ANATOMY AND PHYSIOLOGY OF GASTROINTESTINAL TRACT:

The digestive system is composed of the stomach, small intestine (Duodenum, Jejunum, and Ileum), and large intestine. The GIT is a muscle tube that runs from the mouth to the anus and has the job of absorbing nutrients and excreting waste through physiological processes including secretion, motility, digestion, absorption, and excretion. The stomach is a J-shaped expansion of the GIT, which is split into the anatomical regions: cardiac, fundus, body, and antrum⁷.

The stomach's primary job is to hold food and combine it with gastric secretions before discharging its contents (called chyme) at a regulated rate that is appropriate for digestion and absorption via the pyloric sphincter and into the small intestine. The stomach takes up roughly 50 ml of space when it is empty, but when it is full, this space can reach 1litre. The successive layers, from outside to inside, of the GIT walls, from the stomach to the large intestine, share the same fundamental organisation of tissues: serosa, intermuscular plane, longitudinal muscle, circular muscle, submucosa, muscularis mucosae, lamina propria, and epithelium. In addition to longitudinal and circular muscle, the stomach features a third muscular layer known as the "oblique muscle layer" located at the tip of the stomach, which extends over the stomach and the upper regions of the stomach. The different layers of smooth muscles are responsible for the movement of GIT, i.e. the emptying of the gastric tract and the intestinal transit.

The stomach is divided into three regions (figure 1)⁸

· Fundus

· Body

· Antrum Pylorus

The proximal part is composed of the fundus and the body and acts as an unmined material storage, while the antrum is the main place for mixing motions, acting as a gastric pump by propelling action. Gastric emptying occurs during fasting and fed states^{9, 10}. However, the pattern of mobility in both states is different. During fasting, a series of electrical events occur between the intestines, and each 2 to 3 hours pass through the intestine. This cycle is called interdigestive myloelectric cycle or migration myloelectric cycle (MMC), and is divided into four stages. Figure 2 shows the events¹¹

1. Phase I (Basal phase): lasts 30-60 minutes without contraction.

2. Phase II (pre-burst phase): last for 20-40 minutes with intermittent action potential and contraction. With the progression of the phase, the intensity and frequency also increase gradually.

3. Phase III (Burst Phase): This phase lasts between 10 and 20 minutes and includes short-term intense and regular contractions.

4. Phase IV: Duration 0 to 5 minutes, transition period between Phase III and Phase I

After taking a mixed meal, the pattern of contraction changes from the fast state to the feeding state. It is also known as digestive motility pattern and contains continuous contractions as in phase 2 of fasting state¹². These contractions reduce the size of the food particles (less than 1 mm) that flow to the pylorus in the suspension. During the initiation of the MMC in the fed state, the onset of the gastric evaporation rate is delayed, which causes a slowdown. Scintigraphic studies to determine the rate of gastric exhaustion have revealed that controlled oral release forms of the drug are subject to complications such as short gastric retention time and unpredictable gastric emptying rate.

Figure 2: Phases of gastric motility and gastric emptying rate

Factors Affecting Gastric-retention Time of Dosage Forms:

In the development of stomach-retention dosage forms, there are many parameters related to the anatomy and physiology of the stomach that must be taken into account. These parameters are-

1. Size of the particles: They must be within the range of 1–2mm in order to pass through the pyloric valve to the small intestine¹³.

2. Density: The density of dosage form should be less than gastric content (1.004g/ml).

3. Size: Dosage form with a diameter of more than 7.5 mm has more gastric period of residence than the dosage form with a diameter of 9.9mm.

4. Shape of the dosage form: Ring and tetrahedron devices with a flexible module of 22.5 to 48 KSI (Keto pound/inch2 shows 90 to 100% of the Gastric Retention Time (GRT).

5. Single/Multiple Units: Multiple units are preferable due to predictable release profiles, joint administration of different units and greater safety margins.

6. Food intake: The duration of gastro-retention is longer in the food state.

7. Nature of meals: Indigestible polymers and fatty acids change the motion patterns of the stomach into a feeding state, which reduces gastric volume and prolongs the release of drugs.

8. Calorie content: When eating high-protein and high-fat meals, you can increase GRT by 4-10 per day.

9. Feed frequency: Due to the low frequency of MMC, the GRT may increase more than 400min when multiple meals are compared to a single meal.

