Formulation And Evaluation Of Floating Drug Delivery For The Treatment Of Ulcer And Antibiotic Caused By H.Pylori Infection

The Oral Drug Delivery System is recognized for its convenience, non-invasive nature, and high patient compliance, making it the most favored method to administer medication. Most treatments initiate with this approach due to its cost-effectiveness and ease of use. When ingested, the drugs are absorbed systemically through the gastrointestinal tract, rendering them effective for acute and chronic conditions. Despite its popularity, oral drug delivery presents challenges, particularly concerning drug bioavailability and therapeutic efficacy. A significant advancement in this field is the development of sustained-release systems, which aim to maintain stable drug concentrations in the plasma over extended periods. This innovation reduces the frequency of dosing and enhances patient adherence. The concept was first introduced by Lipowski, a pioneering formulation chemist, in the late 1930s, laying the groundwork for modern sustained-release technologies that are now vital to oral medication delivery. These systems are designed to overcome the limitations of traditional drug delivery methods, which often result in fluctuating drug levels and associated side effects. By providing a controlled release of medication, sustained-release systems minimize adverse effects and enhance patient comfort, ensuring a more reliable therapeutic outcome. An example of this innovative approach is bilayer tablets, which can administer different medications with distinct release profiles. They focus on improving patient compliance, managing release patterns, and enhancing drug bioavailability, oral drug delivery systems have seen significant advancements. These innovations are poised to continue shaping the future of pharmacotherapy. Floating systems are low-density and buoyant, allowing them to float over gastric juices and maintain stability of longer activity. Davis initially found floating systems in 1968. These low-density systems have enough buoyancy to float over gastric contents and remain in the stomach for long periods of time(2). Floating drug delivery systems can sustain medicines with short biological half-lives, increasing efficacy and reducing dose frequency. This element of feds helps improve patient compliance and pharmaceutical therapy[1]. Various buoyant methods have been devised using grains, powders, capsules,tablets, laminated films, and hollow microspheres[3]. Floating medication delivery devices extend the duration of the dose in the gastrointestinal tract and improve absorption. Drugs with higher solubility in acidic circumstances and absorption in the upper portion of the small intestine are more suited for these processes [4]. Floating multi-particulate drugs are free-flowing protein or synthetic polymer powders with a size of fewer than 200 micrometers. Floating multi-particulate drug delivery systems use both non-effervescent and effervescent approaches to ensure gastro-retention. Gastro-retentive systems extend a drug's stomach residence period by several hours. Sustained stomach retention in high pH environments improves bioavailability, reduces drug waste, and improves solubility for less soluble medications in both non-effervescent and effervescent administration systems. Hollow microspheres are spherical particles that lack a core. Long-acting dose forms that release their medication gradually are known as sustained release dosage forms. "Controlled release" describes how the system is Possession of some degree of therapeutic control[6]. It aids in optimising compliance and effectiveness. Normal stomach residence times often fall between five minutes and two hours(3). Floating dose forms are a promising novel dosage form that is rapidly gaining popularity(5). By adding gas-generating agents and the proper excipients, floating dosage forms can be created as tablets or capsules that float in gastrointestinal fluids[7]. While the medication is floating on the contents of the stomach, it is gradually expelled from the system at the ideal rate. Following the release of the drug, the stomach's residual system is emptied[8]. Long-acting dose forms that release their medication gradually are known as sustained release dosage forms.  Low-density systems known as floating systems have enough resistance to float on the stomach and remain floating in the stomach for an extended amount of time without affecting the rate at which the stomach empties. The drug will be released gradually into the system at the appropriate concentration while it floats on the contents of the stomach. As a result, the stomach will be free of the residue. These findings will therefore lead to an increase in GRT and improved flux control in plasma drug concentrations. Additionally, it is helpful for nearby gastrointestinal tracts and local medications, such as antibiotics for Helicobacter pylori infections and medications that are unstable or difficult to dissolve in intestinal fluids [9].

STOMACH ANATOMY

The basic operation of the abdomen is to a method and transport food in the tittle intestine the duration of food is tiny and largely protein square measure digestible.

