INTRODUCTION:

Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, low cost of therapy, patient compliance and flexibility in formulation etc. Oral sustained drug delivery formulations show some limitations connected with the gastric emptying time. Variable and too rapid gastrointestinal transit could result in incomplete drug release from the device into the absorption window leading to diminished efficacy of the administered dose.

It is evident from the recent research and patent literature that an increased interest in novel dosage forms that are retained in the stomach for a prolonged and predictable period of time exists today. Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. One of such difficulties is the ability to confine the dosage form in the desired area of the gastrointestinal tract. To overcome this physiological problem, several drug delivery systems with prolonged gastric retention time have been investigated. Attempts are being made to develop a controlled drug delivery system that can provide therapeutically effective plasma drug concentration levels for longer durations, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug concentration at steady state by delivering drug in a controlled and reproducible manner.

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an inter-digestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours.^1,2,3

This is called the inter-digestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington^4,5.

· Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.

· Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

^·Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.^4,5

· Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.

· After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.

Fig 1: Myloelectric cycle

Basic Anatomy and Physiology of the Stomach:

The digestive system consists of a muscular tube, the digestive tract, also called the gastrointestinal tract (GI) or alimentary canal, and various accessory organs. The oral cavity (mouth), Pharynx, esophagus, stomach, small intestine and large intestine, make up the digestive tract. Accessory digestive organs include the teeth, tongue and various glandular organs, such as the Salivary gland, liver and Pancreas, which secrete their products into ducts emptying into the digestive tract.

Fig 2: Anatomy of the stomach

Anatomy of the stomach:

The stomach has the shape of an expanded J. The shape and size of the stomach are extremely variable from individual to individual and even from one meal to the next. The stomach typically extends between the levels of Vertebrae T7 and L3. The stomach has four main regions:

a) The cardiais the smallest part of the stomach.

b) The fundus is the portion of the stomach that is superior to the junction between the stomach and the esophagus.

c) The body act as a reservoir for undigested material.

d) The antrum is the main site for mixing motions and acts as a pump for gastric emptying by propelling actions.^6,7

Physiology of the stomach:

The stomach is an expanded section of the digestive system between the oesophagus and small intestine. In the empty state the stomach is contracted and its mucosa and sub mucosa are throw up into folds called rugae.

There are 4 major types of secretory epithelial cell that covers the stomach and extends into gastric pits and glands.

· Mucous cells – secrete alkaline mucus

· Parietal cells – secerete HCl

· Chief cells – secerete pepsin

· G cells – secerete hormone gastrin^7,8

ADVANTAGES:

Floating dosage systems form important technological drug delivery systems with gastric retentive behaviour and offer several advantages in drug delivery. These advantages include:

1. Floating dosage forms such as tablets or capsules will remains in the solution for prolonged time even at the alkaline pH of the intestine.

2. FDDS are advantageous for drugs meant for local action in the stomach like antacids.

3. FDDS dosage forms are advantageous in case of vigorous intestinal movement and in diarrhoea to keep the drug in floating condition in stomach to get a relatively better response.

4. Acidic substance like aspirin causes irritation on the stomach wall when come in contact with it hence; HBS/FDDS formulations may be useful for the administration of aspirin and other similar drugs.

5. The FDDS are advantageous for drugs absorbed through the stomach eg: Ferrous salts, Antacids. Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.

6. Controlled delivery of drugs. It minimizes the mucosal irritation by releasing drug slowly.

7. Treatment of gastrointestinal disorders such as gastro esophageal reflux.

8. Ease of administration and better patient compliance.

9. Site-specific drug delivery system.^9,10,11

DISADVANTAGES:

1. Floating system is not feasible for those drugs that have solubility or stability problem in GI tract

2. These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently coat, water

3. The drugs that are significantly absorbed throughout gastrointestinal tract, which undergo significant first pass metabolism, may not be desirable candidate. E.g. Nifedipine.

4. The ability of drug to remain in the stomach depends upon the subject being positioned upright.

5. The residence time in the stomach depends upon the digestive state. Hence, FDDS should be administered after the meal.

