An Overview on Commonly Used Natural & Semisynthetic Polymers Used in The Floating Drug Delivery System

Oral administration is the most convenient and preferred means of any delivery to the systemic circulation. Oral controlled release drug delivery have recently been of increasing interest in Pharmaceutical field to achieve improved therapeutic advantages such as ease of dosing administration, patient compliance and flexibility in formulation. Drugs that are easily absorbed from gastro intestinal tract (GIT) and have short half life are eliminated quickly from systemic circulation. Frequent dosing of these drugs is required to achieve therapeutic activity. To avoid these limitations, the development of oral sustained controlled release formulation is an attempt to release the drug slowly into the gastro intestinal tract and maintain an effective drug concentration in the systemic circulation for long time. After oral administration, such a drug delivery would be retain in the stomach and release the drug in a controlled manner so that the drug could be supplied continuously to its absorption site in gastro intestinal tract.^[1] Gastro retentive drug delivery is an approach to prolong gastric residence time, thereby targeting site-specific drug release in the upper gastro intestinal tract for local and systemic effect. Gastro retentive dosage form can remain in the gastric region for a longer period and   hence significantly prolong the gastric retention time (GRT) of drugs.^[2],[3],[4]

       
           
       
Figure 1: Floating Drug Delivery System

Floating Drug Delivery System

Floating drug delivery system (FDDS) was first described by Davis in 1968 FDDS is an effective technology to prolong the gastric residence time in order to improve the bioavailability of the drug. FDDS are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. ^[5],[6] Floating systems can be classified as effervescent and non-effervescent systems.

This delivery system is desirable for drugs with an absorption window in the stomach or in the upper small intestine. FDDS have a bulk density less then gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time and the drug is released slowly as a desired rate from the system.^[7] After oral administration in the GIT, CO2 is liberated from these drug delivery systems, which reduces the density of the system and makes it float on the gastric fluid. Properties possessed by FDDS

• It should release contents slowly to serve as a reservoir.
• It must maintain specific gravity lower than gastric contents (1.004 – 1.01 gm/cm3).
• It must form a cohesive gel barrier.

Effervescence Agents: Sodium bicarbonate, Citric acid, Tartaric acid, Calcium carbonate, Di-SGC (Di-Sodium Glycine Carbo-nate, CG (Citroglycine).

Figure 3: Effervescent Floating System

Non-Effervescent systems

Non effervescent systems incorporate a high level (20– 75% w/w) of one or more gel-forming, highly swellable, cellulosic hydrocolloids (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose

[HPMC], and sodium carboxymethylcellulose), polysaccharides, or matrix-forming polymers (e.g., polycarbophil, polyacrylates, and polystyrene) into tablets or capsules. Upon coming into contact with gastric fluid, these gel formers, polysaccharides, and polymers hydrate and form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density of and confers buoyancy to the dosage form.^[8]

Hydrodynamically Balanced Systems

These are single unit dosage forms containing one or more gel forming hydrophilic polymers. The polymer is mixed with drug and usually administered in a gelatin capsule. The capsule rapidly dissolves in gastric fluid at body temperature, and hydration and swelling of surface polymers produces floating mass. Drug release is controlled by formation of hydrated boundary at the surface.^[9]

Hollow Microspheres

Hollow microspheres are considered as one of the most promising buoyant systems as they possess the unique advantages of multiple unit systems as well as better floating properties. The general techniques involved in preparation include simple solvent evaporation and solvent diffusion. The drug release and better floating properties mainly depend on type of polymer, plasticizer and solvents employed for preparation. Polymers used may include cellulose acetate, chitosan, Polyvinyl acetate etc.^[10]

Alginate Beads

Multi-unit floating dosage forms were developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hours. When compared with solid beads, which gave a short residence, time of 1 hour, and these floating beads gave a prolonged residence time of more than 5.5 hour.^[11]

       
           
       
Figure 4: Alginate Beads

Layered tablets

Single Layer Floating Tablets

They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms.^[12]

Bilayer Floating Tablets

A bilayer tablet contains two-layer one immediate release layer which release initial dose from system while another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach. ^[13]

Floating DDS Advantages

Certain types of drugs can benefit from using FDDS. These include:

• Drugs acting locally in the stomach.
• Drugs those are primarily absorbed in the stomach.
• Drugs those are poorly soluble at an alkaline pH.
• Drugs with a narrow window of absorption.
• Drugs absorbed rapidly from the GI tract.
• Drugs those degrade in the colon. ^[14]

Disadvantages Of FDDS

1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids.
2. Drugs such as Nifedipine, which is well absorbed along the entire GI tract and which undergo significant first-pass metabolism, may not be suitable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailability. Also, there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.
3. One of the disadvantages of floating that they require a sufficiently high level of fluids in the stomach, so that the drug dosages form float therein and work efficiently^[15]

Polymers used in FDDS

Polymers play a crucial role in the formulation of FDDS, as they ensure buoyancy, control the drug release rate, and maintain the structural integrity of the system. Polymers can be natural, semisynthetic, or synthetic.^[19],[20]

Role of polymers used in GRDDS:-

1. The medicine is encapsulated in a stable matrix made of polymers, which permits regulated release while preserving the integrity of the dosage form. .
2. Many polymers are made to expand when they come into contact with gastric fluids, creating a gel that lengthens the system's stomach retention period and increases its size.[16]
3. To achieve sustained or protracted release profiles, the type and characteristics of the polymer can be changed to regulate the drug release rate.[17]
4. Because the polymers employed in GRDDS are frequently biocompatible, they won't react negatively when they come into contact with stomach tissues.
5. Some polymers improve the dosage form's adherence to the gastric mucosa, which slows the stomach's rapid emptying
6. In order to keep the dosage form buoyant in the stomach environment—a crucial feature for GRDDS—polymers can be used to alter its density. [18]
7. Targeted and regulated medication release is made possible by the engineering of polymers to react to particular environmental conditions, such as pH or enzymes.[17]
8. Polymers improve the stability and effectiveness of the formulation by shielding the medication from degradation brought on by stomach acid and enzymes.

Table 1: Common natural and Synthetic Polymers

Commonly Used natural polymers

Xanthan Gum,Guar Gum,Chitosan,Alginates,etc. are natural polysaccharides commonly used in pharmaceutical applications due to their gelling, thickening, and stabilizing properties.^[21],[22]

Chitosan

Chitosan (CS) is a biopolymer obtained from the deacetylation of chitin. ^[23] n CS is associated with GRDDSs that release the drug in gastric media, in colon-specific systems the dissolution of CS in acidic pH is overcome by association or coating with other polymers.^[24] These systems pass through the stomach quickly without significant drug release, protecting the drugs until they reach the intestine.^[24] In this organ, CS undergoes the action of enzymes from the intestinal microbiota and from its degradation can release the drug.^[25] CS-based systems that present mucoadhesive, swelling, and acid erosion properties emerge as an alternative to explore different delivery strategies for the gastric environment.^[26] During the planning of GRDDSs using CS, some particularities should be taken into account like length of retention on the drug/dosage form in the stomach, penetration in the gastric mucosal layer, stomach pH and stability of the drug/pharmaceutical system and CS protonation, drug's molecule physicochemical parameters, as well as its solubility.^[27]

Pectin

Pectin is a linear polysaccharide, mainly found in plant tissues in combination with cellulose, which can be chosen as a matrix swelling polymer. The main sources of pectin are citrus peel (lemon, orange and lime) and apple pomace. It is a nontoxic, food grade polymer which is widely used as food additive, a thickening agent and a gelling agent in food and pharmaceutical industry.^[28],[29] pectin is used as the swelling polymer because it has the qualities required for designing a FDDS.^[29]  In floating tablet formulations, pectin is often combined with gas-generating agents (such as sodium bicarbonate) that react with gastric acid to produce carbon dioxide. This gas gets trapped in the pectin matrix, reducing the density of the tablet and allowing it to float in the stomach.^[30] In terms of swelling capability, pectin shows the best swelling capability in hydrochloric acid buffer of pH 1.2 compared with other medium such as water and phosphate buffer of pH 6.8 and 7.4. ^[31] This characteristic is ideal for preparing floating matrix tablet as the pectin will swell in contact with acidic gastric content and trap gases generated by the gas generating agent.^[32]

Xanthan Gum

Xanthan gum is a high-molecular-weight polysaccharide produced by the fermentation of Xanthomonascampestris. It is highly soluble in water, forms a gel in aqueous environments, and is widely used for its sustained-release properties in FDDS.^[33] Xanthan gum expands in gastric juices, increasing the buoyancy of the dose form while maintaining a constant drug release profile. Gum's high viscosity helps to preserve flotation and regulate medication release.^[34] Xanthan gum absorbs water quickly after intake, expanding and producing a viscous gel matrix that gives buoyancy. As it hydrates, it forms a barrier that slows medication release via diffusion.^[35] Xanthan gum has pseudoplastic activity (shear-thinning), which aids in the stability of the floating system in stomach fluids. The drug diffuses across the swelling gel layer (Fickian diffusion or anomalous transport dependent on polymer concentration).Higher amounts of xanthan gum might cause gel erosion, which may affect the medication release rate.Furthermore, ionic strength and pH alter the polymer's viscosity and swelling behavior, resulting in varying release profiles across the GI tract.^[36]

Advantages: -

• It is Non-toxic and biocompatible.
• It has High viscosity, which aids in the formulation of stable floating systems.
• Its Swelling properties helps to maintain floatation and control drug release.

Limitations: - It is pH-dependent release rate, which could cause different parts of the gastrointestinal tract to release the drug at different rates.^[37]

Guar Gum

Guar gum is a non-ionic polysaccharide obtained from the endosperms of Cyamposistetragonolobus belonging to family Leguminosae. The various derivatives of Gum are manufactured by chemical reaction of hydroxyl groups with chemicals that aid in; control viscosity, causing gelling and act as preservatives. It is soluble in hot and in cool water but insoluble in most of the organic solvents. It has strong intra and inter hydrogen bonding properties. Its high viscosity and high molecular weight aid in maintaining medication release. When it comes into touch with stomach juices, its capacity to hydrate causes it to enlarge and solidify. ^[38]
When guar gum comes into touch with stomach contents, it expands and creates a very sticky gel. As the medicine is released in a controlled manner, the system's increased volume keeps it afloat. However, the polymer content and environmental factors like temperature and humidity have a significant impact on the drug release profile of guar gum. Guar gum's viscosity can be changed by the presence of electrolytes or variations in the stomach's ionic strength, which can result in irregular drug release and floating profiles.Furthermore, the effectiveness of guar gum varies according on the rate of hydration, which affects its use in FDDS.^[39]

 Advantages: -

• It is in-expensive and readily available.
• It creates viscous gel layer that can reduce the rate at which drugs are released.
• In FDDS, swelling capacity aids in buoyancy maintenance.^[40]

Limitations: -

• It is more Susceptiblele to the microbial contamination.
• It shows Highly variable drug release rates due to its dependency on polymer concentration and hydration level.^[41]

Alginates

Alginate is a natural hydrophilic polysaccharide present in the cell wall of marine brown algae and in capsular polysaccharides of certain bacterial species, such as Pseudomonas. Though microbial fermentation is a feasible procedure, marine brown algae represents the major source of alginates.^[42] Alginate biopolymer is biocompatible, biodegradable and non-immunogenic. Alginates are used as a gas-forming agent. Calcium and sodium alginates are commonly used in FDDS.^[43] Alginates in the presence of calcium ions (Ca?2;?), forms a gel-like matrix & encapsulate the drug.  The gel formed by alginate swells in the acidic environment of the stomach, creating a barrier that slows down the diffusion of the drug. This leads to a prolonged release of the drug over time.^[44]

Starch

Stach is a polysaccharide which is one of the most abundant carbohydrates in the plant world composed of glucose unit. Starch occurs naturally as semicrystalline granules, made up of two polymer components, namely amylose, which is essentially linear, and amylopectin, which is highly branched.^[45] Starch can be used for applications where biocompatibility and safety are required, such as edible and drug carrier materials. However, inherent, strong hydrogen bonds also predominantly exist between starch chains, resulting in poor solubility in most common organic solvents, causing difficulties in the processing and in extending the functionality of starch. Different formulations of hybrid gels can be prepared by dissolving the starch.^[46]

Commonly used semisynthetic polymers

Semisynthetic polymers are chemically modified versions of natural polymers, offering enhanced stability and control over drug release properties. HPMC,CMC & PVP/PVA are widely used polymers in the preparation of floating tablets.^[47]

HPMC, or Hydroxypropylmethylcellulose
One or more of the three hydroxyl groups found in cellulose have been used to replace the hydroxyl groups in hydroxypropyl methylcellulose (HPMC), a type of cellulose ether. Because of its superior gel-forming qualities, HPMC, a non-ionic cellulose derivative, is frequently employed in controlled drug delivery. With a large variety of molecular weights and viscosities available for creating FDDS, it is incredibly adaptable. Hydrophilic (water soluble), biodegradable, and biocompatible. HPMC is a polymer with several uses in medicine delivery, textiles, adhesives, coatings, cosmetics, dyes, and paints.^[48] When it comes to thermoplasticity and organo-solubility, HPMC is superior to its counterparts in methyl cellulose. It creates a hydrated matrix that delays the release of drugs and guarantees flotation. HPMC quickly hydrates and produces a thick gel layer when it comes into touch with gastric contents. By using both diffusion and erosion mechanisms, this gel regulates medication release while providing buoyancy. The medication release from HPMC is more consistent in the stomach's fluctuating pH levels than that of CMC since it is comparatively pH-independent. The most used polymer in FDDS is HPMC because of its high swelling and gel-forming properties. Its stability over a range of pH values guarantees more consistent medication release than natural polymers like guar gum and xanthan gum.^[49]

Advantages

• It has High degree of hydration and gel formation,which provides sustained drug release.
• medication release that is constant regardless of pH.
•  It is perfect for FDDS since it is stable in a range of mechanical situations and temperatures.^[50]

Limitations

• It is Slightly more expensive than natural polymers.

• It may not swell as much as some natural gums, but it compensates through prolonged gel formation.^[51]

Carboxymethyl cellulose: -

CMC is a derivative of the regenerated cellulose with hydroxy-acetic acid CH₂(OH)COOH or sodium monochloroacetate. It is often used as its sodium salt, sodium carboxymethyl cellulose. CMC is water-soluble and is commonly used in drug delivery systems for its film-forming and gelling properties.^[52]

It is commonly used as a viscosity modifier or thickener and to stabilize emulsions in various products, both food and non-food-related. It is mainly used because it has a high viscosity, is nontoxic, and is generally considered to be hypoallergenic. Because CMC is a very hydrophilic polymer, it can quickly absorb water when it comes into touch with stomach contents. Gel formation and swelling are the results of this hydration.^[53] A sticky gel coating surrounds the pill as CMC swells. The buoyancy of the tablet depends on the air being trapped by this gel layer. The tablet can float because the air trapped in the gel and tablet matrix makes it less dense than the stomach contents. This floating mechanism improves drug release and absorption by allowing the tablet to stay in the stomach for a longer amount of time. By acting as a barrier, the gel layer regulates how quickly the medicine diffuses from the tablet.By acting as a barrier, the gel layer regulates how quickly the medicine diffuses from the tablet. Over time, the swelling characteristics of CMC aid in controlling the active pharmaceutical ingredient's (API) release. Because the medication is released gradually while the tablet is in the stomach environment, buoyant and controlled release can result in long-lasting therapeutic effects.^[54]

Advantages: -

• It has Excellent film-forming properties, which aids in the formulation of floating tablets.
• Its is Inert and non-toxic.
• It  can create a gel barrier that slows drug diffusion, resulting in sustained drug release in FDDS.^[55]

Limitations: -

• The medication release from CMC is very sensitive to pH. Its swelling behaviour is impacted by the protonation of the carboxyl groups in acidic conditions.
•  Usually, a diffusion-controlled mechanism governs the drug release from CMC-based FDDS, with some effect from gel layer erosion.^[56]

PVP-PVA

Polyvinyl alcohol has excellent film forming, emulsifying, and adhesive properties. It has high tensile strength, flexibility, as well as high oxygen and aroma barrier. However, these properties are dependent on humidity, in other words, with higher humidity more water is absorbed. Polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) are polymers that can be combined to create a blend with many properties.^[57] The 50/50 PVA/PVP blend has the highest CO2 permeance among tested membranes. This is due to the reduced crystallinity of PVA when PVP is added.^[58] The stability of the PVA/PVP blend depends on its crosslinking density, which increases with more water and heat resistance. Spray-dried PVA-PVP tablets exhibit instantaneous floating with virtually little lag time, remaining afloat for 24 hours without sinking. When both polymers are hydrated, they might both swell. PVP aids in preserving a stable gel structure, whereas PVA expands and becomes more viscous. This swelling helps to prolong stomach retention and adds to the tablet's buoyancy. Drug diffusion is slowed down by the gel matrix that the PVA/PVP combination creates. A sustained release profile results from this. The tablet's high porosity is what gives this system buoyancy. Even under very low pressure, mechanically stable oral DF can be produced thanks to the spray-dried PVA-PVP combination's extraordinarily high compressibility.^[59]

Influence of Polymers: -

Table 3: Influence of Semi synthetic polymers