In-Depth Study into Polymeric Materials in Low-Density Gastroretentive Formulations

pharmaceutics Review In-Depth Study into Polymeric Materials in Low-Density Gastroretentive Formulations Nieves Iglesias, Elsa Galbis , Lucía Romero-Azogil, Elena Benito , Ricardo Lucas, M. Gracia García-Martín and M.-Violante de-Paz * Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, C/Prof. García González, n.º 2, 41012 Seville, Spain; [email protected] (N.I.); [email protected] (E.G.); [email protected] (L.R.-A.); [email protected] (E.B.); [email protected] (R.L.); [email protected] (M.G.G.-M.) *Correspondence: [email protected] Received: 12 May 2020; Accepted: 3 July 2020; Published: 7 July 2020   Abstract: Theextensiveuseoforaldosageformsforthetreatmentofdiseasesmaybelinkedtodeficient pharmacokinetic properties. In some cases the drug is barely soluble; in others, the rapid transit of the formulation through the gastrointestinal tract (GIT) makes it difficult to achieve therapeutic levels in the organism; moreover, some drugs must act locally due to a gastric pathology, but the time they remain in the stomach is short. The use of formulations capable of improving all these parameters, as well as increasing the resident time in the stomach, has been the target of numerous research works, with low-density systems being the most promising and widely explored, however, there is further scope to improve these systems. There are a vast variety of polymeric materials used in low-density gastroretentive systems and a number of methods to improve the bioavailability of the drugs. This works aims to expedite the development of breakthrough approaches by providing an in-depth understanding of the polymeric materials currently used, both natural and synthetic, their properties, advantages, and drawbacks. Keywords: floating; low-density; GRDDS; raft systems; alginate; polysaccharides; cellulose; gums; Carbopol; Eudragit; gastroretentive 1. Introduction Although life expectancy has improved substantially in the world in recent decades, the population is aging, and its quality of life is far from optimal due to the prevalence of chronic diseases. In particular, the main difficulties encountered in achieving effective treatments are related to the transport and the ability to maintain drug concentrations within their therapeutic windows in damaged tissues. The oral route is the most convenient and widely used method of drug administration, representing about 90% of all therapies used [ 1 ]. It has advantages such as being non-invasive, easy to administer (with the consequent high patient compliance) and cost-effective, whilst also being easy to store and transport, and the formulations can easily be modified. However, serious drawbacks to conventional drug delivery systems (DDS) are imposed by the gastrointestinal tract (GIT). Large fluctuations in drugs’ bioavailability are found due to the influence of physiological factors such as variations in pH, high enzymatic activity as well as gastric emptying. In addition, rapid gastrointestinal transit can prevent not only the complete drug release from the dosage form, but also the full drug intake in the absorption zone (most drugs are absorbed in the stomach or the upper part of the small intestine) with the consequence of loss of dose effectiveness. This is the reason why frequent drug administrations are required to maintain the drugs therapeutic plasma level. Gastroretentive drug delivery systems (GRDDSs) have emerged as an ideal approach to overcome these drawbacks. Their main goal is to prolong the gastric residence time (GRT) of the dosage forms in Pharmaceutics 2020,12, 636; doi:10.3390/pharmaceutics12070636 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020,12, 636 2 of 44 the stomach up to several hours, so that the time between dose administration is lengthened and the drug release proceeds at the desired rate [2]. Consequently, GRDDS can play a key role in: (a) Prolonging the delivery in the stomach of particular drugs with local activity in the stomach or the upper part of the intestine (amoxicillin, for eradication of Helicobacter pylori in peptic ulcer diseases) [3]; (b) Slowing down the release of drugs that are soluble at acidic pH (ranitidine, H2-receptor antagonists) [4]; (c) Prolonging the release of drugs with a narrow absorption window, i.e., with low absorption in the lower part of the GIT (levodopa and carbidopa, drugs used in the treatment of Parkinson disease), and drugs with low bioavailability such as the antidiabetic metformin [5–8]. There is an extensive and valuable bibliography related to these devices [ 5 , 9 – 14 ]. Among the main types of GRDDS developed, the most promising are the low-density (floating) systems [ 8 ], which include the raft-forming formulations [ 9 ]. A brief description of the properties, requirements and drawbacks of these systems is summarized in Table 1, along with a summary of commercially available floating GRDDS for the treatment of a variety of pathologies in Table 2. This review focuses on the polymeric materials involved in the preparation of floating gastroretentive drug delivery systems (FGRDDSs). The description of the polymers and their commercial versions with their main properties will be disclosed accordingly, as the main types of FGRDDS are described. Table 1. Properties, requirements and drawbacks of current pharmaceutical technologies for floating gastroretentive formulations. Current Pharmaceutical Technologies for Floating Gastroretentive Formulations Type Requirements Properties/How They Work Drawbacks Low-density/floating systems - d <1.004 g/mL [15]. - Highly swellable gel-forming polymers [16]. - The use of a gas-generating agent [17]. - The use of volatile liquids [18]. - Buoyant. Free volume into the formulation [19]. - They remain in the stomach for a prolonged period (high GRT) while the drug is released [20]. - A low density system may be associated with problems such as sticking together or being obstructed in the GIT, which could produce gastric irritation [9]. - They require high fluid levels in the stomach to float and work effectively [20]. - Drugs with irritant effects on the gastric mucosa are not suitable candidates for low-density systems [5]. - In some cases, the release kinetics of the drug cannot be changed without changing the floating properties of the dosage form and vice versa [9]. Raft-forming systems - Floating properties [14]. - Floating and cohesive hydrogel [20]. - When they come into contact with gastric fluid, they lead to the formation of a continuous floating layer termed as rafts [14]. - They act as blockades between esophagus and stomach [13]. The mechanical strength of the systems is weak and can be easily disrupted by the MMC [13]. GIT: Gastrointestinal tract; GRT: gastric residence time; MMC: migrating myoelectric complex. Pharmaceutics 2020,12, 636 3 of 44 Table 2. Various floating gastroretentive formulations available in the market [9,10,20–23]. Technology/Delivery Systems Brand Name Active Pharmaceutical Ingredient Drug Category Manufacturing Company Bilayer floating capsule Cytotec®Misoprostol Gastroprotective Pfizer, UK HBS floating capsule Madopar HBS®Levodopa and benserzide Anti-parkinsonian Roche, UK HBS floating capsule Prolopa HBS®Levodopa and benserzide hydrochloride Anti-parkinsonian Roche, UK HBS floating capsule Valrelease®Diazepam Anxiolytic Roche, UK Floating, swelling system (Tablet) Inon Ace Tablets®Simethicone, aluminum-magnesium salts Antifoaming agent, antacid Sato Pharma, Japan Minextab Floating®—floating and swelling system Metformin HCl Metformin hydrochloride Anti-hyperglycemic agent Galanix, France Minextab Floating®—floating and swelling system Cefaclor LP Cefaclor Antibiotic Galanix, France Minextab Floating®—floating and swelling system Tramadol LP Tramadol Synthetic opioid analgesic Galanix, France Effervescent floating system (Tablets) Prazopress XL®Prazosin hydrochloride Alpha-1 antagonists Sun Pharma, Japan Effervescent floating system (Film coated tablet) Zanocin OD®Ofloxacin Fluoroquinolone antibiotics Ranbaxy, India Effervescent floating system (Film coated tablet) Riomet OD®Metformin hydrochloride Anti-hyperglycemic agent Ranbaxy, India Effervescent floating system (Film coated tablet) Cifran OD®Ciprofloxacin Fluoroquinolone antibiotics Ranbaxy, India Colloidal gel forming floating system Conviron®Ferrous sulphate Iron deficiency anemia Ranbaxy, India Raft forming system Topalkan®Alginic acid; aluminum-magnesium salts Antacid Pierre Fabre Medicament, France Raft forming system Almagate FlatCoat®Aluminum-magnesium salts Antacid Pierre Fabre Medicament, France Raft forming system Liquid Gaviscon®Sodium Alginate, sodium bicarbonate, calcium carbonate Antacid (in reflux esophagitis) Reckitt Benckiser Healthcare, UK Pharmaceutics 2020,12, 636 4 of 44 2. Single-Unit Low-Density Systems Low-density/floating systems are the most practical and extensively studied gastroretentive dosage forms. However, the design of floating dosage forms is technically demanding. Firstly, traditional in vitro dissolution