Gastroretentive Drug Delivery System

Bhakti Narayan Patil *, Momin Abrarul Haque, Manali Maheshwar Patil., Mayur Suresh Reddy, Ankita Bhagoji Dupare.

M. S. College of Pharmacy, Gaurapur-Kudus Rd, Dist. Palghar, Maharashtra, India.

Article History Received:        15/10/2023 Accepted:        25/10/2023 Published:       01/11/2023

                                                  

Abstract: The most convenient way to deliver drugs is through the oral route because it's easy for patients to take, reliable, and allows for different types of medicines to be given easily. In this review physiology of the stomach along with its motility pattern usually called migrating motor complex (MMC) is discussed. The reason for writing this review about gastroprotective drug delivery systems is to gather recent information about methods that help medicines stay in the stomach for a longer time when taken orally. This is important for controlled release drug delivery to specific sites in the body. To understand why drugs might not stay in the stomach, study the factors that affect gastric retention. Then, discussed various approaches that have been developed to make drugs stay in the stomach. These include methods like making the drug sink in the stomach, float on top, stick to the stomach lining, expand, unfold, use special porous materials, or even use magnets, then advantages, limitations, suitable drug candidates, and factors affecting GRDDS are discussed.   Keywords: Gastroprotective Drug Delivery System (GRDDS), Floating System, High-Density GRDDS, Evaluation Parameter, Gastric Retention Time.

Corresponding Author: Bhakti Narayan Patil Email ID: bhaktinpatil0802@gmail.com

 

 

 

 

 

 

 

 

 

 

 

 INTRODUCTION:    

The main aim of any delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve immediate and then maintain a desired drug concentration.¹ The most practical and preferable method of distribution to systemic circulation is oral administration. The pharmaceutical industry has recently shown an increased interest in oral controlled-release drug delivery to gain better therapeutic benefits such as convenience of dosage administration, patient compliance, and formulation flexibility. To avoid the demerits, the development of oral sustained controlled release formulation is achieved to release the drug slowly into the gastrointestinal tract and maintain an effective drug concentration in the systemic circulation for a prolonged time. Following oral administration, such a drug delivery would be retained in the stomach and released in a regulated manner to allow the drug to be constantly given to its gastrointestinal tract absorption location. Following oral administration, such a drug delivery would be retained in the stomach and released in a regulated manner to allow the drug to be constantly given to its gastrointestinal tract absorption site.²

It is one form of controlled-release medication delivery system that can be retained in the gastrointestinal region for an extended period and change the gastric emptying time and GIT motility pattern is the gastro retentive drug delivery system.³ It can be used to administer medications locally to the stomach and nearby small intestines. Gastro retention aids in improving the accessibility of novel drugs with new therapeutic opportunities and significant patient advantages.⁴

 

PHYSIOLOGY OF GASTROINTESTINAL TRACT

The gastrointestinal tract divided into three main regions

a)      Stomach

b)      Small intestine- duodenum, jejunum, and ileum

c)      Large intestine

The gastrointestinal tract (GIT) is a muscular tube which connects the mouth to the anus. It is 9 meters in length. The physiological processes like digestion, absorption, secretion, motility, and excretion help the body to absorb nutrients and eliminate waste.⁵

Stomach

The stomach contains four main regions: the cardia, fundus, body, and pyloric part.⁶ The proximal part is called the fundus, and the body acts as storage for undigested food. The antrum is the major site for mixing motions which acts as a pump for gastric emptying by propelling actions. The pyloric part is divisible into three regions i.e. pyloric antrum, pyloric canal, and pylorus, which in turn connects to the duodenum.

FIG.1 ANATOMY OF STOMACH

 

 

Different Features of Stomach

Gastric pH: Fasted Healthy Person 1.1 ± 0.15

Fed Healthy Person 3.6 ± 0.4

Volume: Resting volume is about 25-50 ml

Gastric Secretion: Acid, pepsin, gastrin, mucus, and some enzymes about 60 ml with approx. 4 mmol of hydrogen ions/hour.

Effect of Food on Gastric Secretion: Almost 3 liters of secretions are added to the food. Gastro-Intestinal transit time is enhanced.^7,8

Function of Stomach

·         The primary function of the stomach is food preparation and transport.⁹

·         Temporary storage time for the digestive enzymes and pepsins.

