Stay & Deliver: The Science Behind Gastroretentive Drug Delivery Systems – A Review

Drug delivery system’s goal is to deliver a therapeutic amount of drug to the correct location in the body in order to achieve and maintain the desired drug concentration. Because of the low cost of therapy, ease of administration, patient compliance, and formulation Flexibility, the oral route is the most preferred route of drug administration?. One novel approach in this area is  gastro retentive drug delivery system (GRDDSs). Dosage forms that can be retained in the stomach are called GRDDs?.GRDDS are innovative formulations designed to prolong the residence time of drugs in the stomach, enhancing bioavailability and therapeutic efficacy².  Gastro retentive dosage forms (GRDF) are oral dosage forms with Gastric retention capabilities in the GI tract. These systems are highly suitable for drugs that posse’s absorption window constraints, by improving gastric residences with controlled release abilities continuously release active ingredient from the dosage form over prolonged period of time and enhances oral bioavailability before it reaches its absorption site³. Orally administered conventional dosage forms do not have proper Controlled over drug release and lead to high fluctuations in plasma drug concentration. GRDDS  is a type of system which prolongs the residence of administered drug in the gastric region for several hours thereby the bioavailability and solubility of challenging drugs may gets enhanced, and improves the patient compliance?.

Drugs suitable for gastro-retentive drug delivery formulations include drugs that have low absorption in the lower part of the gastro intestinal tract (GIT), unstable, poorly soluble at alkaline pH, short half-life, and show local activity at the upper part of the intestine?. Prolonging the gastric retention of the drugs is sometimes desirable for achieving therapeutic benefits of drug that are absorbed from the Proximal part of the GIT or those are less soluble in or are degraded by alkaline pH or they encounter at the lower part of the GIT. GRDDS are beneficial for such drugs by improving their bioavailability and  therapeutic efficiency ?. Oral formulations play a crucial role in drug administration, yet conventional oral delivery systems often exhibit limited bioavailability due to factors like fast gastric-emptying time. Technological advancements have led to novel pharmaceutical products, particularly controlled release drug delivery systems. GRDDS address challenges associated with conventional oral medications, offering prolonged gastric retention time coupled with extended drug release for improved patient compliance. GRDDS proves beneficial for drugs prone to absorption issues, solubility challenges, and degradation in specific gastrointestinal areas. The review focuses on summarizing in vivo studies of GRDDS, exploring pharmacokinetic parameters, gastro-retention times, and inherent challenges. Effective oral drug delivery aims to achieve and maintain desired drug concentrations, with the oral route being preferred for its cost-effectiveness, ease of administration, and patient compliance. However, physiological limitations such as variable gastric emptying, pH variations, and incomplete drug release necessitate innovations. Floating drug delivery systems (FDDS) with lower bulk density than gastric fluids are explored for gastro retention, releasing drugs slowly for controlled and reproducible therapeutic effects. Various approaches like bioadhesive systems, swelling systems, and high-density systems contribute to achieving controlled gastric retention.¹’²

MERITS OF GASTRO RETENTION DRUGS DELIVERY SYSTEM (²`?)

• It enhances treatment effectiveness by releasing drugs gradually, sustaining therapeutic levels longer. This minimizes concentration fluctuations, ensuring more consistent and improved therapeutic outcomes.
• It is great for treating gastrointestinal conditions like ulcers or bowel diseases. By providing prolonged contact with the affected area, they boost the effectiveness of drugs for better treatment.
• GRDDS, with its controlled release, keeps drug levels steady for a longer time, leading to consistent effects and reducing concentration fluctuations for improved therapeutic outcomes.
• It reduces drug concentration fluctuations, ensuring a steady release. This is crucial for drugs with a narrow therapeutic window, enhancing safety and efficacy by maintaining consistent plasma levels.
• Controlled release in GRDDS minimizes side effects linked to high drug concentrations, reducing the chance of adverse reactions by maintaining drug levels within the therapeutic range.
• It can release drugs at specific spots in the gastrointestinal tract, offering targeted delivery. This is beneficial for drugs absorbed in specific regions, resulting in localized therapeutic effects.

DEMERITS OF GASTRO RETENTION DRUGS DELIVERY SYSTEM (²`?)