10. Gender: Women have a shorter GRT than men.

11. Age: People over 70 have a significantly longer GRT¹⁴.

Advantages of Gastro Retentive Drug Delivery Systems:

· The bioavailability of the therapeutic agents can be significantly improved, especially for those that metabolize in the upper part of the GIT by this treatment of gastrointestinal drugs, which is suitable for the administration of non-gastrointestinal treatments. Several factors associated with the absorption and transportation of drugs in the GIT simultaneously affect the size of the absorption of drugs.

· For drugs with relatively short half-life, continuous release can result in a flip-flop pharmacokinetic and also reduce the frequency of dose and improve patient compliance.

· They also have advantages over traditional systems that can overcome both the difficulties of gastric retention time (GRT) and gastric emptying time (GET).

· The sustained drug's release from the GRDFs allows a prolonged period of time over critical concentrations, thus improving the pharmacological effect and improving overall outcomes.

· Improved first-pass metabolism

· Provides targeted therapy for local diseases in the upper GIT

· Reduces body counter-activity

· Gastro Retentive Drug Delivery can minimize body counter-activity leading to greater drug efficiency.

· Gastro Retentive Dosage Forms minimize fluctuations in the concentrations and effects of the drug^15,16.

Disadvantages of Gastro Retentive Drug Delivery Systems:

· It is not suitable for medications with a limited solubility of acid, for example, phenytoin

· Not suitable for drugs that are unstable in the acidic environment, for example, erythromycin

· Drugs that irritate or cause gastric lesion in slow release, for example, aspirin & NSAIDs

· Drugs that selectively absorb in the intestine for example, corticosteroid.

· A floating drug delivery system requires a high level of fluid in the stomach to run smoothly and operate effectively.

· Drugs that absorb equally well through GIT, for example, isosorbide dinitrate and nifidipine¹⁷.

Suitable Candidates for Gastro Retentive Dosage Forms:

Various drugs have the greatest therapeutic effects when released into the stomach, especially when released continuously and controlledly. Drugs delivered in this way have lower side effects and offer their therapeutic effects without the need for repeated dosages with low frequency¹⁸.These include drugs:

· Have local effects in the stomach, such as antacids and H. pylori drugs viz. misoprostol.

· Has a window for absorption in the stomach or upper intestine.

· Mainly absorbed from the stomach and upper part of the GIT, example: calcium supplements, cinnarazine.

· Drugs with a narrow absorption window, such as cyclosporine, methotrexate, levodopa.

· Degraded drugs in the intestinal or colonic environment, such as ranitidine, metformin HCl and metronidazole.

· Shows low solubility at high pH¹⁹.

Drugs Those are Unsuitable for Gastro Retentive Dosage Forms:

· Drugs with very limited acid solubility such as phenytoin.

· Drugs that are unstable in the gastric environment, such as erythromycin, rabeprazole, clarithromycin, esomeprazole etc

· Drugs for selective release in the colon, such as 5-aminosalicylic acid and corticosteroids.

TYPES OF GASTRO RETENTIVE DOSAGE FORMS:

Over the last few decades, various GRDD approaches being designed and developed including:

1. High density system

2. Low density floating system

3. Mucoadhesive Sytem

4. Extandable system

5. Super porous hydrogel systems

6. Magnetic systems

HIGH DENSITY SINKING SYSTEM:

This approach involves formulating a dosage form that must exceed the normal stomach density (1.004g/ml). These forms are coated with heavy-core drug coatings and mixed with heavy inert materials such as zinc oxides, titanium dioxides, and barium sulfate. The resulting pellets can be covered with dispersion-controlled membrane²⁰. The only major disadvantage of such a system is that it is technically difficult to manufacture such a formula because the dry material it manufactures interacts with the gastric fluid and releases its drug content.

FLOATING OR LOW DENSITY SYSTEM:

In 1968, Davis introduced the first floating system. The bulk density of the dosage forms is less than that of the bulk density of gastric fluid (1.004 g/ml). This allows the system to remain in the stomach and move for a long period of time, while the drug is released from the system at the desired rate during GRT²¹.

Due to its low density, FDDS continues to float over the gastric contents over a long period of time and provide continuous release of drugs. These systems are particularly well studied because they do not adversely affect GIT mobility. After drug release, the rest of the system is empty of the stomach²². These systems are classified into two sub types based on the floating mechanism: non-effervescent and effervescent floating systems.