Structurally the abdomen is split into 3 regions:

Fundus:

proximal part

Body: acts as a reservoir for undigested material,

Pylorus is a site for mixing contents and acts as a pump for gastric emptying by propelling actions.

 the average pH in fasted healthy person is one . 1±0.15, once intake of food the PH scale rises to the level of 3.0 to 4.0 [9]. The stomach is an expanded digestive tube that connects the oesophagus with the small intestine.

When the stomach is empty, it contracts and the mucosa and submucosa develop discrete folds called rugae.  The four major types of secretory epithelial cells that cover the stomach surface and grow to form gastric pits and glands are described below.

• Mucous cells
• Parietal cells
• Chief cells
• G cells

ADVANTAGES

1. Enhanced drug absorption is achieved by prolonging the floating time of the formulation, allowing for increased exposure at the absorption site.
2. Improved bioavailability of the drug is observed.
3. Controlled release of drugs is achieved.
4. Mucosal irritation is minimized due to the steady and controlled release of the active pharmaceutical ingredient (API).
5. It aids in the treatment of various gastrointestinal disorders such as pyrosis, offering localized relief.
6. It simplifies administration and enhances patient acceptance.
7. Reduction in dosing frequency is possible.
8. Specific drug delivery to targeted locations is facilitated.

DISDAVANTAGES

1. A significant limitation of floating dosage delivery systems (FDDS) is the necessity for an adequate volume of liquid in the stomach to facilitate the buoyancy of the dosage form. This challenge can be mitigated by employing bioadhesive polymers to coat the formulation, enabling it to adhere to the moist mucosal surface of the stomach.
2. The ability of the formulation to remain buoyant in the stomach is affected by several variables, including gastric motility, pH levels, and the presence of food, which can fluctuate, making it difficult to maintain consistent buoyancy.
3. Active pharmaceutical ingredients (APIs) that irritate or damage the stomach's mucosal lining are inappropriate for this dosage form.
4. The time it takes for the stomach to empty can vary considerably among individuals.
5. Patients are advised against consuming floating dosage forms prior to sleeping. 6. Certain APIs that face solubility or stability challenges in gastric fluids are not ideal for floating delivery systems.
6. The formulation should be ingested with a glass of water
7. Medications that are absorbed throughout the intestinal tract and are subject to first-pass metabolism are not suitable for this type of delivery system.

 Gastrointestinal Motility Pattern:

 Phase I:

The basal phase characterized by the absence of contractions and a state of silence.

 Phase II:

A pre-burst period where contractions begin to intensify.

Phase III:

The explosive phase marked by large-scale, highly coordinated contractions that facilitate effective evacuation of contents.

 Phase IV:

A transitional phase in which the contractions from the latter part of Phase III gradually fade into the stillness of Phase I.

1. Peristaltic Wave:

This occurs when the distal region of the intestine is adequately relaxed, allowing the longitudinal muscle layer to rhythmically contract and propel the peristaltic wave forward.

2. Segmentation:

This involves the rhythmic atrophy of the circular muscle layer.

3. Ancillary Movements:

Referred to as stomach rest, these movements enable the stomach to relax and retain the ingested food. A food bolus is transferred from the esophagus to the stomach through the lower esophageal sphincter (LES).

Drug Suitable for Gastro retentive Drug Delivery System:[ 11]•

1. Medications Appropriate for Gastro retentive Drug Delivery Systems:

• Medications that exert local effects within the stomach, such as antacids and misoprostol.
• Medications with a narrow absorption window in the gastrointestinal tract, including riboflavin and furosemide.
• Medications that exhibit instability in the colonic environment,
• Medications are effective against typical colonic microorganisms, such as antibiotics targeting Helicobacter pylori.
• Medications with low solubility at elevated pH levels, including chlordiazepoxide and diazepam.