• Gastric emptying times vary between people and can change in one person under different conditions. This variability affects GRDDS effectiveness because they rely on consistent gastric residence times for optimal performance.
• It focuses on gastric retention and may not suit lower gastrointestinal conditions. Targeting drugs to specific areas in the gastrointestinal system might need different delivery strategies.
• It may experience incomplete drug release due to factors like varying gastric pH, motility, and food presence. This variability can impact therapeutic outcomes.
• Food in the stomach can influence GRDDS performance. It may change gastric emptying rates, causing inconsistent drug release and absorption.
• This type of system is not suitable for drug solubility and stability problems in GIT. .Drugs such as Nifedipine, which under goes first pass metabolism may not be desirable for the preparation of these types of systems.
• The drugs which produce irritation to Gastric mucosa are not desirable drug candidates for GRDDS. The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.

APPLICATION OF GASTRO RETENTION DRUGS DELIVERY SYSTEM(¹-¹?)

1. Enhanced bioavailability: GRDF improves bioavailability compared to non-GRDF formulations, influencing drug absorption and transit in the GIT.
2. Sustained release drug delivery: GRDF ensures a slow release, enhancing pharmacokinetics and reducing dosing frequency for drugs with short half-lives.
3. Targeted therapy for upper GIT: Prolonged GRDF administration enables local therapy in the stomach and small intestine, achieving therapeutic concentrations while minimizing systemic effects.
4. Reduced drug concentration fluctuations: GRDF maintains blood-drug concentrations within a narrow range, minimizing fluctuations and preventing adverse effects.
5. Site-specific drug delivery: Floating dosage forms target drugs with limited absorption sites in the upper small intestine, providing local therapeutic levels, limiting systemic exposure, and reducing side effects.
6. Controlled and slow drug delivery: GRDF controls drug release to the stomach, improving local therapeutic levels and decreasing systemic exposure, ultimately reducing side effects.
7. Decreased dosing frequency: Prolonged gastric availability from site-directed delivery systems reduces dosing frequency, enhancing patient compliance and improving therapy outcomes.

MAIN TYPES OF GASTRO RETENTIVE DRUG DELIVERY SYSTEMS¹²

Gastro-retentive drug delivery systems, designed for prolonged retention in the stomach, have garnered significant attention in recent decades due to their potential to enhance the oral delivery of crucial drugs. This technology facilitates sustained release of active ingredients, ensuring prolonged drug input into the upper gastrointestinal GIT. Such sustained retention in the upper GIT  significantly enhances oral bioavailability and therapeutic outcomes for certain drugs. Gastro retentive delivery systems are classified into:

1. Bio-adhesive Drug Delivery System
2. Expandable Drug Delivery System
3. Floating Drug Delivery System
4. High density systems

a. Bio-adhesive System

Bio-adhesive systems are used to improve drug absorption in a specific area of the stomach. They use special polymers that stick to the stomach lining. These systems increase the time the drug stays in the stomach by making it stick better. Some common ingredients used in these systems include polycarbophil, Carbopol, Lecithins, chitosan, gliadin, and alginate. By sticking to the stomach lining, bio-adhesive systems help drugs stay in the stomach longer, improving their effectiveness for local or systemic treatment.

b. Expandable System

Expandable systems are easy to swallow and become much larger in the stomach due to swelling or unfolding. This makes them stay in the stomach longer. Once the drug is released, they shrink and leave the stomach. These systems are made to withstand the stomach’s movements. They’re especially good for drugs with a narrow absorption window because they help the drugs absorb better in the body. The way these systems work is by swelling enough to block the exit from the stomach. This keeps them in the stomach for a long time. Sometimes they’re called “plug type systems” because they can get stuck at the stomach’s exit if they’re too big. The formulation is made to keep the drug in the stomach and release it slowly. These systems can stay in the stomach for hours, even after eating. The amount of swelling is controlled by how the polymers are linked together. If they’re strongly linked, the system swells less and stays intact longer.

c. Floating drug delivery systems

Floating drug delivery systems, designed to have lower density than gastric fluids, remain buoyant in the stomach for an extended period without affecting gastric emptying. This prolonged floating allows slow drug release at the desired rate, followed by the eventual emptying of the residual system from the stomach, leading to increased gastric retention time and better control of plasma drug concentration fluctuations. These systems can be divided into non-effervescent and gas-generating systems. Non-effervescent systems, like the colloidal gel barrier system, incorporate gel-forming hydrocolloids to remain buoyant, forming a gel barrier upon contact with gastric fluid. Microporous compartment systems encapsulate a drug reservoir inside a compartment with pores, allowing gastric fluid to dissolve the drug for absorption. Alginate beads, another non-effervescent system, consist of dried calcium alginate complexes, offering a multi-unit floating dosage form for sustained drug release.

d. High density systems

High density systems utilize sedimentation as a retention mechanism for small pellets, ensuring they are trapped in the folds of the stomach body near the pyloric region, which has the lowest position in an upright posture. These dense pellets, with a density of approximately 3g/cm³, can withstand the stomach wall’s peristaltic movements. By employing such pellets, gastrointestinal transit time can be extended significantly, ranging from 5.8 to 25 hours. Commonly used excipients to increase density include barium sulphate, zinc oxide, titanium dioxide, and iron powder, effectively enhancing the density by up to 1.5–2.4g/cm³.

Figure No:01

Factors Affecting Gastric Retention Time of Dosage Form(¹-¹?)

1. Density:

The dosage form should be less dense than gastric contents (1.004 gm/ml) to optimize retention.

2. Size:

Dosage forms with a diameter exceeding 7.5mm exhibit longer gastric residence times, while a 9.9mm diameter may reduce retention.

3. Shape:

Tetrahedron-shaped dosage forms linger longer in the stomach, ensuring a predictable release profile, especially in multiple unit formulations.

4. Fed or Unfed State:

Gastrointestinal motility during fasting influences gastric retention time (GRT). Migrating Motor Complex (MMC) delays during fasting, leading to longer GRT.

5. Nature of Meal:

Intake of indigestible polymers or fatty acids alters stomach motility to a fed state, reducing gastric emptying rate and prolonging drug release.

6. Caloric Content:

High-caloric food intake, like proteins and fats, can increase GRT significantly.

7. Frequency of Feed:

Successive meals increase GRT compared to a single meal due to the lower frequency of MMC.

8. Gender:

Males generally have a shorter mean ambulatory GRT (3.4 hours) compared to females (4.6 hours) of the same age and race.

9. Age:

GRT tends to be significantly longer in individuals over 70 years of age.

10. Concomitant Drug Administration:

Anticholinergic drugs (e.g., atropine, propantheline) and opiates (e.g., codeine) can extend GRT.

FUNCTIONAL ANATOMY OF STOMACH¹-¹²

In humans, stomach has four parts:

1. Cardiac region
2. Fundus
3. Body or corpus
4. Pyloric region

1. Cardiac Region

Cardiac region is the upper part of the stomach where esophagus opens. The opening is guarded by a sphincter called cardiac sphincter, which opens only towards stomach. This portion is also known as cardiac end.

2. Fundus

Fundus is a small dome shaped structure. It is elevated above the level of esophageal opening.

3. Body or Corpus

Body is the largest part of stomach forming about 75%to 80% of the whole stomach. It extends from just below the fundus up to the pyloric region

4. Pyloric Region

Pyloric region has two parts, antrum and pyloric canal. The body of stomach ends in antrum. Junction between body and antrum is marked by an angular notch called incisura angularis. Antrum is continued as the narrow canal, which is called pyloric canal or pyloric end. Pyloric canal opens into first part of small intestine called duodenum. The opening of pyloric canal is guarded by a sphincter called pyloric sphincter. It opens towards duodenum. Stomach has two curvatures. One on the right side is lesser curvature and the other on left side is greater curvature.

INSIGHTS INTO THE DYNAMICS OF GASTRIC FUNCTIONING¹²³?:

Understanding the intricacies of gastric functioning is pivotal for the success of GRDDS. The human stomach’s anatomical division into the fundus, body, and antrum is crucial in comprehending the dynamics of gastric emptying. During inter-digestive phases, the stomach’s average volume fluctuates between 250 to 500 ml, with the fundus and body acting as a reservoir for undigested material, and the antrum serving as the primary site for mixing actions. The antrum’s role as a pump in gastric emptying, coupled with the influence of the pylorus on gastric residence time, highlights the complexity of the process. At the core of stomach motility lies the migrating motor complex (MMC), orchestrating a systematic motility pattern. This cyclic activity, organized into four distinct phases during the inter-digestive myoelectric cycle, is essential for the digestive process. A comprehensive understanding of these structural components and motility patterns is indispensable for designing GRDDS. These drug delivery systems leverage the orchestrated dynamics of the stomach to achieve targeted drug delivery and prolong gastric retention. In both fasting and fed states, the stomach exhibits different motility patterns. During the fasting state, the MMC governs a series of well-defined phases, while the fed state follows a digestive motility pattern with continuous contractions. The transition between these states influences the rate at which the stomach empties, posing challenges for controlled-release dosage forms due to the unpredictable emptying rate and short time in the stomach.

Suitable drug candidates for gastro -retention:¹?