Non-Effervescent Floating systems:

In non-effervescent systems, highly swelling cellulose derivatives and gel-forming polymers are used. The formulation technique of the non-effervescent system involves mixing drugs with polymers forming gels. Various non-effervescent systems include the Hydrodynamic Balance System (HBS), single floating tablets and double-layers, and microballoon/hollow microsphere²³.

Effervescent floating systems:

The effervescent system includes gas generators and volatile liquids. This approach applies to systems with single and multiple units. In the gas-producing floating system, a mixture of effervescent agents such as sodium bicarbonate, tartaric acid, calcium carbonate and citric acid is used. When this system contacts the gastric fluid, CO₂ is released by the effervescent agent reaction with the gastric fluid. The CO₂ released gas is incorporated into the hydrocolloid matrix, which provides the buoyancy of the tablet and influences the release properties of the drug²⁴.

MUCOADHESIVE SYSTEM:

These are developed to perform drug absorption in a specific way at a specific location. In this method, bioadhesive polymers are used to bind to the mucous surface epithelium of the stomach and thus increase the retention time of the stomach. These polymers are natural such as sodium alginates, gelatin gum, and semi-synthetic polymers such as HPMC, carbopol, sodium carboxy methyl cellulose, and the adhesion of polymers to mucous membranes can be achieved by hydration, bonding, or receptors²⁵.

Various adhesion mechanisms are:

Wetting theory, the ability of bioadhesive polymers to spread and make intimate contact with mucin layers.

Diffusion theory, the physical tie-in of the mucin chain to a soluble polymer or the interpenetration of the mucin chain to the structure of the polymer.

Absorption theory, bioadhesion are caused by secondary forces such as vander Walls and hydrogen bonding.

The electronic theory, proposes an attractive electrostatic force between the glycoprotein mucine network and the bioadhesive material²⁶. The main limitation of this system is that it is difficult to maintain bioadhesion due to the rapid mucin transfer in the GIT²⁷.

SWALLABLE SYSTEM OR EXTANDABLE SYSTEM:

These are the dosage forms that, after swallowing, expand to the extent that prevent their exit from pylorus. Consequently, the form of the dose is retained in the stomach for a longer period of time. These systems may be called plug-type systems because they tend to remain recorded in the Pylori sphincter if the expansion diameter exceeds about 12-18mm. The balance between the degree of cross link between polymer chains maintains the extent and duration of the swell. A high cross-link speeding up the system's capacity to increase and maintain its physical integrity over a long period of time^28,29.

SUPER POROUS HYDROGEL SYSTEM:

These are different from conventional systems by swelling. The absorption of water by conventional hydrogels is a very slow process, requiring several hours to reach balance and prematurely removing dosage form³⁰. Superporous hydrogels have a diameter of >100 micro m and expand to equilibrium in a few minutes due to rapid water consumption through open pores interconnected by capillary rain. They expand to a larger size and have sufficient mechanical resistance to withstand gastric contraction pressure. This is achieved through the co-financing of the hydrophilic particles, Ac Di- Sol³¹.

MAGNATIC SYSTEM:

The dosage form consists of a small internal magnet placed on the abdomen and placed over the stomach position. Using extracellular magnets, the gastric living time in the dosage form can be extended^{32, 33}. It has some disadvantages, such as external magnets must be positioned with some precision and the patient does not comply so it is not very used.

CONCLUSION:

According to literature surveys, many drugs have recently been developed as floating drug delivery systems with the aim of limiting the region of drug release to the stomach for continued release. The principle of buoyant preparation provides a simple and practical approach to increasing the gastric time of treatment and ensuring the long-term release of drugs. The conclusion is that GRDDs offers various potential benefits to drugs with low bioavailability. Drug absorption in the intestines is a very variable process, and prolonged gastric retention of the dosage forms increases the time of absorption of drugs. Control of the passage of gastrointestinal tissue by oral administration with GRDD systems can improve the bioavailability of drugs that exhibit a specific absorption site.

CONFLICT OF INTEREST:

The authors have no conflicts of interest.

REFERENCES:

1. Rouge N, Buri P, Doelker E. Drug absorption sites in the gastrointestinal tract and dosage forms for site specific delivery. Int J Pharma. 1996; 136:117-139.