·         Chemical digestion –pepsins break down proteins into polypeptides.

·         Development and secretion of intrinsic factor needed for absorption of vitamin B12 in the terminal ileum.

·         Preparation of iron for absorption- the acid environment of the stomach solubilizes iron salts, essential for iron absorption in the small intestine.¹⁰

Motility Pattern / Migrating Myoelectric Cycle (MMC)

Phase I: (Basal Phase) Period of no contraction, lasts from 40 to 60 minutes

Phase II: (Pre-burst Phase) Period of intermittent contraction, lasts for 40 to 60 minutes

Phase III: (Burst Phase) Period of regular contraction at the maximum time that migrates distally. lasts for 4 to 6 minutes

Phase IV: Period of transition between phase III and phase l, lasts for 0 to 5 minutes ¹¹

 

FIG.2 A Simplified Schematic Representation of The Interdigitate Motility Pattern, Frequency of Contraction Forces During Each Phase, And Average period For Each Period.⁴

 

 

ADVANTAGES

·         To bypass the first-pass metabolism of the drug.

·         Very good accessibility.

·         To increase bioavailability¹²

·         Improve the solubility of medications that are poorly soluble in high pH can control therapeutic levels to reduce the occurrence of fluctuations

·         Suitable for medications whose absorption from the stomach depends on pH¹³

·         Appropriate for medications that break down in the colon or spinal column

·         Possible to lower the dosage size

·         Reduce drug waste

·         Helpful in attempting local delivery of drug to the stomach and proximal part of the small intestine.

·         More effective treatment with short-lived drugs

·         Enhances patient compliance,

·         Maintains the ideal therapeutic plasma and tissue concentrations for an extended period with no change in drug level.¹⁴

 

DISADVANTAGES

·         It is not suitable for the drugs whose absorption is good in the lower part of GIT

·         Poor IVIV (In Vitro and In Vivo) correlation.

·         Higher cost of formulation

·         Drugs that irritate the stomach lining or that are unstable in an acidic environment should not be formulated in a gastro-retentive drug.^15,16

·         Bio / mucoadhesive systems have problems with high takings of the mucus layer, thick mucus layer, and related limitations of soluble mucus

·         Difficulty in achieving the intended result and issue with dose dumping.

·         Gastric retention depends on many factors like gastric motility, pH, and the presence of food. Hence, the dosage form can withstand the grinding and churning force of the peristaltic wave of the stomach

·         Recover of the drug is difficult in case of toxicity, poisoning, or hypersensitivity reaction.¹⁷

 

NEED OF GRDDS

·         Within the pharmaceutical sector traditional oral delivery is commonly used to treat diseases. However, traditional distribution has many inconveniences and the main disadvantages are non-site specificity.

·         Gastro-retentive delivery is one of the site-specific deliveries for the delivery of drugs in the stomach as well as in the intestine. It is attained by retaining dosage form in the stomach and the drug is released in a controlled manner to specific sites either in the stomach, duodenum, or intestine.

·         Today’s Pharmaceutical field is focusing on such drugs that require site specificity.¹⁸

·         Conventional oral delivery is mostly used in the pharmaceutical field for the treatment of various diseases. Conventional delivery has many drawbacks and the major drawback is non-site specificity.¹⁹

 

FACTOR AFFECTING GRDDS

1. Density of dosage form

The density of the dosage form should be in the range of 1g/cm3 to 2.5g/cm. If the dosage form has having density lower than the gastric fluid it can enhance the GRT.

2. Shape and size of dosage form

The shape and size of the dosage forms are useful in designing indigestible single-unit solid dosage forms. Size must be larger than 7.5 mm in diameter. Dosage forms having a diameter of greater than 7.5 mm show a good gastric residence time compared with one having 9.9 mm.²⁰ Shape of dosage forms Ring and tetrahedron devices with flexural modulus of 22.5-48 KSI (keto pound/ inch show 90-100 % gastric retention times (GRT).

