Available online on 15.11.2021 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2021 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                           Review Article 

Floating Drug Delivery System an Aid to Enhance Dissolution Profile of Gastric

Yadav Shalini  *, Yadav Saurav , Mishra Amar, Kumar Ashutosh and Kushwaha S. Sandhya

Dr. M.C. Saxena College of Pharmacy, IIM Road-Lucknow, Uttar-Pradesh, India

INTRODUCTION

Whereas drug delivery has advanced enormously, oral administration has garnered greater emphasis and success, as gastrointestinal physiology allows more dose form versatility than other approaches. The use of gastro-retentive systems is the oral technique for prolonged medication release. The goal is to increase the delivery duration of drugs in the gastric region¹. For medical compounds with poor solubility and weak intestinal resistance, fluid drug delivery systems (FDDS) for the stomach retaining of the drug have been created. The premise for FDDS is to reduce the density of the dose form to have it float on them. FDDS are low-density hydraulically operated systems with adequate boosting to float above the stomach content and remain in the stomach flourishing for a longer amount of time without influencing the gastric vacuum rate. The remaining system is Evacuated with the medication release from the stomach. This leads to increased gastric dwell duration and management of variations in plasma medicinal products. The idea of flourishing preparation provides a simple and practical technique for increasing stomach residence duration for the dose and long-term release of medicines ². In order to achieve better therapeutic effectiveness of the medication substance in some conditions, it is desired to extend the stomach retention of an administered system. Medication which are less accessible and destroyed by alkaline pH exhibit greater absorption in the proximal portion of the gastrointestinal tract have prolonged gastric retention. Moreover, prolonged gastric retention and thus various advantages, including enhanced bioavailability and therapeutic efficiency with decrease of dosage frequency, are offered for the continuous supply of medicines to the belly and proximal small gut in the treatment of some ulcers³. Gastro-retentive dosage forms (GRDF) are intended to be retained and released in the gut for an extended duration of time and therefore enable the medication to be continuously and prolongedly input into the upper section of the gastrointestinal tract (GI). In recent decades, this technique has attracted considerable attention because of its potentials to improve oral delivery of several essential medicines, which are likely to substantially increase the oral bioavailability and/or therapeutic result of prolonged retention in the upper GI tract⁴.

Part of the proximal developed by fundus in the stomach. The body is the reservoir for ungroomed materials, and the antrum is the primary location for the mixing of gestures and serves as a stomach emptying pump by action pushing^5,6. In both the fasting and fed phases, gastric emptying takes place. In fasting conditions, the inner digestive myoelectric migrating cycle (MMC) is split into four phases and is held in a 2–3-hour period⁷.

1. Phase I (base phase) with frequent contractions lasting between 40 and 60 minutes.
2. Phase II (pre-burst phase) takes 40 to 60 minutes with sporadic activity and contraction potential.
3. Phase III (starting phase) takes between 4 and 6 minutes. It contains strong and regular short-term contractions. Because of this wave, all the non-digested material is drawn down into the small Dram from the stomach. The housekeeping wave is also known.
4. Phase IV lasts between 0 and 5 minutes, occurs respectively phase III and phase I in two consecutive cycles.

Figure 1: GIT motility model

The rate of contractions differs between fasting and one in the gastric phase when a combination meal is consumed. This is also coined as the regularity of intestinal motility and involves continuous contractions in fasting condition Phase II. These contractions reduce the proportion of the suspended nutrient particles (to below 1 mm) to the pylorus. During MMC's feedstock start, the stomach emptying rate is slowed^8,9.

PRINCIPLE TYPES OF GASTRIC RETENTION SYSTEMS

 The gastro-retention systems are intended for extended time to be kept within the stomach to release the active components of the drugs and allow the medication to enter the upper section of the gastrointestinal tract on a continuous and prolonged basis. Over recent decades, this technique has received huge attention because of its potential to improve the oral administration of several essential medicines, which are able to improve their oral bioavailability and/or therapeutic effect with longer retention in the upper GI tract.