2. Lopes, C.M.; Bettencourt, C.; Rossi, A.; Buttini, F.; Barata, P. Overview on gastroretentive drug delivery systems for improving drug bioavailability. Int. J. Pharm. 2016, 510, 144–158.

3. Sarkar D, Nandi G, Changder A, Hudati P, Sarkar S, Ghosh LK. Sustained release gastroretentive tablet of metformin hydrochloride based on poly (acrylic acid)-grafted-gellan. Int J Biol Macromol 2017; 96:137-48.

4. Aoki H, Iwao Y, Mizoguchi M, Noguchi S, Itai S. Clarithromycin highly-loaded gastro-floating fine granules prepared by high-shear melt granulation can enhance the efficacy of Helicobacter pylori eradication. Eur J Pharm Biopharm 2015; 92:22-7.

5. Vivek M, Chandrashekhara S, Nagesh C, Bhavesh V, Mihir S, Bhavesh S. An Update on Gastroretentive Drug Delivery System: A review. Research J. Pharma. Dosage Forms and Tech. 2012; 4(3): 143-152.

6. Jassal M, Nautiyal M, Kundlas J, singh D. A review: Gastroretentive drug delivery system (GRDDS). Indian J. Pharm. Biol. Res. 2015; 3(1):82-92.

7. Hwang, K.M., Cho, C.H., Tung, N.T., Kim, J.Y., Rhee, Y.S., Park, E.S. Release kinetics of highly porous floating tablets containing cilostazol. Eur. J. Pharm. Biopharm. 2017; 115: 39–51.

8. Talukder R. and Fassihi R., Gastroretentive delivery systems: A mini review. Drug Dev. Ind. Pharm., 2004; 30(10): 1019-1028.

9. Thapa, P.; Jeong, S. Effects of Formulation and Process Variables on Gastroretentive Floating Tablets with A High-Dose Soluble Drug and Experimental Design Approach. Pharmaceutics. 2018; 10: 161.

10. Patel K, Chouksey R. A Recent Advantage on Gastroretentive Drug Delivery System: An Overview. Research Journal of Pharmaceutical Doasge Forms and Technology. 2023; 15(1): 36-4.

11. Mandal, U.K., Chatterjee, B., Senjoti, F.G. Gastro-retentive drug delivery systems and their in vivo success: A recent update. Asian J. Pharm. Sci. 2016; 11: 575–584.

12. Cvijic, S., Ibric, S., Parojcic, J., Djuris, J. An in vitro-In silico approach for the formulation and characterization of ranitidine gastroretentive delivery systems. J. Drug Deliv. Sci. Technol. 2018; 45: 1–10.

13. Tripathi J, Thapa P, Maharjan R, Jeong SH. Current state and future perspectives on gastroretentive drug delivery systems. Pharmaceutics. 2019; 11:1-22.

14. Waghmare Sneha S, Kadam Trupti V, Darekar A B, Saudagar R B. A review : Floatable Gastroretentive Drug Delivery System. Asian J. Pharm. Res. 2015; 5(1): 51-60.

15. Odeku, O., Aderogba, A., Ajala, T., Akin-Anjani, O., Okunlola, A. Formulation of floating metronidazole microspheres using cassava starch (Manihot esculenta) as polymer. J. Pharm. Investig. 2017; 47: 445–451.

16. Suradkar P, Mishra R, Nandgude T. Overview on Trends in Development of Gastroretentive Drug Delivery System. Research J. Pharm. and Tech. 2019; 12(11):5633-5640.

17. Amit Kumar Nayak , Ruma Maji, Biswarup Das. Gastroretentive Drug Delivery Systems: A Review; Asian Journal of Pharmaceutical and Clinical Research. 2010; 3(1): 2-10

18. Patil, H., Tiwari, R.V., Repka, M.A. Recent advancements in mucoadhesive floating drug delivery systems: A mini-review. J. Drug Deliv. Sci. Technol. 2016; 31: 65–71.

19. Hardikar, S., Bhosale, A. Formulation and evaluation of gastro retentive tablets of clarithromycin prepared by using novel polymer blend. Bull. Fac. Pharm. Cairo Univ. 2018; 56: 147–157.