6. Not suitable for drugs that cause gastric lesions e.g. Non steroidal anti inflammatory drugs. Drugs that are unstable in the strong acidic environment, these systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout the gastro intestinal tract.

7. The mucus on the walls of the stomach is in the state of constant renewal, resulting in the unpredictable adherence.

8. Faster swelling properties are required and complete swelling of the system should be achieved well before the gastric emptying time.

9. The ability to float relies in the hydration state of dosage form.

10. In all the above, the most important and primary requirement for the success is the physical integrity of the system.^12,13,14

Factors:

A) Formulation Factors:

i. Size of tablets:- Dosage form having diameter of more than 7.5 mm have more gastric residence time than that of 9.9 mm diameter dosage form.

ii. Shapes of dosage form:- The shape of the dosage form is one the factors that affects its gastric residence time. Six shapes (ring tetrahedron, Cloverleaf, string, pellet and disk) were screened in vivo for their gastric retention potential.

iii. Single or multiple unit formulation:- Multiple unit formulation show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.

iv. Density:- The density of a dosage form affects the retention of drug in the stomach and determine the location of the gastro retentive system in the stomach. Those with low density tend to float on the gastric fluid surface while high density systems sink to bottom of stomach.

v. Viscosity of Polymer: Viscosity of polymer and their interaction greatly affect the drug release and rafting properties. Low viscosity polymers were found to be more suitable candidates because they enhance rafting properties. An increase in polymer viscosity a decrease in the release rate was observed.^15,16

B) Idiosyncratic Factor:

i) Gender:-Mean ambulatory GRT in males (3.4 ± 0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface.

ii) Age: Elderly people, especially those over 70, have a significantly longer GRT.

iii) Posture:-GRT can vary between supine and upright ambulatory states of the patient.

iv) Fed or unfed state:- Under fasting conditions, the GT notility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that covers every 1.2- 2 hours. However, in the fed state, MMC is delayed and GRT is considerable longer.^17,18

v) Frequency of Feed:- The GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.

Applications:

Floating drug delivery offered several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability.

These are

· Site Specific drug delivery

· Sustained drug delivery

· Absorption Enhancement

· Enhanced bioavailability

· Enhanced first- pass biotransformation

· Sustained drug delivery reduce frequency of dosing

· Targeted therapy for local ailments in the upper GIT.

^·Reduced fluctuations of drug concentration¹⁹

Approaches to design Floating Dosage Forms:

1. Single-unit dosage forms:

In low density approach, the globular shells with density lower than that of gastric fluid can be used as carrier for drug for making single-unit floating dosage form. These shells are then further coated with a mixture of drug polymer. The product floats on the gastric fluid and gradually releases the drug for a long period of time.

In Fluid-Filled floating chamber type of dosage forms, a gas-filled flotation chamber is incorporated into microporous components that cover the drug reservoir. This device should be of swelable size. Device remains floats, within the stomach for a long period of time and slowly releases the drug.

2. Hydro dynamically balanced systems (HBS) enhance the absorption because they are designed such that they stay in GIT sore prolong time. These dosage forms much have a bulk density of less than 1. Drugs which have a better solubility in acidic environment and site specific absorption in the upper part of GIT are suitable candidates for such systems

2) Multiple-unit Dosage Forms:

The aim of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multiple-unit floatable dosage form have been designed like Microsphere, carbon dioxide-generating multiple-unit oral formulations etc.²⁰

Mechanism of Floating System:

Different methods are used to enhance the retention time of formulation in stomach. It includes introducing floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high- density systems, modified shape systems, gastric emptying delaying devices and co administration of gastric-emptying delaying drugs. Floating drug delivery systems (FDDS) have always bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. The system is floating on the gastric content, the drug is released slowly at the desired rate from the system.

After release of drug, the residual system is emptied from the stomach. This result in an increased GRT and a better control of the fluctuation in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principal, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force Kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object.

Fig 3: Mechanism of Floating system

The object floats better if F is on the higher positive side. This apparatus help in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intra gastric buoyancy capability variations.^20,21

F = F (buoyancy) – F (gravity) = (Df – Ds) gv

Where,

F = Total vertical force

Df = Fluid density

Ds = Object density

V = Volume and

g = acceleration due to gravity

CLASSIFICATION:

Classification of Floating Drug Delivery Systems (FDDS)

(A) Effervescent FDDS

(I) Gas generating system

(II) volatile liquid containing system

(B) Non- Effervescent FDDS

(I) Colloidal gel barrier system

(II) Microporous compartment system

(III) Floating microsphere

(IV) Alginate floating beads.

A) Effervescent System FDDS: These are matrix type of system. Prepared with the help of swellable polymer such as methylcellulose and Chitosan and various effervescent compounds. Ex: sodium bicarbonate, tartaric acid, citric acid. These are formulated in such a way that when they come in contact with gastric content, co2 is liberated and gets entrapped in swollen hydrocolloid which provides buoyancy to dosage form. The design of delivery system was based on swellable asymmetric triple layer tablet approach^21.

I) Gas Generating Systems; These are low density FDDS is based on the formation of co2 within the device following contact with body fluids. The materials are fabricated so that upon arrival in stomach, co2is librated by acidity of the gastric content and is entrapped in the gellified hydrocolloid this produce upward motion of the dosage form and maintain its buoyancy. Decrease in specific gravity cause dosage form to float on the chyme. The co2 generating components may be intimately mixed within the tablet matrix in which case a single layer or bilayered is produced which contain the gas generating mechanism in one hydrocolloid containing layer and the drug in the other layer formulated for a sustained release effect^{22- 24}

II) Volatile Liquid Containing Systems (Osmotically Controlled DDS); As an Osmotically controlled floating system, the device comprised of a hallow deformable unit that was convertible from a collapsed position after an extended period of time. A housing was attached to the deformable unit and it was internally divided into a first and second chamber with the chambers 4(8) 40 separated by an impermeable, pressure responsive movable bladder. The first chamber contain an active drug, while the second chamber contain a volatile liquid, such as cyclopentane or ether that vaporises at physiological temperature to produce a gas, enabling the drug reservoir to float. To enable the unit to exit from the stomach, the device contained a bioerodible plug that allowed the vapour to escape^25.

B) Non-Effervescent FDDS; Non-Effervescent FDDS use a gel forming (or) swellable cellulose type of hydrocolloids, Polysaccharide, matrix forming polymer like polycarbonate, polymethacrylate and polystyrene. One of the formulation methods involves the mixing of the drug with gel forming hydrocolloids which swell in contact with gastric fluid after oral administration and maintains integrity of shape and a bulk density barrier, the air trapped by swollen polymer confer buoyancy to the dosage forms^26.

I) Colloidal Gel Barrier Systems (Hydrodynamic Balanced Systems); Such system contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This prolongs GRT and maximizes the amount of drug that reaches its absorption site in the solution form for ready absorption, this system incorporates a high level of one or more gel-forming highly soluble cellulose type hydrocolloid e.g. (HPMC), polysaccharides and matrix forming polymer such as polycarbophil, polystyrene and polyacrylate. On coming in the contact with GI fluid, the hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface^27.

II) Microporous Compartment Systems; This technology is based on the encapsulation of a drug reservoir inside a Microporous compartment with pores along its top and bottom walls. The peripheral wall of the drug reservoir compartment is completely sealed to prevent any direct contact of gastric surface with the undissolved drug. In the stomach, the floatation chamber containing entrapped air causes the floatation chamber containing entrapped air causes the delivery system to float over the gastric content. Gastric fluid enters through the aperture, dissolves the gastric fluid to an extent that it prevents their exist from the drug and carrier the dissolved drug for continuous transport across the intestine for absorption²⁸.

III) Floating Microspheres/Micro balloons Hallow microspheres are considers as most promising buoyant system as they are more advantageous because of central hallow space inside the microsphere. Hallow microsphere is loaded with drug in their outer polymer shelf were prepared by a novel emulsion solvent Diffusion method^29.