Ideal candidates for the delivery of gastro-retention medicines:

1. A drug that acts in the stomach locally.
2. Medications that are mostly taken in the stomach.
3. Medicines those are not very soluble in alkaline ph.
4. Medicines that are quickly absorbed by the GI tract.
5. Medications in the intestines that deteriorate.

Figure 2: Categorized as following gastro retentive delivery method.

Figure 3: Bio-adhesive mechanism of drug molecule on mucous layer

1. Expandable systems: Extensile gastric retentive systems are readily ingested, and owing to swelling or developing processes, the stomach retention duration is much higher¹¹. When the stomach is evacuated after release, its proportions are decreased. A merger of significant dimensions and high dose stiffness increases gastro-retentiveness to endure peristalsis and mechanical stomach contractility. The in vivo absorption effects were enhanced by narrow absorption window medicines in these systems. This system's expansion mechanism swells in a way that impedes the pylorus from exiting. The dose form is therefore kept for a long time in the stomach. These can be referred to as "plug-type system" since they tend to remain lodged on the pyloric sphincter when the diameter in their enlarged condition exceeds around 12-18mm. The recipe is designed to store the medication in a stomach cavity and to regulate it. For several hours, even in the fed condition, such polymer matrices persist in the stomach cavity.
2. High density systems: This technique comprises the creation of dose shapes with densities which must exceed the usual stomach content density (~ 1,004 gm/cm). This sort of formulations is created by covering the medicine in a hefty core or 3mixed with inert ingredients. Barium sulphate, iron powder, zinc oxide and titanium oxide etc. are the inert materials. Material density up to 1,5-2,4 gm/cm rises. For a considerable extension of 3gastric residency period, a density of over 32.5gm/cm seems essential¹².
3. Floating drug delivery system: Floating systems are moderate systems that hover over the intestinal fluid and exist in the stomach for a considerable length of time¹³. The medication is slowly released from the system when the gastric content is released and the rest of the system is removed from the stomach at the correct rate after the drug is administered. As a consequence, stomach retention is improved and the variations in plasma drug concentration are better controlled⁹. The medication is released slowly at the required concentration in the circulation as the system floats in stomach content. The debris from the stomach is therefore cleansed. These findings will result in GRT increase and improved flux management at concentrations of plasma drugs. However, the floating style minimum level (F) requires also that floats on the surface of meals provide a dependable dose form for the stomach content that is minimal to acquire a right to retain the concept of flooding¹⁴. It is also beneficial for local medicines such as antibiotics for Helicobacter pylori for proximal gastrointestinal (GI) treatments for a peptic ulcer¹⁵ and for medications difficult to dislocate or not durable in gastrointestinal secretions¹⁶.

Table 1: Elucidation of merits and the downsides of floating drug delivery system

Criteria for selecting drug applicants for the system of floating medicines:^25,26,27

• Medicines with limited window absorption in GIT (e.g. L-DOPA, paminobenzoic acid, furosemide, riboflavin).
• Drugs that are effective regionally in the stomach (e.g. misroprostol, antacids).
• Drugs in the intestine or colonic environment that are unstable (e.g. captopril, ranitidine HCl, metronidazole).
• Medicines which trouble typical colonic bacteria (e.g. antibiotics used for the treatment of Helicobacter pylori, such as tetracycline, clarithromycin, amoxicillin).
• Medicines with low high pH dissolution. (e.g. diazepam, chlordiazepoxide, verapamil).

FLOATING SYSTEMS MECHANISM:

Floating drug delivery devices (FDDS) have a relative density lower than stomach juices and are therefore suspended in the digestive system for longer periods of time without impacting the the pace of digestion. During floating on the stomach contents, the medication is freed at the recommended intervals from the system. The residual system is emptied of the stomach once the medication is released. The GRT is improved and variations in plasma medication concentrations are better controlled. However, a minimum amount of floating force (F) is necessary in inclusion to the minimal gastric content needed to assure that the floating force is properly maintained in the dose forms on the meal's surface. A new apparatus for determining the resulting weight was published in the literature for the appraisal of floating force kinetics. So to retain the submerged item, the device continually measures the force corresponding to F (depending on time). If F is on the upper positive side, the item floats better. This device serves to optimise the stability and endurance of the floating forces produced by FDDS, to avoid unpredictable fluctuations in intra-gastric buoyancy³⁵.

F = F buoyancy - F gravity = (Df - Ds) gV 

Where, F= total vertical force,

 Df = fluid density, 

Ds = object density, 

V = volume and

 g = acceleration due to gravity.

Figure 4: Mechanism of floating drug delivery system

Table 2: Relative comparison between conventional and gastro-retentive drug delivery system 

Figure 5: Floating system classification³¹

Different forms of Non-effervescent Systems are explored below.

1. Bilayer floating tablet: The floating tablet of the two-layer Bilayer has an instant release tablet which releases the initial dosage of the system and the continuous discharge stratum accumulate gastric fluid to the surface, retains the bulk density and remains hovering in the gut⁶.
2. Colloidal gel barrier system: This method extends the stomach retention period and optimizes the quantity of medicines which arrive at the absorption site. It comprises drugs that contain gel-forming hydrocolloids, to keep their stomach content booming. This system includes hydrocolloid cellulose type gel-forming polymers such as hydroxypropyl methyl cellulose (HPMC), polysaccharides and polymers forming matrix, such as polycarbophils, plastics and polyacrylates. Hydrocolloid hydrates in the course of providing an environmental gel colloid barrier when it is in touch with the gastro-intestinal (GI)^36,37.

Figure 6: Colloidal gel barrier system 

1. Microporous compartment systems: A microporous portion features a bundled medication reservoir on the upper and base of the wall. The drug container on the outer wall is totally screened to dissolve the insoluble medicines in the stomach. The entangled ones are used to float the system on the fluids of the stomach into the fluid orifice, which dissolves the medicines to be metabolized into the bowel³⁸.

Figure 7: Microporous compartment system.

1. Hollow microspheres: Hollow microballoons used by emulsion solvent diffusion technique, are microballoons that use medicine on the polymer's exterior shell. Solution of ethanol: aqueous dichloromethane and enteric PVA solution at a 400°C turning temperature. By vaporising dichloromethane, the resultant gas stage is distributed into polymer gout, producing an internal hollow in a polymeric microsphere, with the pharmaceutical being an internal cavity on the polymer's microsphere. The microballs float on the top of acidic dissolving medium which maintain a surfactant longer than 12 hours (in vitro)³⁵.
2. Alginate beads: The floating multi-unit dose forms consist of freezing alginate calcium. Calcium alginate can be precipitated with round beads with 2.5 mm diameter, which is soluble in calcium chloride solution, which can form a pore system that can strengthen its ability to float over 12 hours and be longer³⁹.

Figure 8: Schematic representation for alginate bead preparation.

2. Raft Systems: Involve alginate gels in raft forming systems. These have a carbonate element that bubbles in the gel when reacted with stomach acid and allows it to float. The raft process convoluted in the formation comprises the creation, with each part of the fluid swells, of a constant layer called a raft, of viscous cohesion gel in interaction with stomach contents. Due to the low volume density creating CO2 production, this raft floats with stomach juices. The antiacids and medicines supplied for gastrointestinal infection and illnesses have been given great attention in these systems^40,41.
3. Effervescent System: Preparation is intended for the production of carbon dioxide gas in an effervescent system. Carbonates, gas production and other organic acids are one of them. The formulation design aims at reducing the density system that can float in the stomach juice¹³. In the case of one layered tablet, the free CO2 gas can be mixed quickly in the tablet matrix⁹.
4. Volatile liquid containing systems: This is a floating system that is osmotically regulated and consists of a void deformable unit in convertible, collapsed shape. Home would be linked to its deformation unit and split into a first and second chamber by a moving unit that is impermeable and sensitive to pressure. The first chamber normally holds an active drug, while the second chamber is used for the production of a gas by vaporization of a volatile fluid such cyclopentane or ether, which allows the drug reservoir to float. With the assistance of an eroding plugs that enabled the vapor to evade, the unit is removed from the gastrointestinal^36,37. The ethyl cellulose covering is water-permeable, releasing CO2 from it⁴².

POLYMERS USED FOR FLOATING DRUG DELIVERY SYSTEM

Figure 9: Classification of polymers used on the basis of origin

Some of them are described as below.

1. Chitosan: Chitosan is a bio-poly amino-saccharide, which is synthesized by alkaline chitin deacetylation. The deacetylation grade and molecular weight of chitosan are available in various grade levels, and the solubility may also be modulated from modestly acidic medium to watery⁴³. The proportion of deacetylation influences essentially the polymer characteristics of dispersion, hydrophobicity and the potential to interact with polyanions electrostatically by altering the number of amino groups protonatable^44,45. In 0.5-8% concentration, chitosan is utilized in production of the microsphere. Acetic acid is utilized primarily as a carrier for the composition preparation at a concentration of 0.5-3 percent. Dichloromethane and ethanol are also used in some situations in 1:1 ratio^46,47,48,49.
2. Sodium Alginate: Alginate is a natural abundant component obtained by brown algae and bacteria in the soil⁵⁰. The ionotropic gelation technique is used to produce alginate beads. Beads with a diameter of about 2.5mm may be produced, which causes a precipitation of calcium alginate by adding sodium alginate solution in aqueous calcium chloride solutions. The beads are then frozen into liquid nitrogen, separated and freeze at −40°C for 24 hours, which produces a porous structure that is capable of maintaining a floating force of 12 hours. The sodium alginate is used to manufacture beads with 1-6 percent concentration^51,52,53,54. The alginate gel particles are pH-sensitive, that is, they remain unaltered in water or in acid, but quickly swell to a size higher than the original size in phosphate buffers of pH 7.0. These alginate properties may be of value in medicines which are acid-sensitive as they may be protected against gastric jus attacks and may release xerogels into the gut at desired rates⁵⁵.
3. Ethyl-cellulose And Hydroxy Propyl Methyl Cellulose: A long-chain polymer of b-anhydro-glucosic units combining with acetal linkage is ethyl-cellulose (ethyl ether of the cellulose). The primary hydrophilic vehicle utilized in the manufacturing of oral controlled drug delivery system is hydroxy propyl methyl cellulose (semi-synthetic polymer). It is member of the hydrophilic polymer’s family^56,57. HPMCs such as K4M, K100M, K15M, etc. are utilized in the management of floating microspheres and tablet compounds^58,59. Ethyl-cellulose is amongst the most often accessed polymers for microsphere preparation. It is also utilized for improved outcomes at concentrations of up to 20%⁵⁹.
4. Acrylic Acid Derivatives: The main derivatives utilized in the production of floating microsphere are Eudragit and Carbopol. Eudragit is an acrylic and methacrylic acid precursor. There are different degrees of Eudragit used to prepare floating microspheres. For the production of floating microspheres, Eudragit RL, E, and RS grades is utilized. RL 100 and RS 100 are granular in these grades and commonly utilized compared to any other plastic, which is pH-independent, mucoadhesive, swelling polymer^60,61. Carbopol is a variant of acrylic acid that is used for floating foodstuffs because of its high mucoadhesive and swelling characteristics. The floating tablets made with Carbopol and other polymers minimize the floating lag time and also offer a better outcome with Eudragit^62,63.

METHOD OF PREPARATION:

1. Solvent evaporation method: Employing solvent diffusion and evaporation techniques, a hollow inner core was produced with the floating multi-particulate dose. After the polymer is immersed into a solvent, it is dissolved into the organic polymer solution. The drug solution is later homogenized into an aqueous medium of PVA to produce O/W emulsion. The organic solvent is then evaporated or continually stirred as the temperature rises. The withdrawal of a solvent leads polymer to seize the gout contact with the oil in water (O/W), creating a hollow chamber and enabling it to float. Among the polymers that are being used in the improvement of these floating systems include cellulose acetate, polyvinyl acetate, chitosan, acrylate, Eudragit, Methicillin, polyacrylate, polycarbonate, Carbo-polite, polyethylene oxide and agar. The polymer and drug regulation rate were disintegrated by methylene chloride. In the organic phase that was produced the polypropylene powder was then distributed. In the aqueous phase of polyvinyl alcohol (PVA), the resulting suspension was then emulsified. Until being dried in a desiccator with enough silica gel, the macro-particles were tamed and washed with cold water; all of these are uneven in form and size and have a porous structure⁶⁵.
2. Emulsion solvent diffusion method: A new technique of diffusion of emulsion solvents is being implemented with micro-balloons (hollow microspheres) in their external polymer shell. A polymer and medicament mixture are injected into an aqueous polymer solution in ethanol methylene chloride (vinyl alcohol). Enclosed methylene chloride evaporates and the microparticles create interior voids⁶⁴.
3. Ionotropic Gelation Method: In the vicinity of counter-ionic polyelectrolytes, the inclination to cross link promotes ionotropic gelation, which leads to beads production. Since usage of Chitosan, Alginates, CMC and gellan gum for drug encapsulation, this method of gelation has been frequently used to bead preparations. These anions build mesh-like structures by coupling them with versatile cations and engage gelation mostly by combining them with anion chunks. Hydrogel beads are created if the drug-loaded polymer solution is dropped into a versatile cationic aqueous phase⁶⁵.

Table 3: Factors affecting gastric residence time of the floating drug delivery system 

FDDS PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetic Aspects

1. Significantly enhanced Bioavailability: With the exception of several bioavailability reasons, FDDS has examined the excellence of bioavailability for some medicines with narrow therapeutic window attributable only to the poor GI uptake. The medicines evaluated with a restricted absorption window, FDDS, showed that the molecule might be more bioavailable at a particular location. In compared with the intake of traditional formulation, the bioavailability of hovering Riboflavin and Levodopa control release (CR) systems is boosted.
2. Enhanced first-pass biotransformation: Similarly, the pre-systemic metabolism of the tested chemical has enhanced the reason for FDDS substantially when supplied sustainedly in the metabolic enzymes (P450 cytochrome, in particular CYP3A4) rather than with bolus input, in the active transport companies with limited capacity activity.
3. Decreased dosing frequency: The varied investigations show that medicines with relatively brief, biologically-living biological halves, a sluggish input from continuously releasing and controlled floating pharmacokinetics flip-flop system ensured at decreased dosage frequency have been seen. This characteristic is linked to better patient conformity and enhances treatment.
4. Targeted treatment in the upper GIT for local conditions: For local treatment in the stomach and small intestine, lengthy and continuous use of medication from the floating systems into the gut can be beneficial.

Pharmacodynamic aspects

1. Reduced drug concentration fluctuations: Continuing intake of the drug following controlled release of the Gastro-retentive dosage form (CRGRDF) generates blood concentration in a smaller range in comparison to instant release dosage forms. Fluctuations in drug effects are therefore reduced and concentration can be prevented dependent on maximal dosages. For medications with a low therapeutic index, this is particularly imperative⁷².
2. Minimized colon adverse event: In the scenario of a gastro-retentive shape on the gastric in the FDDS the persistence of drug reduces the number of medications reaching the colon. Unwanted drug activity in the colon can therefore be averted. This pharmacodynamic feature offers the justification for floating formulations of beta-lactam antibiotics which are exclusively absorbed by the small intestine and which cause the growth of bacteria in the colon⁷³.
3. Reduced body counteractivity: The pharmaceutical reaction, which interferes with natural physiological processes, in many circumstances causes a rebound activity of the body, which reduces drug activity. Low drug intake into the body, as in FDDS, reduces counter-activity and increases drug efficiency.

Table 4: Evaluation of floating drug delivery system 

CONCLUSION

Drug absorption is a very varied operation in the gut, and prolonged stomach retention of the dose form prolonged the permeation period. FDDS provides a possible gastro retention strategy. The objective is to increase bioavailability in the area of the gastrointestinal system with a small absorption window. By lengthening GI time, the solubility of medicinal products less soluble at high pH and reducing the waste of medicines is improved, thereby reducing plasma levels. While some challenges to produce extended gastric retention still need to be developed, a great number of firms focus on the commercialization of this method.

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