methods are not able to predict in vivo behavior with a sufficiently high accuracy [ 24 ]. Secondly, neither the European Pharmacopeia nor the American Food and Drug Administration (FDA) describe any specific methods to assess dissolution behavior and floating characteristics of these formulations. Thirdly, methods for preparing floating gastroretentive systems are often cumbersome and expensive. Finally, cost-effective large-scale production of floating drug delivery systems (FDDS) remains a challenge [25]. The benefits of low density/floating systems are rooted on the buoyancy of the dosage in the gastrointestinal fluids. Its bulk density must be lower than that found in gastric fluids (1.004–1.010 g/mL) to ensure their floatability on the gastric fluid and hence to prolong their GRT [ 18 ] (4–24 h depending on the system) [26]. A low-density system requires high fluid levels in the stomach to float and work effectively and to avoid gastric irritation. Therefore, drugs with irritant effects on the gastric mucosa are not suitable candidates for such formulations [2]. To make the formulations float in the stomach, several approaches have been developed (Table 3). One of the most common systems uses a swollen polymeric material. The gel-forming formulation entraps air, leading to systems with low density. This is the case for hydrodynamic balanced systems (HBS) and raft systems. The density of the floating dosage forms can be reduced even further by using additives that generate a gas, such as CO 2 once the polymer swells, making them less dense than the gastric fluids. CO 2 is produced from an acid-base reaction in which a CO 2 generating salt, such as bicarbonate and carbonate salts, is involved [ 17 , 27 , 28 ]. One example of an effervescent system is the reaction of citric acid and sodium bicarbonate, where the optimal stoichiometric ratio for gas generation is reported to be 0.76:1, respectively [ 29 ]. To prevent the presence of gastric acids from interfering with the CO 2 formation, the formulations usually incorporate biocompatible acids such as tartaric acid and citric acid. Carbonate or bicarbonate may be present in the amount ranging from 5% to 50% and preferably from about 10% to 30% by weight of composition [ 13 ]. The effervescent effect, along with the swelling characteristic of hydrophilic polymers, can improve the overall floating behavior of the dosage form, i.e., floating lag time (FLT) and floating duration [27]. Although CO 2 systems are the most prevalent, the reduction in the formulation density can also be achieved by the incorporation of air-filled chambers. For example, floating alginate beads of Ranitidine HCl, with air compartments inside to increase its residence time in the stomach, were reported [ 30 ]. Another option is the vaporization of volatile solvents confined in inflatable chambers that, once warmed into the human body can vaporize [ 18 ]. The most commonly used volatile solvents are acetone (b.p. 56 ◦C) [31] and dichloromethane (b.p. 39.6 ◦ C) [ 32 ], or even mixtures of several solvents [33,34]. The incorporation of low-density materials in the formulations such as mineral and natural oils like liquid paraffin, olive oil and sunflower oil [ 3 , 35 , 36 ] have also been used. Non-ionic emulgents can also be used such as PPO-based triblock-copolymers (Poloxamer ® [ 37 ]) and glyceride-derivatives. Gelucire ® composites are examples of non-ionic emulgents, composed of mixtures of mono, di and triglycerides with PEG esters of fatty acids [ 38 ]. In addition, several glyceryl fatty acid esters have been chosen, such as glyceryl palmitostearate (Precirol ® ATO 5, equivalent to Gelucire ® 54/02) and glyceryl behenate (Compritol ® 888, equivalent to Gelucire ® 70/02). The first was used as a meltable binder and the esters of behenic acid as lipophilic diluents [ 6 ]. These compounds improve the buoyancy of the formulation (for periods even longer than 24 h), increase drug entrapment efficiency for lipophilic drugs and also impose a hydrophobic barrier towards the drug escaping from the matrices, which results in higher drug entrapment with prolonged drug release behavior [ 36 ]. Some authors have also reported the formation of floating microparticles with the use of synthetic polymers foams such as polypropylene foam powder [39] and porous polystyrene-based matrices with very low density [40]. Pharmaceutics 2020,12, 636 5 of 44 2.1. Hydrodynamic Balanced Systems (HBS) Hydrodynamic balanced systems (HBS) involve mixing the drug with a gel-forming polymer. The floatability of a non-effervescent systems relies on two possible mechanisms: the first one depends on the incorporation of a high level (20–75% w/w) of one or more gel-forming polymers that, with the drug, allows the formulation to remain buoyant over the gastric fluids [ 16 ]. When the gel-forming polymer hydrates, a gel barrier is built that controls the fluid penetration into the device and the consequent drug release from the formulation. In this system, the drug is mixed with the polymer and filled in the gelatin capsule. In effervescent formulations, a permeable outer barrier can help as the air entrapped by the swollen polymers aids the buoyancy of these dosage forms [5,20]. HBS are useful for the controlled release of drugs, which have a better solubility in gastric environments, i.e., drugs soluble at acidic pH, like the cationic molecule metformin [ 41 ]. They are also of interest for the formulations of drugs that are primarily absorbed in the stomach, such as amoxicillin [ 42 ]. However, as HBS is a matrix formulation, the release kinetics of the drug cannot be changed without changing the floating properties of the dosage form and vice versa [9]. For these systems one or more gel-forming and/or highly swellable polymers are used. One of the main types are cellulosic hydrocolloids, particularly, hydroxypropylmethyl cellulose (HPMC), which is the most commonly used for the development of non-effervescent floating systems. Other semisynthetic cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) are also of interest. Another group are polysaccharides, most of them heteroglycans, for example sodium alginate (NaAlg) and the natural gums guar gum, carrageenans, gellan gum and xanthan gum [5,20]. The properties of selected semisynthetic cellulose derivatives as well as the most relevant swelling gums used in floating formulations are described below. 2.1.1. Cellulose Derivatives Cellulose type hydrocolloids are the largest group of polymers with high swelling and gelling capacities. Cellulose is the most abundant polysaccharide available worldwide and is considered an almost inexhaustible source of raw material for the increasing demand of environmentally friendly and biocompatible products. Gelling and/or matrix forming materials for floating GRDDS must be hydrophilic and able to swell with a relevant amount of water. However, because of its highly crystalline nature with a high density of inter-chain hydrogen bonds, cellulose is not soluble or swellable in water. This highly effective spatial arrangement is facilitated by the β -1,4 linkages between glucopyranose units. Hydrogels prepared from unsubstituted cellulose have been scarcely reported because of its insolubility in aqueous solutions and in most organic solvents [ 38 ]. In order to solubilize cellulose, various substitutions have been incorporated along the glucopyranose backbone, which help break down its crystallinity. Once this 3D structure is denatured and a synthetic modification occurs, the presence of side segments prevents an organized 3D disposition from being achieved, leading to a looser material with more internal clearance. The material is then capable of absorbing a greater proportion of solvent molecules. The polymer solvation, and especially, hydration, depends on the cohesion force or the integrity of the polymer networks, which is influenced by the hydroxyl groups and size of the substituents [39]. Cellulose ethers are the most widely used polymers in GRDDS. They are semisynthetic and are prepared from natural cellulose by alkylation reactions. The chemical structures of several cellulose derivatives are recorded in Table S1 (Supplementary Information, SI). For inflatable systems, the use of the appropriate derivative is a key factor. Pharmaceutics 2020,12, 636 6 of 44 Table 3. Selected examples of single-unit low-density systems. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. HBS Capsule HPMC K4M or PEO (60 K, or WSR 303, or WRS 301) Metformin hydrochloride EC, CAP, LP 12 h . . . 