20. Ashwini A Zanke, Hemant H Gangurde, Ananta B Ghonge, Praful S. Chavan. Recent Advanced in Gastroretentive Drug Delivery system (GRDDS). Asian Journal of Pharmaceutical Research. 2022; 12(2): 143-9.

21. Rossi, A., Conti, C., Colombo, G., Castrati, L., Scarpignato, C., Barata, P., Sandri, G., Caramella, C., Bettini, R., Buttini, F. Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations. Drug Dev. Ind. Pharm. 2016; 42: 332–339.

22. Srika S. Lokhande. Recent Trends in Development of Gastro-retentive Floating Drug Delivery System: A Review. Asian J. Res. Pharm. Sci. 2019: 9(2):91-96.

23. Kim, S., Hwang, K.M., Park, Y.S., Nguyen, T.T., Park, E.S. Preparation and evaluation of non-effervescent gastroretentive tablets containing pregabalin for once daily administration and dose proportional pharmacokinetics. Int. J. Pharm. 2018; 550: 160–169.

24. Shaik K, Hindustan A A, Haranath C, Peddagundam B, Jyothika L, ksheerasagare T. Gas generating Floating Tablets: A Quick Literature Review for the Scholars. Asian Journal of Research in Chemistry. 2022; 15(2):171-5.

25. Patil, H., Tiwari, R.V., Repka, M.A. Recent advancements in mucoadhesive floating drug delivery systems: A mini-review. J. Drug Deliv. Sci. Technol. 2016; 31: 65–71.

26. Sawanny R, Sharma A, Jain S, Mukherjee S, Khamkat P. Gastro Retentive Drug Delivery System: Latest Approach towards Novel Drug Delivery. Research Journal of Pharmacy and Technology. 2023; 16(1): 453-458.

27. Kumar U, Lal K, Patel N, Lekhraj, Praksh J, Omkar, Gurjar R, Gupta A, Praksah C, Agrawal M, Ajazuddin, Tripathi D K, Alexander A. Understanding the concept of Mucoadhesive Drug Delivery System: A Novel Approach over Conventional Dosage Forms. Res. J. Pharma. Dosage Forms and Tech. 2018; 10(2): 103-108.

28. Rahul P, Jadhav, Suraj B, Kumbhar, Manohar D, Kengar. Design and In-vitro Evaluation expandable Gastro retentive tablets of Diltiazem Hydrochloride. Asian J. Pharm. Tech. 2020; 10(2): 53-59.

29. Streubel A, Siepmann J, Bodmeier R. Drug delivery to the upper small intestine window using Gastroretentive technologies. Curr Opin Pharmacol. 2006; 6: 501-508.

30. Gouda K H, Kishore V S, Balaji N, Kumar V V, Raghuram N. An Overview on various Approaches for Gastroretentive Drug Delivery systems. Research J. Pharma. Dosage Forms and Tech. 2011; 3(4): 159-168.

31. El-said, I.A., Aboelwafa, A.A., Khalil, R.M., ElGazayerly, O.N. Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: In vitro and in vivo evaluation. Durg Deliv. 2016; 23: 101–112.

32. Satinder Kakar, Deepa Batra, Ramandeep Singh, Ujjwal Nautiyal. Magnetic Microspheres as Magical Novel Drug Delivery System: A review. Journal of Acute Disease. 2013:1-12.

33. Nayak AK, Maji R, Das B. Gastroretentive Drug Delivery System a review; Asian Journal of Pharm Clin Res. 2010; 3(1): 2-10

Received on 12.06.2023 Modified on 24.07.2023

Asian J. Research Chem. 2023; 16(6):453-458.

DOI: 10.52711/0974-4150.2023.00075

Sr. No.	Parameters	Conventional DDs	Gastro Retentive DDs
1	Toxicity	High risk of toxicity	Low risk of toxicity
2	Patient compliance	Less	Improved patient compliance
3	Drugs with narrow absorption window in small intestine	Not suitable	Suitable
4	Drugs having rapid absorption through GIT	Not much advantageous	Very much advantageous
5	Drugs which degrades in the colon	Not much advantageous	Very much advantageous
6	Drugs acting locally in the stomach	Not much advantageous	Very much advantageous
7	Drugs which are poorly soluble at an alkaline pH	Not much advantageous	Very much advantageous
8	Dose dumping	High risk of dose dumping	No risk of dose dumping⁶

INTRODUCTION: