solution. HPMC films are generally odorless and tasteless, and can be effectively used in reducing absorption of oil from fried products such as French fries because of their resistance to oil migration [177]. It is extensively used in the food industry as a stabilizer, as an emulsifier, as a protective colloid, and as a thickener. HPMC is used as a raw material for coatings with moderate strength, moderate moisture and oxygen barrier properties, elasticity, transparency, and resistance to oil and fat. It is also used as a tablet binder and as a tablet matrix for extended release [178]. The potential application of HPMC in biomedical field has attracted great attention of both scientists and academicians because of its excellent biocompatibility and low toxicity.

Biopolymer composites are very promising materials because they are easy to process, eco-friendly in nature, and offer better properties. HPMC, being a biodegradable polymer, has also been used to prepare biocomposites. Several studies have been carried out to investigate the influence of different additives on the physicochemical properties of HPMC. Dogan et al. [179] investigated the influence of microcrystalline cellulose (MCC) filler in HPMC matrix with an attempt to improve the mechanical properties of HPMC films without affecting their water permeability properties. In a similar study, various types of cellulose derivatives such as cellulose nanofibers (CENFs), cellulose nanowhiskers (CNWs), etc. were incorporated in HPMC matrix to enhance its properties [180]. Rao et al. [181] prepared zinc oxide (ZnO) reinforced HPMC composites and investigated their structural, surface wettability properties and antimicrobial properties. The HPMC/ZnO composites showed promising bacterial resistance. The contact angle was decreased when ZnO content was increased. Ghosh et al. [182] prepared graphene oxide (GO) reinforced HPMC nanocomposite films using solution casting technique. The content of GO was varied from 0.02 to 1.3 wt.%. The obtained results confirmed the formation of exfoliated HPMC/GO composites with enhanced mechanical properties (tensile strength, Young’s modulus, and elongation at break) of HPMC film with respect to GO loading. In addition, the thermal stability of HPMC/GO composites has improved as compared to neat HPMC which is ascribed to the excellent thermal stability of GO. Priya et al. [183] prepared chitosan nanoparticles and incorporated into HPMC matrix to form CSNP/HPMC composite films for food preservation applications. HPMC can also be used to prepare composite films with lipids which can be used for preservation of food.

11.3.2.3 Methyl-hydroxy-propyl-cellulose

Increasing the polymer molecular weight (Patural et al., 2011) from 2.25 × 10⁵ g mol⁻¹ to 9.1 × 10⁵ g mol⁻¹ leads to an increase in both water retention and consistency coefficient in mortars. The water retention of MHPC was studied by Bülichen and Plank (2013) in cement pastes and in a gypsum plaster utilizing the filter paper test. The water-retention capacity decreased significantly in the calcium sulfate system. Thus, higher dosages of MHPC were required in the gypsum plaster to attain water-retention values comparable to those in cement. It was determined that sulfate anions hinder the formation of colloidal associates, which presents the key process to achieve water retention. This observation explains the higher dosages required in CaSO₄ systems.

The flexural strength of cement pastes decreases with increasing MHPC/cement ratio, which is a result of the retarding action of the polymer on cement hydration. A chemical interaction via cross-linking between MHPC-oxygen and the metal ions/free valences on the cement surface forms an organo-mineral phase responsible for this effect (Coarna et al., 2004).

Dynamic Coating with Hydroxypropyl Methylcellulose

In another system, the dynamic agent used for partial coating is hydroxypropyl methylcellulose (HPMC). In this approach, some interesting variants have been adopted. A new capillary is first rinsed for 20 min with 1 M NaOH and then for 10 min with 0.1 M NaOH containing 0.3% HPMC. It is during this final washing that conditioning of the capillary and partial coating with HPMC occurs. This etching procedure (with 1 M NaOH), followed by a short renewal of the dynamic coating (0.3% HPMC in 0.1 M NaOH) is shown to provide data of the highest reproducibility. The sample proteins are dissolved in 2.5% Ampholine solution, without any addition of HPMC. The anolyte is the standard 10 mM phosphoric acid solution, whereas the catholyte consists of 20 mM NaOH in the presence of 0.1% HPMC. The sample is introduced as a plug, occupying only 10–50% of the capillary length at the anodic side, the remaining being filled with catholyte. Since the entire stack of proteins will eventually be displaced towards the cathode by the EOF, this initial sample plug distribution allows more time to reach a good focusing pattern prior to sample passage in front of the detector.

4.431.3.2.1 Natural and semisynthetic polysaccharides

Another biocompatible polysaccharide that attracted considerable attention due to its low cytoxicity is chitosan. Chitosan (Figure 8) is a linear polysaccharide containing β-(1→4)-linked chains of d-glusosamine. It is produced commercially by alkaline N-deacetylation of chitin and, therefore, contains various amounts of randomly distributed residues of N-acetyl-d-glusosamine. Chitosan is soluble in acids but forms gel-like precipitates at neutral pH. Ruel-Gariepy et al.⁸⁸ and Chenite et al.⁸⁹ proposed a composition of chitosan (∼2 wt% solution) with β-glycerophosphate (∼0.25 mol l^− 190), which forms stable neutral sols in cold. At ambient temperature, the viscosity of the solution increases after 3 months in storage indicating a slow process of gel formation. At 37 °C, a solid gel forms within 5 min for a mixture (1:1) of 84% and 94% deacetylated chitosan.

Solubility of chitosan in water is increased by β-glycerophosphate forming ionic pairs with its amino groups and by additional hydration of the complex by hydrogen bonding of the polyol residues to water. Dehydration of the polymer chains and increased polymer–polymer interactions govern the gelation at elevated temperatures. The LCST of chitosan complexes decreases with the degree of deacylation; for 91% deacylated chitosan, the LCST is 37 °C.⁸⁹ Subcutaneous injection of the sol in rats demonstrated that low deacylation of chitosan promoted both the rate of degradation of the implant and the inflammatory reaction. The 91% deacylated chitosan implant had a residence time of several weeks and produced no noticeable inflammation. Chitosan implants formulated with chondrocytes promoted the formation within the implant of proteoglycan-rich areas typical of normal cartilage.

Interested in understanding the ability of chitosan to promote the healing of cartilage microfractures, Simard et al.⁹¹ investigated the recruitment of neutrophils by chitosan implants as the function of the degree of deacylation. While 80% deacylated chitosan attracted neutrophils in dose-dependent manner, 90% decylated chitosan was not an attractant. Nevertheless both chitosan preparations failed to elicit the release of granule enzymes or the generation of superoxide anions. Both chitosan preparations were internalized by polymorphonuclear neutrophils.

Low density polyethylene (LDPE)

Low density polyethylene (LDPE) film was coated with nisin using methyl-cellulose (MC)/hydroxypropyl methylcellulose (HPMC) as a carrier (Cooksey, 2000). Nisin coated onto a LDPE film to inhibit Micrococcus luteus and the microbiota of raw milk during storage was pH and temperature dependent (Mauriello et al., 2005). Low-density polyethylene (LDPE) films coated with a mixture of polyamide resin in i-propanol/n-propanol and a bacteriocin solution showed an antimicrobial activity against Micrococcus flavus. The incorporation of 1.0% w/w potassium sorbate in low-density polyethylene films lowered the growth rate and maximum growth of yeast, and lengthened the lag period before mould growth (Han and Floras, 1997). Benzoic anhydride impregnated with low density polyethylene (LDPE) films completely suppressed the growth of Rhizopus stolonifer, Penicillium species and Aspergillus toxicarius on potato dextrose agar (PDA). Similarly, LDPE films that contained benzoic anhydride delayed mould growth on cheese (Weng and Hotchkiss, 1993). LDPE film containing benzoic anhydride demonstrated the efficiency against mould growth of packaged cheese and toasted bread (Dobiáš et al., 2000). LDPE films impregnated with either 1.0% w/w Rheum palmatum and Coptis chinensis extracts or silver-substituted inorganic zirconium retarded the growth of total aerobic bacteria, lactic acid bacteria and yeast on fresh strawberries (Chung et al., 1998). Imazalil concentration of 2000 mg/kg LDPE film delayed A. toxicarius growth on potato dextrose agar, while LDPE film containing 1000 mg/kg Imazalil substantially inhibited Penicillium sp. growth and the growth of both of these moulds on cheddar cheese (Weng and Hotchkiss, 1992). The incorporation of 1% w/w grapefruit seed extract in LDPE film used for packaging of curled lettuce reduced the growth rate of aerobic bacteria and yeast (Lee et al., 1998). LDPE films incorporated with clove showed a positive antimicrobial effect against L. plantarum and F. oxysporum.