Various drugs exhibit their greatest therapeutic effect when released in the stomach, especially when the release is prolonged in a continuous, controlled manner. This sustained release in the stomach reduces side effects and eliminates the need for frequent dosing. It is particularly beneficial for drugs that are poorly absorbed in the stomach or upper part of the small intestine, where absorption occurs rapidly. Examples include Riboflavin, Levodopa, calcium supplements, Chlordizepoxide, Cinnarazine, antacids, and Misoprostol. GRDFs are essential for these drugs, leading to extensive research in both academic and industrial sectors to develop such delivery systems. These efforts have resulted in the development of GRDFs based on various approaches tailored to the specific properties of the drugs.

Commonly used drug in formulation of Gastro retentive dosages forms ¹²•¹³

Therapeutic Effectiveness in the Stomach:

Gastro retentive Drug Delivery Systems (GRDDS) are beneficial for drugs with optimal therapeutic effects when released in the stomach in a continuous, controlled manner. This approach minimizes side effects and allows for sustained therapeutic effects, eliminating the need for frequent dosages.

Improved Absorption Properties:

Suitable candidates for Controlled-Release Gastro retentive Drug Formulations (CRGRDF) typically exhibit poor colonic absorption but have better absorption properties in the upper part of the gastrointestinal tract (GIT). This includes molecules with a narrow absorption window in the GIT, such as Riboflavin and Levodopa, or drugs primarily absorbed from the stomach and upper GIT, like Calcium supplements, Chlordiazepoxide, and Cinnarazine.

Localized Stomach Action:

Drugs that act locally in the stomach, such as Antacids and Misoprostol, are considered appropriate candidates for gastro retentive systems. This targeted delivery enhances the drug’s effectiveness in treating localized conditions within the stomach.

Colon-Specific Characteristics:

Certain drugs with characteristics suitable for gastro retention include those that degrade in the colon (e.g., Ranitidine HCl and Metronidazole) and drugs that disrupt normal colonic bacteria (e.g., Amoxicilline trihydrate). These features ensure the drugs remain in the desired region for optimal therapeutic effects.

Table of Candidate Drugs:

The table provides examples of drugs suitable for gastro retentive drug delivery systems, including Verapamil, Nifedipine, Omeprazole, Atenolol, Propranolol, Diltiazem, Lidocaine, Clarithromycin, and Ramipril, along with their respective bioavailability percentages. These drugs exemplify the diverse categories and bioavailability ranges of suitable candidates for gastro retentive dosage forms.

FORMULATION STRATEGIES OF GRDDS(³-?)

Gastro retention methods (GRDDS) work in different ways like floating, sticking, expanding, and making dense formulations. Each way has its own benefits, letting us customize how we use them based on the drug and treatment needs².

Floating Systems

Floating GRDDS stay on top of stomach contents by using buoyancy, ensuring the drug is released slowly over time. These formulations usually include things that create gas or have low density to help them float.

Bioadhesive system

Bioadhesive GRDDS use sticky polymers that stick to the stomach lining, helping the drug stay put through adhesive interactions. This is especially handy for drugs that need close contact with the mucosal surface to be absorbed better.

Expandable Systems

Expandable systems get bigger when they touch stomach fluids, helping them stay in place by growing in size. This expansion keeps the drug from moving too quickly through the digestive system.

High-Density Systems

High-density GRDDS use heavier materials to make sure the dosage stays in the stomach by creating a difference in density with gastric contents. This is often done by adding metals or dense materials to the formulation.

0. 1. Evaluation of powder blend
1. Angle of Repose
2. Bulk Density
3. Percentage porosity
   2. Evaluation of tablets

1. 1. Buoyancy capabilities
   2. In vitro floating and dissolution behaviour
   3. Weight variation
   4. Hardness & friability
   5. Particle size analysis, surface characterization(for floating microspheres and beads):
   6. X-Ray/Gamma Scintigraphy
   7. Pharmacokinetic studies

EVALUATION OF POWDER BLEND

1. 1. 1. 1. Angle of Repose

The Angle of Repose is the maximum angle achievable between the surface of a powder pile and the horizontal plane. A lower angle of repose indicates improved flow properties. This angle (θ) can be calculated by measuring the height (h) of the powder pile and the radius of its base (r) using a ruler, expressed by the formula

Tan θ = h/r.....1

1. 1. 1. 2. Bulk Density

Bulk density is the overall density of a material, considering both interparticle spaces and intraparticle pores. It is determined by dividing the weight of the powder by the bulk volume of the powder, as expressed in the formula:

Bulk density =  Weight of the powder

         Bulk volume of powder

When particles are densely packed, significant gaps may exist between them. The entrapment of powder facilitates the shifting of particles, minimizing voids and determining the bulk volume. Substituting this volume for a given weight of powder in the equation (2) allows the calculation of bulk density.