. Food intake and Its nature

Food intake, the nature of the food, caloric content, and frequency of feeding have a profound impact on gastric retention. The presence/absence of food in the stomach influences the gastric retention of the dosage form. Greater acidity and caloric value show lower gastric emptying time (GET), which can improve the gastric retention of dosage forms.

4. Effect of gender, posture, and age

normally females have slower gastric emptying times than males. The effect of posture does not have any difference in the mean gastric retention time (GRT) for individuals in the upright, ambulatory, and supine states. In case of elderly persons, gastric emptying is decrease.²¹

6. Caloric content

If the meal is high in proteins and fats GRT can be increased by 4 to 10 hours.²²

7. Frequency of the meal

The GRT is increased by over 400 minutes when successive meals are given compared with a single meal due to the decreased frequency of MMC.

8. Single/ multiple unit formation

Multiple unit formulations can show a more predictable release profile and not significantly impair performance due to failure of units, which gives permission to co-administration of units with different release profiles or containing incompatible substances and permits a greater margin of safety against dosage form failure compared with single unit dosage forms.

9. pH of Stomach

The particle size must be in the range of 1 to 2 mm to pass through the pyloric valve into the small intestine. The stomach pH in the fasting state is ~1.5 to 2.0 and in the fed state is 2.0 to 6.0.

10. Other factors

·         Diseased states of the person (chronic disease, diabetes, etc.)

·         Body mass index

·         Physical activity

·         Molecular mass and lipophilicity of the drug which depend on its ionization state.

SUITABLE DRUG CANDIDATE FOR GRDDS

·         The drugs that are locally active in the stomach e.g. Misoprostol, antacids, etc.

·         Drugs that have narrow window for GIT absorption (e.g. L-DOPA, P-aminobenzoic acid, furosemide, riboflavin).

·         Drugs that are not stable in the intestinal or colonic environment.

·         Drugs that have a low solubility at high pH.²³

·         Drugs that are poorly soluble in intestinal fluids (Furosemide, Diazepam, Verapamil)

·         Drugs that are absorbed rapidly in the GI tract (Metronidazole, Tetracycline)²⁴

·         Degrade in the intestines

·         It must be controlling the drug release profile

APPROACHES OF GRDDS

High-Density GRDDS

The density of systems ranges from 2.5 to 3.0 g/ml. These formulations help to withstand gastric disturbances and peristaltic movements. Titanium oxide, iron powder, barium sulphate, zinc oxide, etc. are used to increase the density of the dosage forms. However, the main disadvantage of this system is increased dose size to attain high density.²⁵

FIG.3: GRDDS BASED ON HIGH DENSITY SYSTEM

 

Raft Forming System

These are formed by the process of carbon dioxide bubble entrapment with an in-situ gelling mechanism. A solution containing sodium alginate as in situ gel former and bicarbonates or carbonates which act as effervescent agents is formed first. The in-situ gel former swells and it gets in contact with the gastrointestinal fluid and forms a cohesive gel that entraps carbon dioxide make it to float. They are used for the treatment of gastroesophageal reflux.²⁶

FIG.4 GRDDS BASED ON RAFT FORMING SYSTEM

 

Modified Shape and Swelling System

With these swelling and expanding systems the in vivo and in vitro systems succeeded in retaining the dosage form within the stomach. These are otherwise called plug-type systems because these are facilitated with an increased size of the system above the diameter of the pyloric sphincter. The polymer gets swelled once it comes in contact with the gastrointestinal fluid and hence type of polymer used and its viscosity affect the sustained delivery of the drug. Super porous polymers with a swelling ratio of 1:100 (rapid swelling nature) increase the efficiency of the system.²⁷

FIG.5 GRDDS BASED ON POLYMER SWELLING SYSTEM

 

Bioadhesive / Mucoadhesive System

These systems resist the gastric emptying time for a long period by attaching to the mucosal lining of the stomach wall and are hence named bioadhesive or mucoadhesive systems. It also facilitates local drug delivery. Pectin, lectin, Carbopol, gliadin, carboxymethylcellulose, polycarbophil, chitosan, etc. are some of the bioadhesive polymers.²⁸

FIG.6 GRDDS BASED ON MUCOADHESIVE SYSTEM

Magnetic System

This method is to improve the gastric retention time which is based on the principle that the dosage form contains a small internal magnet that is placed on the abdomen over the position of the stomach. However, the external magnet must be positioned with a degree of precision.

 

FIG.7 GRDDS BASED ON APPLICATION OF MAGNETIC FORCE

 

Floating Drug Dosage System

1.      Non-Effervescent System

2.      Effervescent System

Non-Effervescent System

These systems were further classified into

1. Microporous Compartment System

In this system, the drug reservoir is encapsulated inside a microporous compartment which has a pore along its bottom and top walls. The floatation chamber containing entrapped air causes the delivery system to float over the gastric fluid enter through the aperture, dissolve the drug, and carry the dissolved drug in the stomach and proximal part of the small intestine for absorption.

FIG.8 MICROPOROUS COMPARTMENT SYSTEM

 

2. Alginate System

These are spherical with a diameter of 2.5 mm. These are prepared by calcium alginate precipitation which occurs when sodium alginate solution is added dropwise into the calcium chloride aqueous solution. Thus, formed beads are filtered and dried. The formed beads are capable of maintaining bouncy for 5-6 h.²⁹

3. Hollow Microsphere/Microballons

These are prepared by a novel emulsion solvent diffusion method. These are prepared when the ethanol solution of the drug and an enteric acrylic polymer is added into an agitated polyvinyl alcohol solution at 40⁰C. The microspheres with internal cavities were formed when gas was generated in the dispersed polymer due to the evaporation of ethanol. The gastroretentive time of these microspheres is more than 12 hours.

4. HBS Hydrodynamically Balanced Systems

These systems mainly involve a mixture of drugs and hydrocolloids that form a gelatinous barrier when it comes in contact with the gastric fluid due to swelling of the combination. It remains floating in the stomach for a prolonged period as its bulk density is less than one in gastric fluid.³⁰

FIG.9 HBS

 

 

 

5.Layered Tablet

Layered tablets is most popular because of their ease of preparation, cheaply, and high stability.³¹

a)      Single Layered Floating Tablets

b)      Double Layered Floating Tablets

Effervescent System

These systems was further classified into

1.Volatile Liquid Containing System

They have inflatable chamber that contains a liquid for e.g. ether, cyclopentane, that form into gas at body temperature to cause the inflation of the chamber in the stomach. These systems osmotically control floating system containing a hollow definable unit. There are two chambers in the system first chamber contain the drug and the second chamber containing the volatile system.

2.Gas Generating System

The main mechanism is involved in this system is the production of CO2 gas due to reaction between sodium bicarbonate, citric acid and tartaric acid. The gas produced results in the reduction of density of the system, thereby making it float on the gastric fluids. Salts and citric/tartaric acid release CO2, which entrapped in the jellified hydrocolloid layer of the system which decrease its specific gravity and making it float over time. Various polymers used in preparation of gas generating systems are sodium alginate, chitosan, HPMC etc.

3.Matrix Tablet

There are two types, single layer, and bilayer matrix tablets. The single-layer matrix tablets is prepared by using a drug and a hydrocolloid forming gel, while the bilayer matrix tablet contains one immediate-release layer and other sustained release layer.³²

4.Floating System With Ion Exchange Resin

These floating systems are mainly formed because to prolong the gastric residence time of dosage form using ion exchange resin. They involved drug resin complex beads loaded with bicarbonate ions and which coated with hydrophilic polymers. which result the generation of CO2 gas when it comes in contact with  gastric fluid and causes the beads to buoyed.

5. Superporous Hydrogel

Superporous hydrogels is the three-dimensional network of hydrophilic polymers which have numerous super-size pores inside them. The swelling of superporous hydrogels caused by the mechanism of capillary wetting through interconnected open pores. To composed superporous hydrogels, specific ingredients like initiators and cross-linkers are used to start the cross-linking. Other excipient used in superporous hydrogel is foam stabilizers, foaming aids, and foaming agents.