1.131.2 Hydrogels in Drug Delivery

There are more than 100 prescription drugs in the US market, in which one excipient is commonly used, that is, hydroxypropyl methylcellulose (HPMC). Although this polymer is water soluble, it provides gelling properties when exposed to an aqueous environment. HPMC with different degrees of substitutions is used in tablet form to control the release of the drug over a longer period of time. Apparently, there are two features that enable the HPMC to function as a controlled delivery system. First, it is very hydrophilic due to its hydroxypropyl contents. Second, the HPMC chains are in a very compressed form in a tablet, which prevents them from a fast dissolution in the aqueous environment. These two features provide gelling properties such as those found in a chemically cross-linked hydrogel. Although there is no chemical cross-linker in the HPMC structure, the applied pressure during tablet preparation supplies enough entanglement and barrier for the retarded dissolution of the polymer.

4.2 Supersaturable SEDDS

Supersaturable SEDDS (SS-SEDDS) is another form of SEDDS which have a reduced amount of surfactant and a crystal growth inhibitor such as HPMC (Sarpal et al., 2010; Singh et al., 2009). These formulations have also been developed to reduce the surfactant-related side effects and achieve rapid absorption of poorly soluble chemotherapeutic agents. Supersaturation enhances the thermodynamic activity to the chemotherapeutic agent beyond its solubility limit, and therefore, improves both the rate and extent of oral absorption (Gao and Morozowich, 2006). Various viscosity grades of HPMC are excellent crystal growth inhibitors and effectively suppress the precipitation of drugs. The ability to generate a supersaturated state by HPMC chains may be due to the formation of widely spaced cellulosic polymer network in water (Pellett et al., 1997; Gao et al., 2006; Morozowich et al., 2006). SS-SEDDS formulations have been extensively studied for oral delivery of chemotherapeutic agents such as paclitaxel (Gao et al., 2003), docetaxel (Chen et al., 2011), and so on, and constitute a part of the next section.

14.18.3 Alginates in Oral Delivery Systems

Dennis et al. (2002) filled hard gelatin capsules with a mixture of drug, alginate, and a pH-independent polymer (HPMC). Upon ingestion, the capsules absorbed gastric fluid thereby initiating surface hydration of the polymer. The formation of a surface gel layer led to air entrapment and the capsules began to float. Over time, the gel layer eroded resulting in the movement of the gel–dissolution interface toward the core of the capsules. Eventually, the device lost its floatability and passed into the intestinal tract where the alginates dissolved (due to the basic environment in the intestine), thereby making the delivery system more porous leading to drug release (see http://patents1.ic.gc.ca/details?patent_number=2081070).

Alginates have good mucoadhesive properties and have been used in combination with chitosan in various biomedical applications because of this property. Miyazaki et al. [244] developed alginate–chitosan tablets for the sublingual delivery of ketoprofen. Tonnesen and Karlsen [146] reported that alginate microparticles showed strong mucoadhesion toward the stomach mucosa. Coating of the particles with chitosan did not change their mucoadhesion property. Such examples demonstate that alginate-based systems can be developed for drug delivery in the stomach.

Mandel et al. [132] reported that alginate-based formulations containing antacids and H₂-receptor blockers can be used in the treatment of heartburn and esophagitis by acting as a barrier against acid reflux. Katayama et al. [245] developed a liquid preparation consisting of sodium alginate and ampicillin (an antibiotic) for the eradication of Helicobacter pylori. Once ingested, this preparation apparently spreads on the stomach wall releasing the incorporated drug on the mucosa. Finally, sodium alginate has been used to mask the bitter taste of drugs such as amiprilose hydrochloride.