1. 1. 1. 3. Percentage porosity

 Whether the powder is porous or nonporous, the Total porosity expression for the calculation remains the same. Porosity provides information about hardness, disintegration, total porosity etc.

% porosity, € = void volume x100

Bulk volume

% porosity, € = (bulk volumetrue volume) x100

True density

EVALUATION OF FLOATING TABLETS(¹¹)

1. 1. 1. Measurement of Buoyancy Capabilities of FDDS:

Floating behavior assessment through weight measurements. Experiment conducted in deionized water and simulated meal. Results indicate enhanced floating with higher molecular weight polymers, particularly in the simulated meal medium.

1. 1. 2. In Vitro Floating and Dissolution Behavior:

Dissolution tests conducted using USP dissolution apparatus. USP 28 protocol involves allowing the dosage unit to sink before blade rotation. Standard USP or BP methods are not reliable predictors for in vitro performance of floating dosage forms. Pillay et al used a helical wire sinker to inhibit swelling and slow drug release. Development of a method involving full submersion under a ring or mesh assembly showed increased drug release. Method proved more reproducible and consistent. No significant change observed in drug release for a highly water-soluble drug (diltiazem) using the proposed method, suggesting dependency on uninhibited swelling, surface exposure, and drug solubility in water.

1. 1. 3. Weight Variation:

Composite samples of tablets (usually 10) are taken and weighed during the compression process. The composite weight, divided by 10, provides an average weight, but this has a limitation of averaged values.United States Pharmacopeia (USP) sets limits for permissible weight variations in individual tablets expressed as a percentage of the average weight. USP weight variation test involves weighing 20 tablets individually, calculating the average weight, and comparing individual weights to the average.Tablets meet the USP test if no more than 2 tablets are outside the percentage limit, and no tablet differs by more than 2 times the percentage limit.

1. 1. 4. Hardness & Friability:

Hardness, or tablet crushing strength, is defined as the force required to break a tablet in a diametric compression test.Devices such as Monsanto tester, strong Cobb tester, Pfizer tester are used for hardness testing. Friability is assessed using the Roche Friabilator, subjecting tablets to abrasion and shock for 100 revolutions. Generally acceptable compressed tablets lose less than 0.5 to 1.0% of their weight. Effervescent tablets may undergo high friability losses, requiring special stack packaging.

1. 1. 5. Particle Size Analysis, Surface Characterization (for Floating Microspheres and Beads):

Particle size and size distribution of beads or microspheres determined in the dry state using optical microscopy. External and cross-sectional morphology (surface characterization) assessed by scanning electron microscope (SEM).

1. 1. 6. X-Ray/Gamma Scintigraphy:

X-Ray/Gamma Scintigraphy is a popular evaluation parameter for floating dosage forms. Aids in locating dosage form in the gastrointestinal tract, predicting gastric emptying time, and passage in GIT.Inclusion of a radio-opaque material enables visualization by X-rays, while a γ-emitting radionuclide allows indirect external observation using a γ-camera or scintiscanner.

1. 8. Pharmacokinetic Studies:

Integral part of in vivo studies. Example study: Sawicki investigated the pharmacokinetics of verapamil from floating pellets filled into a capsule, comparing with conventional verapamil tablets.Floating pellets showed higher tmax and AUC (0-infinity) values compared to conventional tablets.

Formulation Strategies of floating GRDDS²:

1. Gas-Generating Systems:

• Use effervescent agents like bicarbonates and carbonates that react with stomach fluids, producing carbon dioxide for buoyancy.
• Gas entrapment systems trap volatile liquids or gases, creating buoyancy when they contact stomach contents.

2. Low-Density Systems:

• Employ hollow microspheres or porous matrices with lightweight cores, allowing the dosage form to float on stomach fluids.
• Capitalize on the physical properties of the formulation to achieve buoyancy.

3. Bioadhesive Systems:

• Involve mucoadhesive polymers that stick to the stomach lining, preventing early movement and maintaining sustained buoyancy.
• Bioadhesive microspheres or nanoparticles enhance adhesion, extending the time the dosage form stays in the stomach.

4. Expandable Systems:

• Swelling systems use hydrophilic polymers that expand when they touch stomach fluids, increasing size and buoyancy.
• Unfolding systems have dosage forms that expand or unroll in the stomach, promoting buoyancy through increased surface area.