7–12 h (97%) Physical blending EC, CAP, LP: release modifiers.Best results: HPMC +EC. [41] HBS Capsules HPMC (Metolose 65SH) L-DOPA Carrageenan 3–5 h 0 s 3–5 h (≈48–100%) Physical blending Carrageenan promoted water uptake. [43] Tablets HPMC K15M Propranolol hydrochloride NaCMC or Carbopol 934P **Citric acid and NaHCO3 2h–>12 h 7–26 s >12 h (79–87%) Direct compression ≥27.5% of HPMC was needed to maintain matrix integrity. Ionic interaction of NaCMC with drug. Carbopol 934P reduced FLT in contrast with NaCMC. Effervescent. [44] Tablets HPMC K15M Venlafaxine hydrochloride Hydrogenated cottonseed oil, Carnauba wax Cetyl alcohol *NaHCO3 >24 h 24–104 s 24 h (>95%) Melt granulation and compression Cottonseed oil, carnauba wax, cetyl alcohol: Hydrophobic meltable materials and behave as retardant agents. Effervescent. [45] Tablets HPMC (METHOCEL™ K100LV, K100M, K15M) Pregabalin PVPP/Croscarmellose (Na) Cetyl alcohol/Glyceryl behenate MCC 6.6 – >24 h 0.3–5.3 min 24 h (≈100%) Wet granulation and compaction Cetyl alcohol/Glyceryl behenate: floating-assistance agents. PVPP/Croscarmellose sodium: swelling and disintegrating agents. [46] Bilayer Tablets HPMC (K4M, K15M, K100 M) Pioglitazone (PG) Metformin hydrochloride (MH) Layer of PG: NaCMC. Layer of MH: MCC, stearyl alcohol. *NaHCO3. 24 h (in vitro) 5 min PG: 5 min (100%) MH: 12 h (>95%) Wet granulation and compaction NaCMC: disintegrant agent. Stearyl alcohol: floating-assistant agent. In vivo evaluation. Effervescent. [47] Tablets HPMC K4M G43/01 Famotidine *NaHCO310 – >24 h 52 – >300 s 8–12 h (80–100%) Melt granulation and compression G43/01: hydrophobic meltable binder. Effervescent. [48] Tablets HPMC K4M Polyox WSR 303 Baclofen *NaHCO3 >12 h (in vitro) 4–5 s >6 h (in vivo) 12 h (in vitro) 2.34–2.43 times increase in bioavailability (in vivo) Direct compression In vivo studies. Effervescent. [49] Pharmaceutics 2020,12, 636 7 of 44 Table 3. Cont. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. Tablets HPMC (Methocel™ K4M, K15M, K100M) Polyox™ (WSR 1105)Xanthan gum Ofloxacin **Citric acid and NaHCO3 >24 h 20–200 s 24 h (≈55–100%) Direct compression Polyox™WSR 1105/Xanthan gum: gelling agents. Drug release rates retarded by HPMC with higher viscosities. Effervescent. [50] Tablets HPMC (different viscosity grades)HPC (different viscosity grades)PEO WSR 303 Metformin hydrochloride MCC *NaHCO324 h 1–60 s 6–24 h (100%) Direct compression HPMC, HPC, PEO: hydrophilic gel-forming polymers. NaHCO3: gas forming /drug retardant agent. Effervescent. [8] Tablets HPMC (intragranular) PVPP (extragranular) Pregabalin HPC (intragranular) PEO, MCC (extragranular) >24 h 8–21 s 24 h (≈75–100%) Wet granulation and compaction HPMC and PVPP were critical excipients in buoyancy and dissolution. HPMC, PVPP: release retardants. PVPP improved buoyancy. [26] Tablets HPMC combined or not with a gum (Guar gum, Xanthan gum or Karaya gum) Atorvastatin calcium PVP (K-30) MCC 6–12 h 6–20 min 6–12 h (≈96%) Direct compression Combination of HPMC and guar gum enhanced bioavailability of the drug. [51] Tablets HPMC K15M NaAlg Ciprofloxacin hydrochloride MCC *NaHCO3, CaCO3 8 – >12 h (in vitro) 8–165 s 12 h ( in vitro ) ( ≈ 65–100%) Direct compression Floating and bioadhesive properties. NaAlg or HPMC: release retardant.NaAlg shortens FLT. CaCO3: gas forming agent and crosslinker. Effervescent. [27] Tablets HPMC K4M NaAlg Carbomer 934P Imatinib mesylate MCC *NaHCO3 18 – >24 h (in vitro) 23–119 s 24 h (≈44–76%) Wet granulation and compaction NaAlg, Carbomer: release retardant. In vivo studies (rabbits). Effervescent. [52] Pharmaceutics 2020,12, 636 8 of 44 Table 3. Cont. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. Tablets HPMC Functionalized calcium carbonate (FCC) Paracetamol MCC, CaCO3, mannitol . . . . . . Wet granulation and compaction HPMC: binder for wet granulation. MCC, CaCO3, mannitol: for comparison on compactability with FCC-based tablets. FCC-based tablets with mechanical properties ≥to those with MCC. [53] Coated Tablets HPC (different viscosity grades) Ofloxacin MCC NaAlg (coating layer) *NaHCO3 (coating layer) >12 h 15–38 s 12 h (≈70–100%) Wet granulation and compaction Combination of HPC with different viscosity grades allowed to adjust FLT, FT and drug release. NaAlg behaved as a release retardant. Effervescent. [54] Tablets HEC NaAlg Pentoxifylline MCC *NaHCO3>24 h 26–55 s 24 h (≈90–100%) Wet granulation and compaction HEC and NaAlg used as gel-forming polymers. Effervescent. [55] Tablets HEC NaCMC Losartan *NaHCO316 h - >24 h 1–4.5 min 24 h (≈30–80%) Direct compression HEC imparted enhanced floating capacity. Tablets with higher NaCMC content had longer FLT. Effervescent. [56] *NaHCO 3 : gas forming agent, **Citric acid/NaHCO 3 : gas forming mixture. Abbreviations: CAP: Cellulose acetate phthalate; EC: Ehytl cellulose; FCC: Functionalized calcium carbonate; FLT: Floating lag time; FT: Floating time; G43/01: Gelucire ® 43/01; HBS: Hydrodynamic balance system; HEC: Hydroxyethyl cellulose; HPC: Hydroxypropyl cellulose; HPMC: Hydroxypropylmethyl cellulose; LP: Liquid paraffin; MCC: Microcrystalline cellulose; MH: Metformin hydrochloride; NaAlg: Sodium alginate; NaCMC: Sodium carboxymethyl cellulose; MCC: Microcrystalline cellulose compression enhancer; PEO: Polyethylen oxide; PG: Pioglitazone hydrochloride; PVP: Polyvinyl pyrrolidone; PVPP: Polyvinylpolypyrrolidone (Crospovidone). Pharmaceutics 2020,12, 636 9 of 44 As can be seen, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose, (NaCMC), contain protic and/or ionic groups such as hydroxyl groups, in the case of HPMC, HPC and HEC, or carboxylate groups, as in the case of sodium CMC. As the pK a of CMC is 4.0 [ 40 ], the ratio of ionized groups will depend on whether the treatment is conducted in fasted conditions (pH of the gastric fluid: 1.5–2.0 [ 20 ]; non ionized carboxylic acid groups predominate) or fed conditions, in which the pH can raise to values close to 6.0 [20], with the consequent ionization of the acidic groups. •Hydroxypropylmethyl Cellulose and Methyl Cellulose (HPMC and MC) Hydroxypropyl methylcellulose (HPMC) is the most important hydrophilic carrier material used for the preparation of oral controlled drug delivery systems (Table S1) [ 57 ]. Also known as hypromellose, HPMC belongs to the group of cellulose ethers in which one or more of the three hydroxyl groups from the cellulose glucopyranose units have been substituted forming ether linkages. It is, therefore, a semisynthetic polymer prepared from highly purified natural pulp that is etherified with the combination of methyl chloride and propylene oxide to form a water-soluble, non-ionic cellulose ether [ 58 ]. The most widely used commercialized HPMC belongs to the trade names Methocel ® and Pharmacoat®. As HPMC is a biocompatible and viscoelastic polymer, it can be used as eye drops [ 58 ], or a controlled-delivery component in oral medicaments. An in-depth study on the role played by HPMC on the release of drugs from several pharmaceutical devices has been published by Siepmann and Peppas [ 57 ]. It was observed that HPMC had the ability to control drug release since it exhibited swelling, erosion and diffusion fronts. Displaying the possibility to formulate it with various excipients and being nontoxic and cost-effective, HPMC is a well-established material for the modulation of drug release in pharmaceutical formulations [ 59 ]. Numerous examples of its use in oral formulations can be found in the scientific literature. For example, hydrophilic polymers are often used to control the drug release rate in FGRDDS. Hydrodynamically balanced systems containing 500 mg of metformin have been prepared as a single unit floating capsule using HPMC K4M as the matrix forming polymer, PEO as the swellable additive, and ethyl cellulose (EC) as the release modifier. The best formulation demonstrated an in vitro release of 97% in 12 h in simulated gastric fluid at pH 3 and it followed zero order release kinetics. Other release modifiers such as cellulose acetate phthalate (CAP), and liquid paraffin (LP) were also tested [ 41 ]. In addition, matrices with insufficient porosity can be made to float by reducing the compaction pressure and increasing their porosity with carbon dioxide bubbles obtained from the reaction of sodium bicarbonate with the acidic dissolution medium. This was the case of floating formulations of captopril in which sodium bicarbonate in HPMC (Metolose) matrix formulation were used, so that the gastric retention time was improved by increasing the hydration of the dosage form and hence, increasing the surface area of drug diffusion [19]. •Hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC) Owing to its low Tg, HPC has been used as the main matrix-forming polymer in formulations prepared by hot-melt extrusion and 3D printing technologies, implying that the formulations could be processed at a relatively low temperature [ 60 – 62 ]. HPC has demonstrated its capacity to yield bioadhesive films [ 63 ]. The role of selected additives on the bioadhesive properties of HPC-based films was investigated and it was concluded that the incorporation of Carbomer 971P and a polycarbophil into HPC films increased bioadhesion significantly when compared to the film containing HPC and PEG 3350. However, few examples are found in GRDDS in which HPC is the main polymeric material. Its use is usually linked to other widely used polymers such as sodium alginate and HPMC. For example, Kim et al. [26] prepared new HPMC-based gastroretentive non-effervescent tablets with floating and swelling properties for once-daily administration of