For improvement of gastric retention time super porous hydrogels of average pore size >100 micro meter, swelling to the equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous interconnected open pores.³³

EVALUATION

IN VITRO EVALUATION

A. FLOATING SYSTEM

1. Buoyancy Lag Time

It is the time taken up by dosage form to float on the top of the dissolution medium after being placed in the medium.³⁴

2. Floating Time

Test for floating is normally done in SGF-Simulated Gastric Fluid maintained at 37⁰C. The time for which the dosage form continuously buoyancy on the dissolution media is called floating time.³⁵

3. Specific Gravity / Density

Density can be measured by the displacement method using a displacement medium such as Benzene.

B. SWELLING SYSTEMS

1. Swelling Index

Later immersion of swelling dosage form into SGF at 37⁰C, the dosage form is removed at normal intervals, and dimensional changes are determined in terms of enhanced tablet thickness/diameter with time.³⁶

2. Water Uptake

It is an indirect determination of the swelling property of the swellable matrix.

Water uptake = WU = (Wt. – Wo) x 100 / Wo

Where, Wt. = At time t weight of the dosage form, Wo = Initial weight of the dosage form.

IN VITRO DISSOLUTION TEST

In vitro dissolution test is normally done by using of USP apparatus paddle and GRDDS is placed in the other conventional tablets.

IN VIVO EVALUATION TEST³⁷

1. Radiology

X-ray is widely used for the evaluation of internal body systems. Barium Sulphate is most widely used as Radio radio-opaque marker. So, BaSO₄ is incorporated into the dosage form, and X-ray images are taken at different intervals to see GR.

2. Scintigraphy

Similar to X-ray, -emitting materials are introduced into dosage form and then images are taken by scintigraphy. Widely used -emitting material is ⁹⁹Tc.

3. Gastroscopy

Gastroscopy is a peroral endoscopy normally used in fibre optics or video systems. Gastroscopy is used to find optically the effect of retard in the stomach. It gives a detailed evaluation of GRDDS.

4. Magnetic Marker Monitoring

In this technique, the dosage form is magnetically marked by introducing iron powder inside, and images are taken by very sensitive bio magnetic measurement equipment. The advantage of this method is that it is radiation-free and not hazardous.

5. Ultrasonography

Used sometimes, not used normally due to, it is not traceable in the intestine.

6.¹³C Octanoic Acid Breath Test

 ¹³C Octanoic acid is introduced into GRDDS. In the stomach because of the chemical reaction, octanoic acid releases CO2 gas that comes out in breath. The important Carbon atom that comes in CO2 is changed with a ¹³C isotope. So, the time up to which ¹³CO2 gas is seen in breath is considered as the gastric retention time of dosage form. As the dosage form comes into the intestine, there is no reaction and no CO2 liberate. So, this method is cheaper than others.

 

APPLICATION OF GRDDS^38,39,40                       

Sustained Drug Delivery

GRDDS float on the gastric contents for an extended period, and these systems have bulk density<1

Site-Specific Drug delivery

This delivery system is most useful for drugs that are absorbed from the stomach or the proximal part of the small intestine, especially concerning their use in the treatment of H. Pylori infections

The fluctuation of Drug Concentrations can be reduced

This property is important for drugs with a narrow therapeutic index. Fluctuations in drug effects are reduced and concentration-dependent adverse effects that are related to the peak concentration can be prohibited.

Absorption Enhancement

This is important in the case of drugs that are absorbed from the upper part of the GIT and formulating this type of drugs as GRDDS can enhance the poor bioavailability, thereby greater their absorption

FIG.10 APPLICATION OF GRDDS

 

CONCLUSION

The above literature concludes that GRDDS is one of the efficient techniques to maintain the sustained release of drugs in the gastric environment and it enhances its absorption and bioavailability. The principle of buoyant preparation is a simple and practical approach to achieve increased gastric residence time for the dosage form and improved patient compliance. GRDDS has many advantages as compared to other drug delivery systems. To avoid first-pass metabolism of orally administered drugs these systems are most important. Therefore, conclude that these dosage forms will play a vital role in the future and have the potential to improve results. Ultimately GRDDS is a simple as well as effective drug delivery system.

ACKNOWLEDGEMENT

I would like to thank Professor Mr. Momin Abrarul Haque, for sharing his experience and knowledge in this article. I also thank other faculty members of M.S. COLLEGE OF PHARMACY, DEVGHAR.

 

 

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