Cellulose Derived Hydrocolloids and Microcrystalline Cellulose

Microcrystalline cellulose (MCC) has been used for over 40 years to provide physical stability and texture modification in a wide variety of food applications. The purification process utilized to manufacture microcrystalline cellulose renders the polymer into a highly functional food ingredient. Refined pulpwood is most commonly used as the starting raw material for manufacturing MCC. The pulping process is utilized to remove lignin, polysaccharides, low molecular weight cellulosic material, and extractives. Strong mineral acid hydrolysis is employed to remove all amorphous cellulose portions of the fiber. Following the steps of neutralization, washing, and filtration, the purified microcrystalline cellulose wetcake is diluted in water, and spray-dried to provide large particulate (noncolloidal) MCC. Noncolloidal MCC products are useful in food as a source of fiber and bulk and may also be used as anticaking agents for oily substances such as shredded cheese. The MCC wetcake can also be subjected to a wet mechanical disintegration step prior to drying. In this process, the cellulose particles are separated to submicron size and co-dried with carboxymethylcellulose (CMC) or other functional hydrocolloids, for example, alginate and pectin. These are often referred to as colloidal grades of microcrystalline cellulose and represent the category of MCC products most commonly used in food applications as stabilizers and texture modifiers.

MCC can be used in virtually all food segments that require unique stabilization solutions or bulk filler properties to develop stable and palatable products. Properly utilized, MCC can provide heat stability in bakery applications and suspension of insoluble particulates in beverages. Other examples include fat and solids substitution in salad dressings and heat shock stability and texture enhancement in frozen desserts. Stabilizers can have a tendency to disrupt flavor release and interfere with processing efficiencies. Microcrystalline cellulose is known to impart clean flavor without masking desirable flavor profiles. Manufacturers also rely on the unique rheological properties of microcrystalline cellulose to assist in processing. The combined attributes of texture modification, physical stability, and processing advantages associated with MCC make it a versatile stabilization ingredient.

MCC products were developed to provide special functional properties for specific end uses. These functional properties include ice crystal control, texture modification, emulsion stabilization, heat and foam stability, suspension of solids, and fat replacement. When MCC/hydrocolloid grades are properly dispersed, the cellulose particulates and soluble hydrocolloid set up a network. It is the formation of this insoluble cellulose structural network that provides the functionality [2].

The modification of the functional properties of MCC, by coprocessing formulations with other hydrocolloids, has resulted in the discovery of several potentially useful MCC alloys, each offering special properties for specific uses: a colloidal MCC/CMC product (Avicel RT 1133) has the ability to meet the requirements of retort sterilization while minimizing total process time; an ultra fine MCC/CMC/CaCO₃ composition, which is an effective suspending agent in calcium fortified milk, has been made by adding CaCO₃ during coprocessing; MCC has also been coprocessed with high methoxyl pectin to provide colloidal MCC stabilization in low pH protein-based beverage systems; MCC/CMC formulation exhibits unique structural properties, that is, high degree of elasticity indicative of a well-dispersed and stable system. Because of this property, the MCC/CMC (Avicel BV-1518) provides effective low viscosity suspension in neutral beverages (calcium fortified milk, chocolate beverages). In addition to neutral pH beverages, other market opportunities include nondairy and dairy desserts (texture modification), aerated food systems (foam stability), low pH sauces and dressings (emulsion stability), squeezable mayonnaise (viscosity control), and UHT cooking cream (uniform shelf-life consistency without gelation).

Health and well-being are among the most important drivers of growth in applications of MCCs. A great variety of MCC and coprocessed MCC products (Avicel, Avicel Plus, Gelstar, Microquick, Novagel, Viscarin, Hobart, Kitchenaid, and Kenwood) are available, mainly marketed by FMC Corporation, Premark Feg LLC, Whirlpool Properties, Inc., and Kenwood Manufacturing LLC. In the United States, microcrystalline cellulose has GRAS status and has been used safely in foods for over 30 years. In Europe, microcrystalline cellulose is listed in Annex II of the Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives [4]. It is approved as E460(i) in the list of Microcrystalline cellulose permitted emulsifiers, stabilizers, thickening, and gelling agents for use quantum satis, the level required to achieve a given technological benefit [5] (Table 7.2).

5.3 Drug-excipient interactions

FEX Form I was separately mixed in 1:1 ratios with sodium carbonate, mannitol, magnesium stearate, colloidal anhydrous silica, povidone K90, crospovidone, and hydroxypropyl methyl cellulose. The blends were stored at 40 °C/75% relative humidity, and 65 °C for 30 days. In case of drug–sodium carbonate mixture at 40 °C/75% RH, a liquefaction tendency was observed, with reduction in enthalpy value (ΔH) of FEX peak at 200–205 °C in DSC, and a concomitant decrease in assay value. No evidence for instability was noted with other excipients, indicating their compatibility with FEX.