pregabalin in which the amount of HPC and crospovidone (cross-linked poly(vinyl pyrrolidone), PVP) were found to be critical factors affecting Pharmaceutics 2020,12, 636 16 of 44 Table 4. Chemical composition and properties of selected polycarbophil and Carbopol varieties. Trade Name/Variety United States (USP/NF) (a) (after 1 January 2006) Viscosity, cP (b) (0.5 wt% at pH 7.5) Molecular Weight between Adjacent Cross-Links [92] Molecular Weight, Da [92,97] Crosslinker Type (b) Use (b) Residual Solvent (b) Others (b) Carbopol ® 971P Carbomer Homopolymer Type A (c) 4000–11,000 237,600 Lightly cross-linked 1.25 ×106Allyl ethers of sucrose or pentaerythritol Oral and topical Ethylacetate (<0.5%) More efficient in controlling drug release than Carbopol® 974P Carbopol®71G Carbomer Homopolymer Type A (c) 4000–11,000 237,600 Lightly cross-linked 1.25 ×106Allyl ethers of sucrose or pentaerythritol Oral and topical Ethylacetate (<0.5%) Free-flowing granular form of Carbopol 971P NF Carbopol ® 974P Carbomer Homopolymer Type B (d) 29,400–39,400 104,400 Densely cross-linked 3×106Allyl ethers of sucrose or pentaerythritol Oral and topical Ethylacetate (<0.5%) Highly crosslinked polymer Carbopol®934 Carbomer Homopolymer Type B (d) 30,500–39,400 104,400 Densely cross-linked 3×106Allyl ethers of sucrose or pentaerythritol Topical Benzene (<0.2%) (e) Carbopol®5984 EP and Ultrez 10 NF polymers Carbopol ® 934P Carbomer Homopolymer Type B (d) 29,400–39,400 104,400 Lightly cross-linked 3×106Allyl ethers of sucrose or pentaerythritol Topical or Oral Benzene (<100 ppb) High purity grade of Carbopol ® 934 (e) Carbopol ® 974P Noveon® AA-1 Polycarbophil 2000–12,000 Lightly cross-linked 7×105[97]Divinyl glycol Topical or Oral Ethyl acetate (<0.45%) – Carboxylic acid content for Carbopol (Assay %): 56.0–68.0%. the pK a of the carbopols and polycarbophils was reported to be 6.0 ( ± 0.5) [ 63 ]. The Carbomers Monograph in the European Pharmacopeia stipulates that benzene is limited to 2 ppm. (a) UPS-NF: Combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF) (https://www.uspnf.com/; accessed in May 2020). (b) https://www.lubrizol.com/Health/Pharmaceuticals/Excipients/Carbopol-Polymer-Products (Accessed in April 2020). (c) Carbomer Homopolymer Type A: Viscosity Specified (cP): 4000–11,000. (d) Carbomer Homopolymer Type B: Viscosity Specified (cP): 25,000–45,000. (e) Recommended non-benzene substitute products. Pharmaceutics 2020,12, 636 17 of 44 •Poly(ethylene oxide) (PEO) The trademark POLYOX ™ (from Industrial Cellulosics, DUPONT [ 98 ]) denotes a group of water-soluble resins (WSR) based on poly(ethylene oxide)s (PEO) available in a wide range of molecular weights and specific viscosities (Table S4). They display a fast-hydrating behavior and can quickly form hydrogels. PEO can be used as hydrophilic polymers in pharmaceutical formulations due to their excellent matrix forming properties. PEO is non-toxic, highly water-soluble and swellable, insensitive to the pH of the biological environments and ease to produce. PEO of high molecular weights have been successfully applied in controlled release dosage forms, because the rate of swelling and erosion of the polymer allows the sustained release of APIs. High molecular weight PEO exhibits a viscoelastic nature in its swollen state because it can form dense polymeric networks in aqueous environments [ 99 ]. Consequently, PEO is of interest as an additive to reinforce the mechanical properties of highly swellable and mechanically robust matrix tablets. For example, in matrices based on the mixture of crospovidone, poly(acrylic acid) and xanthan gum, the mechanical strength of the tablets improved substantially when PEO of high molecular weight (1000, 4000 or 8000 kDa) was added (PEO weight content =20%). The mechanical strength of the tablets was found to improve by increasing the PEO molecular weight [82]. Regarding the release kinetics of hydrophobic drugs (such as β -lapachone), PEO can be used as a release retardant. Tablets containing β-lapachone and PEO of the highest molecular weights showed zero-order kinetics. It is worth noting that the higher the molecular weight of PEO, the lower the swelling indices of the tablets, probably due to the more hydrophobic and largely entangled structure, thereby delaying the diffusion of water molecules into the matrices and leading to a slower release of the drug [82]. Polyox ® materials usually form part of multi-polymeric matrices. For example, by means of an experimental 3 2 model design, Thakar et al. aimed to improve the bioavailability of baclofen in floating tablets based on the swelling polymer HPMC K4M, Polyox WSR 303 as a release retardant and sodium bicarbonate as a gas generating agent [ 49 ]. The optimized floating dosage form was studied in vivo in rabbits and provided prolonged gastric residence time as well as an increase in bioavailability (2.34 times) compared to the commercial formulation. Another example is the preparation of HPMC-based floating tablets using sodium carbonate and citric acid as gas forming agents. In this case, xanthan gum and Polyox WSR 1105 were used as gelling agents, and hence, retardant agents for ofloxacin-controlled release [ 50 ]. The authors demonstrated that the floating tablets of ofloxacin prepared using gelling agents like Polyox and xanthan gum in combination with various grades of HPMC were found to be effective to sustain the drug release up to 1 day, with this latter property being dependent on polymer concentration. The work of Shishu et al. [ 100 ] presents a floating system of 5-fluorouracil using hydrocolloids, such as hydroxypropyl methylcellulose (HPMC) and Carbopol ® 934P, and gas forming agents like sodium bicarbonate and citric acid. Different grades of the poly (ethylene oxide) (PEO; grades–WSR 1105, WSR 301, WSR 303, WSR 60 K and WSR N80) have been used for HBS with metformin as API. From the in vitro buoyancy studies, it was observed that PEO WSR 60K and PEO WSR 303 and HPMC K4M containing formulations showed good buoyancy, with floatation time up to 12 h in citrate phosphate buffer at pH 3.0. However, amorphous or partially amorphous polymers can experience a phenomenon known as physical ageing [ 101 ]. They undergo volume and enthalpy relaxations during their storage below Tg due to the non-equilibrium nature. The volume relaxation results in the densification of the non-crystalline phase with the consequent changes in the physical thermal and mechanical behavior of the amorphous polymer [ 102 ]. When these polymers are used in controlled-release formulations, changes in drug release profiles can be observed. This is the case of PEO-based dosage forms. Due to its partly amorphous structure, PEO experienced structural changes linked to physical ageing. Both the hydration properties of the API and the molecular weight of the polymer influenced the effect of PEO’s physical aging and, therefore, the release properties of the drug from the matrix [103]. Pharmaceutics 2020,12, 636 18 of 44 •Kollidon®SR Kollidon ® SR is a mixture of poly(vinyl acetate) (PVAc) and povidone (poly(N-vinyl pyrrolidone), PVP) and its main use is as a matrix retarding agent. It is particularly suitable for the manufacturing of pH-independent sustained-release matrix tablets by direct compression or hot melt extrusion. PVAc is a plastic material that produces a coherent matrix even under low compression forces. When the tablets are introduced into gastric or intestinal fluid, the water-soluble PVP is leached out to form pores through which the active ingredient slowly diffuses outwards. Kollidon ® SR contains no ionic groups and is therefore inert to drug substances and its sustained-release properties are unaffected by ions or salts [104]. 