Drugs Unsuitable for Gastroretentive Drug Delivery System:[11]•

Medications Inappropriate for Gastro retentive Drug Delivery Systems:

• Medications with limited solubility in acidic conditions, such as phenytoin.
• Medications that are unstable under gastric environmental conditions, for example, erythromycin.
• Medications primarily utilized for their targeted release in the colon, such as 5-aminosalicylic acid and corticosteroids

1. CLASSIFICATION OF GRDDS: [12-16]

Gastroretentive Dosage Forms (GRDF) are defined as dosage forms that can be retained within the stomach. Types of Gastroretentive Dosage Forms: [16]

1. High-density system
2. Floating system
3. Swelling system
4. Expandable system
5. Superporous Hydrogel
6. Mucoadhesive or Bioadhesive System
7. Magnetic System

 High-Density System:

This category of GRDF possesses a density of approximately 3 g/cm?3;, allowing them to be retained within the rugae of the stomach. These systems can remain in the lower stomach region as long as their density does not exceed the threshold of 2.4-2.8 g/cm?3;. A significant challenge associated with this system is the technical difficulty in manufacturing large quantities of the drug product.

 Swelling and Expandable System:

The expandable GRDF typically features three configurations: a compact form for easy oral ingestion, an expanded form that occurs within the stomach to prevent passage through the pyloric sphincter, and a reduced form that is achieved when retention is no longer required. Swelling is generally induced by osmosis, while unfolding is a result of mechanical shape memory.

 Mucoadhesive or Bioadhesive System:

 These systems incorporate bioadhesive agents that facilitate adherence to the stomach lining, thereby preventing gastric emptying. Bio/Mucoadhesive systems attach to the gastric epithelial cell surface or mucin, prolonging gastric retention time (GRT) by enhancing the intimacy and duration of contact between the dosage form and the biological membrane.

 Superporous Hydrogel:

 These swellable systems feature an average pore size exceeding 100 ?m and can rapidly swell to equilibrium within a minute due to the swift absorption of water through capillary action in multiple interconnected open pores. They expand significantly and are expected to possess sufficient mechanical strength to withstand the pressures exerted by gastric contractions.

 Magnetic System:

Magnetic dosage forms are equipped with an external magnet and a small internal magnet that regulates their retention within the stomach. The Floating Drug Delivery System (FDDS), also known as Hydro-dynamically Balanced Systems (HBS), consists of low-density formulations designed to remain buoyant on the surface of gastric contents.[12,18]. This characteristic allows them to stay in the stomach for prolonged durations, facilitating the controlled release of the active pharmaceutical ingredient at a predetermined rate. By floating on the gastric contents, these systems enhance gastro-retention time and minimize fluctuations in drug release, thereby effectively managing the pharmacokinetic profile of the drug to target specific sites for optimal pharmacological effects.

CLASSIFICATION:

 A. Effervescent FDDS

1. Gas generating system

2. Volatile liquid containing system

 B. Non-Effervescent FDDS

1. Colloidal gel barrier system
2. Bi-layer floating tablets
3. Microporous compartment system
4. Floating Beads/ Alginate Beads
5. Micro balloons/ Hollow Microspheres

C. Raft forming system

Effervescent FDDS

 Effervescent system: They contain gas-creating substances (sodium bicarbonate, tartaric acid or citric acid) to attain floating ability. The gas which is generated is CO2. Once gas-generating agents come in meet with the acidic pH solution, immediately carbon dioxide is generated from the drug delivery system reducing the density of the system and thus causing it float on the gastric content. The buoyancy can also be attained by utilising swellable polymers like Hydroxypropyl methyl cellulose, chitosan [19,20].

Effervescent is further divided into following:

A.Gas generating systems:

It utilizes effervescent reaction between carbonate/ bicarbonate salts and citric/tartaric acid. CO2 is released in water . The dosage form is put into the beaker, it will sink to the bottom of the beaker and with the release of gas itwill rise up and float [21-23].

 Evaporative liquid containing formulations:

 It consists of an inflatable chamber with a liquid like ether that releases gas at body temperature leading to floatation of the chamber in the stomach. The inflatable chamber consists of a pool of medicines in a gelatin capsule. The capsule releases the stored drug after intake with the inflatable chamber leading to the formation of gas bubbles and permits unconstrained ejection of the inflatable systems from stomach [24].

B.Raft forming systems:

Gel forming polymer like sodium alginate is used mixed with gas generating agents like sodium carbonate. Once gel developed and this gel come in contact with the gastric fluid, the gas carbon dioxide produced is trapped within the gel, the gel swells forming a layer called as rafts. These rafts remain on the gastric fluid and shown in fig 5. Such systems are used for delivering antacids like aluminiuhydroxide, calcium carbonate, etc. The mechanical strength of this system is weak and can be destroyed by MMC.

Non-Effervescent system:

 This system uses swellable cellulose type polymers or gel forming polymers or matrix forming polymers like HPMC, chitosan, Carbopol, agar, sodium alginate, etc.

Non-Effervescent system can be classified as follows:

A.Colloidal gel barrier system:

This formulation comprises of drug with gelforming hydrocolloids so that it can remain float in the gastric fluids. This method contains different highly soluble gel-forming cellulose type hydrocolloid of high level like HPMC, HEC, polysaccharides, matrix forming polymer like polystyrene, polyacrylate. Drug release from Colloidal gel barrier system .When the formulation comes in meet with the stomach juice, the hydrocolloids, hydrate then they may lead to the formation of colloid gel barrier on its surface [25].

B.Microporous membrane systems:

 In this, the drug is encapsulated in a very small pores or channels with diameters in the micron or nanometer range compartment with pores on it’s above and below . The side walls are secure to prevent association with acidic fluid with the API. The floating compartment containing the accidental air leads to the floatation of the transport device above the simulated digestive fluid. The simulated digestive fluid across through the opening, diffuse the drug and conveys the diffused drug across the intestine for assimilation

C.Alginate beads:

This system of spherical beads of roughly  2.5 mm in diameter [26]. These beads are formed by placing the sodium alginate solution into aqueous calcium chloride solution leading to the precipitousness of calcium alginic acid. They are divided, quickly frozen in liquid nitrogen, and then freeze-dried at 40 ° C for 24 hours, resulting in the production of a porous system that can float for more than 12 hours. Sodium alginate + Calcium Chloride ? Calcium alginate + NaCl

D.Hollow Microspheres/Micro balloons:

Their preparation is done by Solvent Evaporation Method Mostly used polymers are polycarbonate, calcium alginic acid, Eudragit, etc. The above formulations can float over acidic dispersion media containing surface active agents for about 12 hours [27]. Release pattern from micro ballons

1. Mucoadhesive systems:

Bio-adhesive formulations are utilized as a delivery device inside the lumen to upgrade drug absorption in a site-explicit way. This technology includes the utilization of mucoadhesive polymeric materials, which can hold fast to the epithelial membrane surface in the stomach [28]. Bio-adhesive polymeric systems hold fast to Review On Gastro Retentive Drug Delivery System: That expands the gastric retention by the closeness and time of contact between floating formulation and the biological membrane. The commonly used excipients in these systems are chitosan, gliadin, alginate, Carbopol, etc. Surface epithelium adhesive capabilities have been observed and used for the GRDDS reliant on bio-adhesive polymers. A drug's capacity to adhere to a mucus layer boosts the duration that it remains in one particular organ site, which improves its local or systemic activity.  The muco-adhesion of dosage forms depends on their ability to attach to the mucosal surface in several ways.

The mechanisms are as follows [29, 30]:

1. The Wetting Theory: Relies on the bio adhesive polymer’s ability to disseminate and create intimate contact with the mucous layers.
2. The Diffusion Theory: Suggests that mucin strands are physically ensnared by flexible polymer chains, or that mucin strands are interpenetrated into the permeable structure of the polymer substrate.
3. The Absorption Theory: Recommends that bioadhesion depends on some forces like Vander Waal forces, hydrogen bonding etc.
4. The Electron Theory: It says that there is the presence of some appealing geostatic forces between the bioadhesive substance and the glycoprotein mucin.

1. Expandable systems:

Gastric retention of drug delivery systems conceivably improved by enlarging its size before reaching the diameter of pylorus. If the formulation is able to achieve a size larger than pylorus, then the gastric retention of that dosage form may be prolonged. So, this immense size should be attained fastly or else the formulation will be emptied from the stomach. Thus, the requirements for developing an expansible system for prolonging residence time are a small setup for oral admission; an extended floating form and a small form empowering capabilities have been observed and used for the creation of GRDDS reliant on bio-adhesive polymers. They should also be capable to withstand contractility and peristalsis of the stomach [31].capabilities have been observed and used for the creation of GRDDS reliant on bio-adhesive polymers. A drug's capacity to adhere to a mucus layer boosts the duration that it remains in one particular organ site, which improves its local or systemic activity removal following drug discharge from the system. They should also be capable to withstand contractility and peristalsis of the stomach [31].

2.Unfoldable and swellable systems:

Unfoldable and swellable systems have been used for developing an efficient gastroretentive drug delivery system. They utilize environmentfriendly polymers. Their idea is based on a carrier like a capsule that can be extended in the gastric region. This system with expanded size but with absence of high rigidity are not able to hold in the gastric region leading to brief hinder and disease of the stomach. So, rigidity of these systems is also essential for designing such a gastroretentive delivery. Swellable systems are likewise held in the intestinal tract due to their mechanical properties. expanding drug delivery system conceivably poses a danger of permanent floating in the gastric area and could prompt life-threatening impacts upon taking in the formulation. Also, they are economically cheap. A main benefit of these formulations is in the autonomy of their efficiencies on the filling condition of the stomach [31].

2. High Density (Sinking)System:

The retention mechanism for this system is alluviation, as they are frequently low amount to be floated within the pleat of the body of stomach near the colonic region properly . The density of the dose form should exceed the density of the gastric fluid (1.004 gm/cm3 ). They are formed by coating the drug on a heavy core or by mixing with inert substances like zinc oxide, iron oxide etc. The density is increased by 1.5-2.4 gm/cm3 . For significant prolongation of the GRT, the density should be close to 2.5 gm/cm3 . But the efficacy of this system in humans is little [32]

3. Super Porous Hydrogel Systems:

The conventional hydrogels are slower and take a few hours to achieve the equilibrium during which the pervious swollen having aperture size greater than 100 micrometer swells to adjust size may happen within a few minutes .Due to the quick retention of water by capillary wetting via various open pores interconnected, they swell to an enormous size and are expected to have adequate mechanical solidarity to deal with the pressure because of the gastric contraction, which is acquired through the articulation of hydrophilic particulate materials.

4. Magneto Methods:

 Magneto method is grounded on a basic principle that the formulation consists a small inner magnet and a magnet is placed on the stomach from outside to bring the magnetic dosage form to the favorable position. Some authors have noticed that the gastric resident time and blood plasma drug engrossment were enhanced in the presence of the external magnet. These systems used for performing an in-vivo experiment in rabbits by using bio adhesive granules containing ultra-fine ferrite. The found out that by an external magnetic field, all the granules in the stomach were retained for more than 2 hrs. Since, this system requires specific positioning of the magnet, so it faces low patient compliance. Hence, these systems requried

THERAPY FOR Helicobacter pylori INFECTION BY GRDDS:

Helicobacter pylori is one of the most well-known pathogenic bacterial contaminations, including some staid diseases like peptic ulcers, Review On Gastro Retentive Drug Delivery System: Treatment Of Helicobacter Pylori Infections Section H. pylori is primarily found in the gastric mucosa or at the point where the mucous layer and the stomach's antral epithelial cells meet.  The disclosure of these bacterial parasites has reformed the therapy of peptic ulcers. Most antibiotic drugs are less effective against H. pylori in a single antimicrobial is not enough for a complete  H. pylori infection. This is a direct result of low concentration arriving at the microorganism under the mucosa. For the complete removal of H. pylori, a coalescence of more than one antibiotic and anti-secretory agents is needed, yet these regimens are not completely compelling. Also, other problems are there like patient compliance, bacterial resistance, side effects, etc. Techniques have been used for H. pylori from the abdomen. Since the conventional formulations don’t stay in the stomach for a longer period, they are not able to convey the antibacterial substances to the site of disease in compelling concentrations and complete active forms. One approach to improve the adequacy in the complete removal of H. pylori is the delivery of the antibiotic natively in the stomach so that more medicine will be able to permeate the  The new drug delivery system was residence time in the stomach for the complete removal of H. pylori effectively. Various drug delivery systems developed are polyelectrolyte-coated multi-layered liposomes (Nanoparticles), floating in situ gelling systems, etc[33-36].

Evaluation of Floating Drug Delivery System