IV) Alginate Beads / Floating Beads; Multi-unit floating dosage forms have been developed from freeze calcium alginate [30]. Spherical beads of approximately 2.5mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride. Causing the precipitation of calcium alginate. The beads are than separated, snap-frozen in liquid nitrogen and freeze-dried at 400C for 24 h, leading to the formation of a porous system, this can maintain a floating force for over 12 h. these floating beads gave a prolonged residence time of more than 5.5 h.³⁰

C) Raft forming systems; Raft forming system have received much attention for the delivery of antacid and drug Delivery for gastro infection and disorders on contact with gastric fluid a gel forming Solution swells and forms a viscous cohesive gel containing entrapped co2 bubbles. Which Forms raft layer on top of gastric fluid which releases drug slowly in stomach. (Often used For gastro esophageal reflux treatment^31.

CONCLUSION:

Recently many drugs have been formulated as floating drug delivery systems with an objective of sustained release and restricting the region of drug release to stomach. The principle of buoyant preparation offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release. The currently available polymer-mediated non effervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be a very much effective approach to the modulation of controlled oral drug delivery. The most important criteria which has to be looked into for the productions of a floating drug delivery system is that the density of the dosage form should be less than that of gastric fluid. And hence, it can be concluded that these dosage forms serve the best in the treatment of diseases related to the GIT and for extracting a prolonged action from a drug with a short half life.

REFERENCES:

1. Hirtz J. The git absorption of drugs in man: a review of current concepts and methods of investigation. Br J Clin Pharmacol. 1985;19: 77S-83S. Pub Med

2. Burns SJ, Attwood D and Barnwell SG: Assessment of a dissolution vessel designed for use with floating and erodible dosage forms. International Journal of Pharmaceutics 1998; 160: 213–18.

3. Baumgartner S, Kristl J, Franc V, Vodopivec P and Zorko B: Optimisation of floating matrix tablets and evaluation of their gastric residence time. International Journal of Pharmaceutics 2000; 195: 125–35.

4. Kharia AA, Hiremath SN, Singhai AK and Jain SK: Design and optimization of floating drug delivery system of acyclovir. Indian Journal of Pharmaceutical Sciences 2010; 72(5): 599-06.

5. Bhowmik D, Chiranjib B, Margret C, Jayakar B and Kumar KPS: Floating Drug Delivery System-A Review. Scholars Research Library 2009; 1(2): 199-18.

6. Arora S: Floating drug delivery system: A review. AAPS Pharma Science Technology 2005; 6(3): 525-28.

7. Timmermans J, Andre JM. Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules: new data for reconsidering the controversy. J Pharm Sci. 1994; 83:18-24.

8. Garg S, Sharma S. Gastroretentive drug delivery systems. Business Briefing: Pharma tech 2003 Web Site. 5^th edition. May 2003.

9. Bechgaard H, Ladefoged K. Distribution of pellets in gastrointestinal tract. The influence on transit time exerted by the density or diameter of pellets. J Pharm Pharmacol. 1978; 30:690-692.

10. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Control Release. 2000; 63:235-259.

11. Timmermans J, Gansbeke VB, Moes AJ. Assessing by gamma scintigraphy the in vivo buoyancy of dosage forms having known size and floating force profiles as a function of time. Vol I. Proceedings of the 5th International Conference on Pharmacy Technology. Paris, France: APGI.1989; 42-51.

12. Martini Frederic H. Fundamental of Anatomy and Physiology. 7th edition, Pearson, 2006; 862-884.

13. Tortora Gerard J., Derrickson Bryan H. Principles of Anatomy and Physiology. Volume - 2. 12th edition, Wiley, 2009; 921-938.

14. Shukla Vaibhav Tomar Preeti, Kharia Ankit Ankit Anand, Chatterjee D.P. Floating Drug Delivery System: An updated review. Journal of medical Pharmaceutical and Allied sciences, 2013; 04: 31-42.

15. Tortora Gerard J., Derrickson Bryan H. Principles of Anatomy and Physiology. Volume - 2. 12th edition, Wiley, 2009; 921-938.

16. Narang N. An updated review on: floating drug delivery system (FDDS). International Journal of Applied Pharmaceutics. 2011; 3, 01-07.

17. Klausner EA, Lavy E, Friedman M, Hoffman A. Novel levodopa gasrtroretentive dosage form: in vivo evaluation in dogs. J Control Release. 2003; 88, 117-126.

18. Rathod H, Patel V and Modasia M. Floating drug delivery system: Innovative Approach of Gastroretention. Int J Pharm Sciences Review and Research. 2010;4(3): 183-191.

19 Jassal Meenakshi, Nautiyal Ujjwal, Kundlas Jyostana, Singh Devendra. A Review: Gastroretenctive drug Delivery system (GRDDS). Indian Journal of Pharmaceutical and Biological Research, 2015; 3(1): 82-92.

20. Shukla Vaibhav Tomar preeti, kharia Ankit Ankit Anand, Chatterjee D.P. Floating Drug Delivery System: An updated reviw. Journal of medical Pharmaceutical and Allied sciences, 2013; 04: 31-42

21. Jain Amit K, Hatila Umashankar. A Review on Floating Drug Delivery System. International Journal of Pharmaceutical Studies and Research, 2011; 2(3): 01-06.

22. Gupta Garima, Singh Amit. A short Review on stomach Specific drug delivery system. International Journal of Pharm Tech Research, 2012; 4(4): 1527-1545.

23. More Swapnil, Gavali Kaustubh, Doke Onkar, Kagawade Prasad. Gastroretentive Drug Delivery system. Journal of Drug Delivery and Therapeutics, 2018; 8(4): 24-35.

24. Dighe Deepak A. Choudhary Naresh H., Thorat Mangesh S. Floating Drug Delivery System: A Novel approach towards Gastro- retention. International Journal Of Pharmaceutical and Chemical Sciences, 2012; 1(3): 1128-1142.

25. Bhardwaj Vishal, Nirmala, Harikumar S.L. Floating Drug Delivery System: A Review. Pharmacophore, 2013; 4(1): 26-38.

26. Kumar Parveen, Nirmala, Kumar S.L. Hari. Approaches For Gastroretentive Drug Delivery Systems. A Review. Journal of Drug Delivery and Therapeutics, 2014; 4(3): 14- 24.

27. Kadam Shashikant M., Kadam S.R., Patil U.S, Ratan G.N., Jamkandi V.G. Review on Floating Drug Delivery Systems: An approach to oral controlled Drug Delivery via Gastric Retention. International Journal of Research in Ayurveda Pharmacy, 2011; 2(6): 1752-1755.

28. Maheta Hemant, Patel MR, Patel KR, Patel MS. Review: An Overview on floating drug delivery system. Pharmatutor, 2014; 2(3): 61-71.

29. Sharma Mansi, Chaturvedi Ashwani Kumar, Singh Umesh Kumar, Gupta Ram Dayal, Gulati Ashwini, Sehgal. Floating Drug Delivery system: A review. AAPS Pharmmasci Tech, 2005; 6(3): 372-390. 30. Arora Shweta, Ali Javed, Ahuja Alka, Khar R.K., Boboota Sanjula. Floating Drug Delivery systems; A Review. AAPS- Pharma Sci Tech, 2005; 6(3): 372-390

30. Ghosh Drishti Rani, Rishikesh Haque Md Anworul, Banue MST Rikta, Rahman M.M, Miah Md. Sium-ulhossain, Rahman Md. Mofizur. Flooting Drug Delivery System: A Review. Journal of Drug Discovery and Therapeutic, 2013; 1(8): 52-59.

31. Kataria Sahil, Middha Skanksha, Bhardwajs, Sanclhu P. Flooting Drug Delivery System: A Review. International Research Journal of Pharmacy, 2011; 2(9): 18-24.

Received on 08.07.2021 Modified on 27.07.2021

Asian J. Res. Pharm. Sci. 2021; 11(4):295-300.

DOI: 10.52711/2231-5659.2021.00046