2.2.2. Synthetic Polymers Used as Excipient in Floating Formulations This section describes the chemical structures and main properties of the plethora of synthetic materials that are extensively found in research works describing floating gastroretentive systems. •Poly(meth)acrylates. Eudragit® Eudragit is a family of co-polymers used as targeted drug release coatings. These polymers allow drugs to be formulated in enteric, protective or sustained-release formulations to prevent the breakdown of the drug until it has reached an area with adequate pH in the gastrointestinal (GI) tract. Once the drug reaches its target area of the GIT (i.e., duodenum and stomach) it will be released from the polymer matrix and absorbed. Targeted drug release is often used to prevent dissolution of a drug in an area where the pH is not adequate for absorption, or to help minimize GIT irritation [105]. Eudragit ® are poly(meth)acrylates whose physicochemical properties are determined by their chemical composition (Table 5and Table S5) and are available in a wide range of different physical forms (aqueous dispersion, organic solution granules and powders). Classification of Eudragit polymers is shown in Table 5. Some categories of the copolymers (Eudragit L, S, FS and E polymers) are soluble in digestive fluids [ 106 ] due to functional groups in their structure that are sensitive to pH. Eudragit L, S and FS are soluble when the carboxylic acid groups of their structure are ionized, i.e., over pH 5.5, pH 6.0 and pH 7.0, depending on the copolymer composition. Thus they are of use as protective coatings in enteric formulations. Conversely, Eudragit E polymers are soluble when the tertiary amine groups are protonated. This occurs at the acidic pH found in the stomach and is of interest in gastric formulations, playing a protective coating role. The insoluble grades (Eudragit RL, RS NE) have a low ratio of permanently ionized quaternary ammonium groups (Eudragit RL and RS) that, even though they are insoluble in aqueous solutions at every pH, they are permeable in digestive fluids. The degree of permeability depends on the ratio of quaternary ammonium groups. The polymers in the insoluble category—Eudragit NE—display low permeability but, when used means that no plasticizer is required in the formulation. Eudragit RL, RS and Eudragit NE copolymers can control the drug release, a property that can be tailored by mixing Eudragit RL and RS polymers at the appropriate ratios. Eudragit ® NM is a neutral copolymer available as an aqueous dispersion that enables sustained release coatings without the need for plasticizer addition [106]. Pharmaceutics 2020,12, 636 19 of 44 Table 5. Chemical composition and properties of selected Eudragit®grades [106]. Eudragit Family Example Composition Monomer RatioMw Functional Group Sensitive to pH Anionic/Cationic/Non-Ionic Groups Soluble in Digestive Fluids Solubility in Aqueous Environments Applications LL 100 MAA-MMA 1:1 125,000 Carboxylic group Anionic 4Soluble at pH >5.5 Enteric formulations Protective coating - Gastroresistance - Controlled drug release in intestine SS 100 MAA-MMA 1:2 125,000 Carboxylic group Anionic 4Soluble at pH >6.0 FS FS 30 D MA-MMA-MAA 7:3:1 280,000 Carboxylic group Anionic 4Soluble at pH >7.0 EE 100 BMA-DMAEMA-MMA 1:2:1 47,000 Tertiary amino group Cationic 4 Soluble in gastric fluid at pH ≤5.0 Swellable and permeable at pH >5.0 Gastric formulations Protective coatings - Moisture/light protection - Odor/taste masking RL RL 100 EA-MMA-TMAEMA 1:2:0.2 32,000 Quaternary ammonium group Cationic 6 Insoluble High permeability pH-independent swelling Tailored drug release - Delay release - Sustained release RS RS 100 EA-MMA-TMAEMA 1:2:0.1 32,000 Quaternary ammonium group Cationic 6 Insoluble Low permeability pH-independent swelling NE NE 30 D EA-MMA 2:1 750,000 6Non-ionic 6 Insoluble Low permeability pH-independent swelling No plasticizer required MAA: Methacrylic acid; MMA; methyl methacrylate; BMA: butyl methacrylate; DMAEMA: N,N-dimethylaminoethyl methacrylate; TMAEMA: trimethylammonioethyl methacrylate; MA: methyl acrylate; EA: ethyl acrylate. Pharmaceutics 2020,12, 636 20 of 44 Physical aging also affects amorphous polymers used in pharmaceutical coating systems. This phenomenon has been shown to cause changes in the mechanical, permeability and drug release properties of polymeric films due to a densification and decrease in free volume of the polymer. A variety of techniques have been used to stabilize polymeric films and prevent aging [ 107 ]. For example, the storage temperature was critical for the stability of theophylline pellets coated with a blend of Eudragit ® RS 30 D and NE 30 D [ 108 ]. The selection of a plasticizer is also a key factor when formulating a polymeric coating dispersion. Studies have been conducted in which beads were coated with Eudragit ® RS 30 D containing 40% ibuprofen as the active ingredient and solid-state plasticizer [ 109 ]. The addition of a miscible, high glass transition polymer is another method that has been shown to stabilize drug release from sustained release coatings. One advantage of coating films that have high Tg is that minimal aging is expected because the storage temperatures are well below the Tg. This has been observed for cellulose acetate phthalate (CAP) films when the salt forming agent 2-amino-2-methyl-1-propanol (MAP) was used for the neutralization and dissolution of CAP in water. CAP/MAP free films were found to be superior to ammoniated CAP films with respect to extent of aging when stored at 40 ◦C [68]. •Crospovidone. Crosslinked poly(N-vinyl pyrrolidone) (PVPP) Crospovidone (trademarks: Polyplasdone ® , Kollidon CL)) is a water insoluble synthetic cross-linked PVP (Table S5). Crospovidone swells without gelling, a property that is advantageous for developing orally disintegration tablets (concentration of 2–5% w/w). When a compaction force is applied, the polymer deforms, then, upon contact with water, it absorbs and regains its normal structure, releasing an amount of energy capable to break the tablet. As the particle size increases, the intra-particular porosity increases, leading to a larger water uptake and faster disintegration. Several grades of crospovidone are available, differing in particle size distribution, bulk density and hydration capacity [110]. Being nonionic in nature, the disintegration efficiency of crospovidone is independent of the pH of the media and thus, a potentially suitable disintegrant for cationic drugs [ 111 ]. This polymer can also be used for solubility enhancement of poorly soluble drugs in the process of coevaporation. This process enables the drug adsorption onto crospovidone in the presence of a suitable solvent, and once the solvent is evaporated, a solid mixture with a faster drug dissolution rate is provided [ 110 ]. Sometimes, crospovidone is included as part of highly hydrophilic matrices, for example, in mixtures with poly(acrylic acid), and xanthan gum. It was found that these polymers, at a weight ratio of 1:1:1, displayed excellent swellable properties [82]. •Sodium croscarmellose. Cross-linked sodium carboxymethyl cellulose Sodium croscarmellose (trade name: Ac-Di-Sol ® ) is an internally cross-linked sodium carboxymethylcellulose used as a superdisintegrant in pharmaceutical formulations (Table S5) [ 111 ]. This material is an insoluble and hydrophilic polymer with enhanced long-term stability. The cross-linking reduces water solubility while still allowing the material to swell and absorb many times its weight in water. As a result, it provides superior drug dissolution and disintegration characteristics, thus improving formulas 0 subsequent bioavailability by bringing the active ingredients into better contact with bodily fluids. It is used in co-formulations of hydrophilic particulate materials [ 5 ]. This polymer is highly effective in direct compression, dry granulation and wet granulation processes [112]. Pharmaceutics 2020,12, 636 21 of 44 •Poly(vinyl acetate) (PVAc) Poly(vinyl acetate) (PVAc, Table S5) is a thermoplastic hydrophobic polymer, soluble in organic solvents and insoluble in water. It is rather brittle below its Tg (ca. 305 K) and very sticky above it. The emulsions of this plastic material, produced on a very large scale, are inexpensive and possess good adhesion to many porous substrates. PVAc serves as the film-forming ingredient in water-based (latex) formulations and is used as a coating polymer since it can provide flexible and water permeable coatings to tablets or other oral formulations [ 85 ]. It is also used in adhesives, as a plasticizer and a thickener in varied applications. When employed in coatings or adhesives, PVAc is often partially hydrolyzed to a water-soluble polymer known as polyvinyl alcohol. •Gelucire® Gelucire ® comprises of a group of poly(ethylene glycol)-based (PEG) surfactants derived from mixtures of mono, di and triglycerides with PEG esters of fatty acids (Table S5), which are widely used in pharmaceutical formulations. Varying the molecular weight of PEG and the fatty acid results in Gelucire-based surfactants with a wide range of HLB and melting point values (33–65 ◦ C). Thus, Gelucire ® grades are named depending on their melting point (the first value) and the HLB (the second value). For example, Gelucire 39/01 has HLB value 1 and melting point of 39 ◦C. Based on their HLB values, Gelucire can be classified into hydrophilic and hydrophobic grades (Table 6). Gelucire with HLB values lower than 6 are hydrophobic; 6–9 are water dispersible and above 9 are hydrophilic. Gelucire 50/13, 44/14, 48/16, 55/18, 35/10 and 48/09 are examples of hydrophilic grades and Gelucire 43/01, 39/01, 33/01, 50/02, 54/02 and 64/02 are examples hydrophobic grades [38]. Table 6. Application of surfactant based on the HLB range [38]. HLB Range Water Solubility Application 1–3 No dispersibility in water Release retardants 3–6 Poor dispersibility in water w/o Emulsifier 6–8 Milky dispersion Wetting agent 8–10 Stable milky dispersion o/w Emulsifier 10–13 Translucent to clear solution Detergents >13 Clear solution Solubilizers The most common grades used in GRDDS are the hydrophobic G43/01 and G39/01 and the hydrophilic G50/13 and G44/14 and are present in multiple-unit floating systems. Owing to their extreme hydrophobicity and low density, hydrophobic Gelucire are considered appropriate lipid carriers and drug release retardants in GRDDS such as multi-unit minitablets [113], lipid-based pellets [ 114 ] and floating granules [ 115 – 117 ]. Thus, sustained-release floating minitablets have been prepared using both G43/01 and G39/01 without the presence of gas generating agents [ 113 ]. They may also be part of lipid matrices in beads [ 114 , 118 ], play a role as floating assistant agents [ 119 ] and be of interest as a hydrophobic meltable binder [48,113]. G44/14 and G50/13 are the most commonly found hydrophilic Gelucire in GRDDS. They are water dispersible and display excellent surfactive power. Consequently, they are widely used to enhance the solubility and wettability of drugs [ 118 ]. Since their composition is mainly constituted by PEG esters, they are chosen as hydrophilic carriers in solid dispersions [114] and are generally used in the preparation of fast release formulations [ 116 ]. Their thermoplastic properties make them useful as meltable binder in melt/fusion processes, for example in fluidized hot melt granulation [120]. Pharmaceutics 2020,12, 636 22 of 44 •Poloxamer. PEO-PPO-PEO triblock-copolymers Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide); PEO-PPO-PEO; Table S5). They are readily soluble in aqueous, polar and nonpolar organic solvents and their aqueous solutions are very stable in the presence of acids, alkalis and metal ions. They can form thermoreversible gels at high concentrations (15–50%, room/body temperatures) that become liquid at cool temperatures. Due to their amphiphilic structure, the polymers have surfactant properties and can be used to either increase the water solubility of hydrophobic substances or the miscibility of two substances with different hydrophobicities [82]. Amphiphilic substances can be used as foaming agents. Foam is defined as a dispersion of gas in a liquid or a solid and the presence of a foaming agent is essential for foam generation and stabilization [ 37 ]. When a foaming agent is added to water, the hydrophobic parts of the molecule arrange themselves in a way to minimize the area of contact with that protic solvent, while the hydrophilic part of the surfactant is responsible for their solubility in water. When a foaming agent is adsorbed into the air–water interface, the surface tension of water is lowered and the surface pressure is increased. Addition of some polymers, which leads to the formation of a surfactant–polymer complex through interactions between polymer and surfactant, contributes to the foam stability. For example, alginate foams were formed by stirring it in the presence of Poloxamer 188. The alginate can wind in microbubbles and stabilize the foam solution. When the foam solution was dripped into CaCl 2 solution through a syringe, porous beads were formed. The water insoluble Ca–Alg was rapidly formed by gelation of alginic acid in the presence of calcium ions [37]. 2.2.3. Some Examples of Floating Tablets HPMC, a hydrophilic gel sustained-release matrix, is present in the preparation of a variety of floating tablets (Table 3). Gastro-floating tablets of pregabalin were prepared with HPMC and the lipophilic cetyl alcohol as a floating-assistance agent [ 46 ]. Other low-density materials such as glyceryl behenate were used for comparative reasons. Qin et al. observed that tablets containing cetyl alcohol floated longer than those with glyceryl behenate because of its lower bulk density. In addition, the use of high viscosity HPMC retarded the release of pregabalin, which is soluble in the medium. The presence of stearyl alcohol further retarded the release because of the resistance of hydration induced by the lipophilic material. Thapa et al. studied the development of gastro-retentive effervescent floating tablets composed of a hydrophilic matrix (PEO, HPMC and HPC) loaded with a high amount of the highly water-soluble drug metformin HCl [ 8 ]. Generally, stronger gel layers control the release of the drug, as well as providing mechanical integrity to the matrices. Among the polymers tested, PEO-based tablets had the lowest floating lag time and quick penetration of dissolution medium into the matrices. They showed the highest gel strength and the lowest drug release rate among the studied systems, whereas HPCM tablets had the lowest strength and the highest drug-release rates. Moreover, the viscosity grade of HPMC also had an impact on the mechanical strength of the gel layer. The high release rates found for HPC-based tablets was associated with poor hydration rates due to low polymer viscosity. Pharmaceutics 2020,12, 636 23 of 44 Mixtures of alginate and HPMC have also been used in floating tablets. Controlled-release floating tablets of ofloxacin were successfully formulated by employing NaHCO 3 as a gas-forming agent, NaAlg as retarding agent and HPMC as a matrix forming polymer. The tablets could float on the surface of artificial gastric fluid for over 12 h and control the drug release for 12 h [ 29 ]. Likewise, effervescent floating tablets of pentoxifylline were successfully prepared by using sodium bicarbonate as a gas-forming agent and a mixture of HEC and sodium alginate as the polymeric matrix. The tablets could float on the surface of the dissolution medium and sustain drug release over 24 h [55]. Floating tablets of the antibiotic ciprofloxacin were prepared by direct compression using carbomer 971, HPMC, xanthan gum and crospovidone and sodium bicarbonate as a gas generating agent. The prepared formulations were able to float for more than 24 h with a really short floating lag time (less than 20 s) and prolonged drug release for 24 h [27]. Kadivar et al. have developed effervescence and swelling floating tablets of superior gastro-retentivity and in vivo efficacy for imatinib mesylate. They were prepared using HPMC K4M, with NaAlg and Carbomer 934P. From studies in New Zealand rabbits it was observed that the gastro-retentive tablets could increase the bioavailability around 1.5 times compared to the conventional tablets (Gleevec) [52]. Effervescent tablets of propranolol hydrochloride based on HPMC K15M were developed by the direct compression method with a sustainable drug release for 12 h in the stomach. NaCMC or Carbopol 934P was added to alter the drug release profile or the dimensional stability of the formulation [44]. Optimal floating tablets must feature two, often self-excluding characteristics: high porosity to promote floatation on the stomach contents, but also sufficient hardness to withstand destruction by gastric peristalsis [ 25 ]. Due to its unique properties, functionalized calcium carbonate (FCC) holds promise in the preparation of FDDS. It is a highly porous material that allows tablets to be further processed to a relative density <1. In the preparation of paracetamol-loaded tablets with HPMC used as a binder and FCC as excipient, it was found that FCC can be compacted into tablets with high tensile strength at compressive pressures, which are much lower than those needed for the compaction of other excipients such as mannitol or microcrystalline cellulose (MCC). The porosity of FCC containing tablets subjected to a compressive pressure of 100 MPa can reach values up to 60%, whereas tablets containing cellulose or mannitol only have 20% void volume. This is of great relevance in the development of low-density tablets [ 53 ]. Eberle et al. designed caffeine floating DDS using the novel excipient FCC. Water-soluble PEO (Polyox ™ WSR 301) and HPMC (Methocel ® K100) were selected as gelation-layer forming polymers to slow down the penetration of liquid into the tablet during dissolution. Citric acid was chosen as the effervescent excipient. The resulting floating tablets exhibited no floating lag time, thus lowering the risk of unpredictable, premature gastric emptying. The tablets displayed sufficient hardness after incubation in dissolution media and may withstand destruction due to gastric peristalsis [25]. 3. Multi-Unit Low-Density Systems Although the use of floating dosage forms is the most widely used method to achieve prolonged GRTs, multiple-unit systems avoid the ‘all-or-nothing’ gastric emptying nature of single-unit systems [ 121 ]. Compared to single-unit formulations, multiple-unit formulations show a more sustained release profile and unaffected overall performance due to unit failure. These features allow the co-administration of units with different release profiles, or incompatible substances, with improved safety margins compared to single-unit dosage forms [ 16 ]. Selected examples of multi-unit FGRDDS are recorded in Table 7. Pharmaceutics 2020,12, 636 24 of 44 Table 7. Selected examples of multi-unit low-density systems. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. CaAlg beadsand solid dispersion NaAlg Famotidine Quercetin (QRT) Eudragit®RL100 PVP K30 *CaCl2 8 h 0 s In vivo studies Ionotropic gelation method Eudragit®RL100: for coating formation. PVP: to form solid dispersion of QRT. [122] Coated chitosan alginate beads NaAlg Chitosan Ranitidine hydrochloride *CaCl2 CaAlg, PVA 72 h 0 s 11 h 100% Ionotropic gelation method With air compartment. CaAlg, PVA: formation of semipermeable coating. [30] Inner porous beads NaAlg Poloxamer 188 Riboflavin *CaCl26 h 0 s 10 h ≈65–85% Ionotropic gelation method Poloxamer 188: foaming agent. [37] CaAlg beads NaAlg Ibuprofen MS LP *CaCl2 8 4.5 min 8 h 35% Ionotropic gelation method MS and LP: floating-assistance and release retardant agents. [36] Coated oil-entrapped Alginate beads NaAlg Sterculia gum Risperidone Olive oil *CaCl2 8 h 3–6 min 8 h 64–83% Ionotropic gelation method Floating and mucoadhesive beads. [35] Coated oil-entrapped Alginate beads NaAlg HPMC Amoxicillin Chitosan Sunflower oil *CaCl2 24 h 46 s In vivo studies Ionotropic gelation method Floating and mucoadhesive beads Chitosan: coating polymer. [3] Hollow CaAlg beads NaAlg Carrageenan Brucea javanica oil *CaCO3 *CaCl2 24 h 0 s . . . Ionotropic gelation method Carrageenan: porogen. CaCO3: release of Ca ion crosslinker and gas forming agent. Effervescent. [123] Calcium pectinate beads LM Pectin HPMC K15M Carbopol ® 934P Polycarbophil Famotidine Cod liver oil *CaCl2 24 h 0 s 8 h (80%) Biphasic release Emulsion gelation Cod liver oil: floating-assistance agent (20% was necessary). Other polymers behave as release retardant. [124] Zinc pectinate Beads LM Pectin Ofloxacin Gellan Gum, Karaya Gum, Xanthan Gum Rice bran oilZnCl2 24 h 0 s 8 h 60–88% Ionotropic gelation method Gellan Gum, Karaya Gum, Xanthan Gum: Release retardants. Rice bran oil: floating-assistance agent. Zinc ions: crosslinker. [125] Coated CaAlg beads NaAlg Gelatin Pectin HPMC Gliclazide *CaCO3 *CaCl2 10 h . . . 10 h At pH 1.2: 33–46% At pH 5.8: 82–95% Ionotropic gelation method CaCO3: release of Ca ion crosslinker and gas forming agent. Effervescent. [126, 127] Pharmaceutics 2020,12, 636 25 of 44 Table 7. Cont. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. Minitablets (MT) G43/01, G39/01 Nimodipine COM PRE 14 h<1 min 12 h (95%) Melt granulation and compression COM: blend of esters of behenic acid with glycerol. PRE: glyceryl palmitostearate COM, PRE, G39/01, G43/01: release retardants. [113] Porous beads Eudragit®LMetronidazole Cetyl alcohol >8 h 0 s 8 h >90% Solvent evaporation and extrusion Cetyl alcohol: floating-assistance agent, porogen, and release retardant. Solvent: acetone and extruded into DCM. [128] Lipid-based beads G43/01 G50/13 Cinnarizine Sterotex® Pluronic®F-127 >24 h 0 s 8 h (≈45–95%) Hot melt method Sterotex®: Hydrogenated cotton seed oil. Pluronic®F-127 enhanced drug release. [118] Lipid-based pellets HPMC K4M G44/14 G50/13 Berberinehydrochloride (BERH) G43/01 COM MCC NaHCO3 5–9 h 0 s 8 h (70–99%) Hot melt method COM, G43/01: release retardants. MCC: spheronizing aid. NaHCO3: gas generating agentEffervescent. [114] Granules HPC G50/13 Metronidazole COM NaHCO3, citric acid PEG 8000 8–0 0 h≈40–100% . . . >10 h (>60%) Fluidized hot melt granulation COM, G50/13: meltable binders. PEG 8000: release enhancer. G50/13 and HPC increased drug release. Citric acid +NaHCO3: gas generating mixture. Effervescent. [120] Granules G43/01 Torsemide . . . 8 h 0 s 8 h (86%) Melt granulation Lipid carrier: G43/01. [115] Microspheres EC Ranitidine hydrochloride PEG 4000 4–10 h 5–10 min 4–6 h (85–100%) Solvent evaporationmatrix erosion method PEG: pore forming agent. PEG (20–33%) induced buoyancy. Reduction in size at higher PEG content. [129] Bioadhesive Microspheres NaAlg Acyclovir LP Technetium-99m SnCl2, CaCl2 >4 h (in vivo) . . . 8 h (in vitro) (40–72%) Emulsification phase separation method Mucoadhesive properties. In vivo studies. (Radio-labeled microspheres). Higher sizes at high polymer conc. Ca ions: crosslinker. [130] Pharmaceutics 2020,12, 636 32 of 44 Table 8. Selected examples of floating gastroretentive drug delivery systems (GRDDSs) prepared by hot melt extrusion and/or 3D printing. Formulation Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Technique Comments Ref. Pellets Eudragit®RSPO HPMC K15M Theophylline Stearic acid 24 h 0 s 12– 18 h (89–96%) HME Eudragit®RSPO: insoluble matrix former. HPMC K15M: for control release. Ethanol: foaming agent. Stearic acid: processing aid. [148] Lipid-based granules G43/01 Cefuroxime Axetil Kolliphor® TPGSG44/14 8–12 h 0 s 12 h (≈20–80%) HME G43/01 imparts buoyancy. Kolliphor ® TPGS and G44/14 behave as release enhancers. Best release profiles with G43/01 and Kolliphor®TPGS. [119] Hollow tubes Eudragit®RSPO Eudragit®E PO Metformin Stearyl alcohol 12 h . . . 4–12 h (98%) HME Sealed hollow tubes with inherent buoyancy. Stearyl alcohol: plasticizer. [149] Tablets HPC Domperidone (DOM) BaSO4 10 h (in vitro) 8–10 h (in vivo, rabbits) . . . 12 h (in vitro) (99%) HME and 3D printing HPC/DOM filaments obtained by HME for 3D printing into tablets. BaSO4: label for in vivo studies. [62] Tablets HPC Theophylline (THEO) Stearic acid 10 h 0 s 8 h (90%) HME and 3D printing HPC/THEO filaments obtained by HME for 3D printing into tablets. Stearic acid: processing aid. [60] Capsular devices HPC EC Theophylline For core tablet: Croscarmellose sodium, MCC, Mg stearate 1.5–6 h 0 s Pulse release with lag time from 0.5 to 6 h HME and 3D printing Core tablet (obtained by compression) into a sealed 3D-printed tablet. Pulsatile DDS with controlled lag time. EC showed significant effect on the lag time (at EC 0.5%, lag time 6 h). [61] Tablets HPCPVP/VA 64 Cinnarizine . . . 6–12 h 0 s 6–12 h (80%) HME and 3D printing PVP/VA 64 improved extrudate physical properties, leading to printable filaments. [150] Tablets HPMC K4MHPMC E15 Dypiridamole MCCPVP K30 >12 h 0 s 12 h (≈40–90%) 3D printing Extrusion-based 3D printing technology. HPMC E15 and PVP: binder agents. MCC: extrusion molding agent. [155] Capsular devices PLA filaments Acyclovir For drug tablets: HPMC, MCCBaSO4 24 h in vitro LGT: 1 min12 h in vivo (beagle dogs) . . . 3 h (in vitro) (80%) 3D printing Acyclovir tablet inside the floating device. BaSO4: label for in vivo studies. [153] Capsular devices PLA filaments Baclofen tablets . . . 24 h 0 s 2–6 h (80%) 3D printing Immediate release drug tablet inside the device. [154] Capsular devices PVA filaments Amoxicillin capsules BaSO4 14 h in vitro 0 s 10 h in vivo (rabbits) 90–180 min (in vitro) (≈80–100%) 3D printing and thermal crosslinking Conventional amoxicillin capsule inside the device. FT increased after crosslinking. BaSO4: label for in vivo studies. [152] Abbreviations: DDS: Drug delivery system; DOM: Domperidone; EC: Ehytl cellulose; FLT: Floating lag time; FT: Floating time; G43/01: Gelucire ® 43/01; G44/14: Gelicire ® 44/14; HME: Hot-melt extrusion; HPC: Hydroxypropyl cellulose; HPMC: Hydroxypropylmethyl cellulose; MCC: Microcrystalline cellulose; PLA: Polylactic acid; PVA: Polyvinyl alcohol; PVP: Polyvinyl pyrrolidone; THEO: Theophylline. Pharmaceutics 2020,12, 636 33 of 44 Dumpa et al. have fabricated, by means of HME/3D printing technologies, filaments of HPC/EC, which were used for the manufacture of core–shell gastroretentive floating tablets with pulsatile delivery of theophylline (the lag time for the pulsatile release of the drug was from 30 min to 6 h) [ 61 ]. The same group has recently reported the preparation of floating tablets for the administration of cinnarizine using HPC and Kollidon ® PVP/VA64 (random copolymer of vinylpyrrolidone and vinyl acetate, ratio 60:40) as matrix forming polymers [150]. Other floating devices such as capsules have been achieved by means of 3D printing of PVA or polylactic acid (PLA) filaments (Table 8) [ 152 – 154 ]. These devices present hollow pockets that allow the systems to float over 24 h. The systems are designed in order to incorporate a conventional drug tablet or capsule inside. 4. Raft-Forming Systems Raft systems mainly focus on achieving localized effects because floating rafts act as blockades between that esophagus and stomach. The formed raft can remain intact in the stomach for several hours, promoting the sustained release of the drug. Thus, they can be used for the effective management of gastric esophageal reflux disease, as well as gastrointestinal infection and disorders [ 13 ]. However, the mechanical strength of the systems is weak and can be easily disrupted by the migrating myoelectric complex (MMC). The strength of the alginate raft is dependent on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate and the presence of aluminum or calcium in the antacid components of the formulation. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that from traditional antacids [14]. Raft-forming systems are another type of FGRDDS. This type of delivery system, initially as a solution form, usually contains sodium alginate (NaAlg) as an in-situ gel forming polymer along with calcium salts as crosslinker donors and/or carbonates or bicarbonates as effervescent agents [ 156 ]. When they come in contact with the gastric fluid, they swell and generate a viscous cohesive gel that contains entrapped carbon dioxide bubbles, leading to the formation of a continuous layer, termed as rafts [ 9 ]. Raft formation occurs rapidly, often within a few seconds of dosing since alginates can be cross-linked with polyvalent cation. The CO 2 gas is generated and lowers the bulk density of the system, and as a result, the rafts float on the gastric fluid. Alginate-based raft-forming formulations (Table 9) have been marketed worldwide for over 30 years under various brand names, including Gaviscon, which is a treatment for heartburn and indigestion including hiatus hernia and gastro esophageal reflux disease [ 14 ]. An interesting raft forming system of curcumin has been prepared using curcumin-Eudragit ® E PO solid dispersion. It aimed to prolong the GRT of curcumin and provide a controlled release therapy to treat gastric ulcer. NaAlg was used as a gelling polymer and calcium carbonate was present in the formulation for generating divalent Ca 2+ ions and carbon dioxide to form a floating raft. These studies demonstrated that the new raft forming systems containing curcumin solid dispersions are promising carriers for a stomach-specific delivery of poorly soluble lipophilic compounds [157]. Pharmaceutics 2020,12, 636 34 of 44 Table 9. Selected examples of raft systems prepared by ionotropic gelation. Matrix Forming Polymers Drug Other Components FT FLT Sustained Release (h) Drug Release (%) Comments Ref. NaAlg Curcumin Eudragit®(R) EPO **CaCO3, *CaCl2 >24 h 3–76 s 8 h 60–85% Eudragit®(R) EPO: drug carrier. Effervescent. [157] NaAlg HPMC K100M Mebeverine HCl (MbH) **CaCO3COM, PRE >12 h 15–25 s 5 h 100% Higher Alg conc. retarded drug release. Lipids: PRE, COM. Floating-assistant agents. In vivo studies. Effervescent. [159] NaAlg Gellan gum (GG) Metronidazole **CaCO3COM, PRE, GMS >24 h 1 min 4–6 h 75–90% Lipids: GMS, PRE, COM. Floating-assistant agents. Ca ions: crosslinker of Alg and GG. GG ↓ gelation capacity. A modification in formulation was needed. Effervescent. [160] NaAlg LM-pectin . . . ***Citric acid + NaHCO3**CaCO3 >8 h 50 s . . . Ca ions: crosslinker of Alg and pectin. Effervescent. [161] LM-pectin Gellan gum Gabapentin GMOEudragit®NE 30D *CaCl2 >24 h 0 s 8 h 55–100% Ca ions: crosslinker of pectin and GG. GMO: floating-assistant agent and drug release retardant. Eudragit ® NE 30D: to coat the drug. [158] Gellan gum HPMC (K100M) Itopride HCl **CaCO3>12 h 76–98 s 10–12 h (>95%) HPMC: drug release retardant. In vivo studies. Effervescent. [78] *Ca ions: crosslinker; **CaCO 3 : release of Ca ion crosslinker and gas forming agent; ***Citric acid +NaHCO 3 : gas-generating mixture. Abbreviations: COM: Compritol 888 ATO; FLT: Floating lag time; FT: Floating time; GG: Gellan gum; GMO: Glyceryl monooleate; GMS: Glyceryl monostearate; HPMC: Hydroxypropylmethyl cellulose; LM-pectin: Low methoxylated pectin; MbH: Mebeverine HCl; NaAlg: Sodium alginate; PRE: Precirol ATO05. Pharmaceutics 2020,12, 636 35 of 44 Pectins behave similarly to NaAlg. Thus, optimized raft forming systems for the water-soluble antiepileptic and anti-neuropathic gabapentin (GBP) were prepared from gellan gum, and low-methoxy pectin. The raft system achieved a zero-order release profile suitable for once-a-day administration. In vivo assessment was performed in rats to evaluate gastric residence of the gel formed. The increment in relative bioavailability of GBP from the optimized formula was 1.7 fold compared to commercially available Neurontin®[158]. 5. Conclusions To date, extensive research work has been conducted on GRDDS to overcome the drawbacks associated with conventional dosage forms, with low-density formulations being the most promising systems. However, there is no single answer to best resolve the problems associated with each dosage form of the countless APIs available in the therapeutic arsenal. Each drug bears its particular needs that must be met by formulations capable of ensuring its bioavailability at therapeutic levels. Therefore, it is essential to assess gastroretentive dosage forms on a case-by-case basis. Critical quality attributes of low-density formulations include buoyancy, floating force, gel strength, in vitro drug release, swelling capacity, hydrogel porosity, tablet tensile strength, etc. From the formulation point of view, understanding polymer behavior and its role in formulations are crucial for the rational development of gastroretentive dosage forms. The choice of polymeric components in each formulation, either alone or in combination, is a key parameter to keep pushing forward the development of gastroretentive formulations. Furthermore, disadvantages associated with floating systems can be overcome by dual-working systems that are, in general terms, less affected by physiological conditions. This review aims to aid the design of such systems through the knowledge of appropriate polymers, or by the development of new materials with tailor-made properties to provide optimal physicochemical properties and in-vitro and in-vivo performance. Supplementary Materials: The following are available online at http://www.mdpi.com/1999-4923/12/7/636/s1, Figure S1. Chemical composition of Methocel products and different types of HPMC (USP) classified according to their degree of methoxyand hydroxypropoxy-substitution. Table S1. Semisynthetic cellulose derivatives. Chemical structures and tradenames. Table S2. Other semisynthetic cellulose derivatives. Chemical structures and tradenames. Table S3. Swelling, gelling and matrix forming materials used for floating GRDDS. Natural gums. Table S4. Matrix forming materials useful in floating tablets. Synthetic polymers. Table S5. Selected polymeric excipients useful in floating tablets. Synthetic polymers. Table S6. Swelling, gelling and matrix forming materials used for floating GRDDS. Alginates and pectins. Table S7. USP specifications for different types of HPMC, classified according to their degree of methoxyand hydroxypropoxy-substitution and their equivalency with Methocel ® produts. Table S8. Properties of various Methocel Cellulose Ethers. Table S9. Chemical composition and properties of Poloxamer grades [14]. Author Contributions: Conceptualization, N.I., M.G.G.-M., and M.-V.d.-P.; Methodology, M.G.G.-M., and M.-V.d.-P.; Validation, N.I., E.G., L.R.-A., E.B., and R.L.; Formal Analysis, N.I., M.G.G.-M., and M.-V.d.-P.; Investigation, N.I., E.G., L.R.-A., E.B., R.L., M.G.G.-M., and M.-V.d.-P.; Resources, E.B., L.R.-A., M.G.G.-M., and M.-V.d.-P.; Writing—Original Draft Preparation, N.I., E.B., and M.G.G.-M.; Writing—Review & Editing, M.-V.d.-P.; Supervision, M.-V.d.-P.; Project Administration, M.-V.d.-P.; Funding Acquisition, M.-V.d.-P. All authors have read and agreed to the published version of the manuscript. Funding: The authors would like to thank El Ministerio de Ciencia, Innovaci ó n y Universidades (MICINN) of Spain (Grants MAT2012-38044C03-01 and MAT2016-77345-C3-2-P), and La Junta de Andaluc í a (Grant P12-FPM-1553) for their financial support. Conflicts of Interest: The authors declare no conflict of interest. Abbreviations APIs Active pharmaceutical ingredients Ac-Di-Sol®Sodium croscarmellose AHA Acetohydroxamic acid BMA Butyl methacrylate CaAlg Calcium Alginate Pharmaceutics 2020,12, 636 36 of 44 CAB Cellulose acetate butyrate CAP Cellulose acetate phthalate CMC Carboxymethyl cellulose CNZ Cinnarizine COM Compritol 888 ATO CTS Chitosan DBS Dibutyl sebacate DCM Dichloromethane DDS Drug delivery system DE Degree of esterification DL Drug loading DMAEMA 2-(N,N-dimethylamino)ethyl methacrylate DOM Domperidone DOS EA Ethyl acrylate EC Ethyl cellulose EE Encapsulation efficiency FCC Functionalized calcium carbonate FDA American Food and Drug Administration FGRDDS Floating gastroretentive drug delivery system FLT Floating lag time FT Floating time G39/01 Gelucire®39/01 G43/01 Gelucire®43/01 G44/14 Gelucire®44/14 G50/13 Gelucire®50/13 GalA D-galacturonic acid GIT Gastrointestinal tract GLB Glibenclamide GMO Glyceryl monooleate GMS Glyceryl monostearate GRDDS Gastroretentive Drug Delivery System GRT Gastric residence time HBS Hydrodynamic balance system HEC Hydroxyethyl cellulose HME Hot-melt extrusion HM-pectin High methoxy pectin HPC Hydroxypropyl cellulose HPMC Hydroxypropylmethyl cellulose HPβCD Hydroxypropyl-β-cyclodextrin LCST Lower critical solution temperature LMP Low methoxylated pectin LM-pectin Low methoxy pectin LP Liquid paraffin MA Methyl acrylate MAA Methacrylic acid MAP 2-amino-2-methyl-1-propanol MB Microballoon MC Methyl cellulose MCC Microcrystalline cellulose MH Metformin hydrochloride MMA Methyl methacrylate MMC Migrating Myoelectric Complex MO Mineral oil MT Minitablets Pharmaceutics 2020,12, 636 37 of 44 MTS Magnesium trisilicate MβCD Methyl-β-cyclodextrin NaAlg Sodium alginate NaCMC Sodium carboxymethyl cellulose PAA Poly(acrylic acid) PEG Polyethylene glycol PEO Polyethylene oxide PG Pioglitazone hydrochloride PLA Polylactic acid PPO Polypropylene oxide PRE Precirol®ATO05 PVA Polyvinyl alcohol PVAc Poly(vinyl acetate) PVP Polyvinyl pyrrolidone PVP/VA Poly(vinylpyrrolidone-co-vinyl acetate) PVPP Polyvinylpolypyrrolidone (Crospovidone) SI Supplementary Information Tg Glass transition temperature THEO Theophylline TMAEMA Trimethylammonioethyl methacrylate TPP Sodium tripolyphosphate WSR Water-soluble resins XrL Crosslinking References 1. 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