INTRODUCTION:

Oral delivery of drugs is by far the best 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.¹ This system has been of limited success in the case of drugs with a poor absorption window throughout gastrointestinal tract. Normal gastric residence times usually range between 5 minutes and 2 hours. In the fastest state the electrical activity in the stomach- the interdigitatemyoelectric cycle or migrating myoelectric complex governs the activity and hence, the transit of dosage forms.

It is characterized by four phases: phase 1- period no concentration, phase 2: period of intermittent contraction, phase 3: period of regular contractions at the maximal frequency that travel distally also known as housekeeper wave. And phase 4: period of transition between phase 3 and phase 1. Gastric emptying is unpredictable if there are physiological problems and other factors like the presence of food. Drugs having a short half-life are oral controlled delivery systems have been designed which can overcome these problems and release the drug to maintain its plasma concentration for a longer period of time.²

Mechanism:

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms. Mucoadhesive systems, gastric-emptying delaying devices. Among these, the floating dosage forms have been most commonly used. Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without of time. While the system is floating is on the gastric contents, the drug is released slowly at the desired rate from the system. After releases slowaly at the desired rate from the system. After release of drug the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal level of floating force is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operas by measuring continuously the force equivalent to F is on the higher positive side. This apparatus helps us in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of the enforceable intragastric buoyancy capability variations.³

F = F buoyancy - F gravity

= (Df - Ds) gv--- (1)

Where,

F= total vertical force,

Df = fluid density,

Ds = object density,

v = volume and

g = acceleration due to gravity.

Factor affecting on floating drug delivery system:

Gastric residence of an oral dosage form is affected by several factors. To pass through the pyrrolic value into the small intestine the particle size should be in the range of 1 to 2mm. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach; hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.

The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chron’s disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally, females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.⁴Gastric residence time of an oral dosage form is influenced by many factors. To pass through the pyloric size should be in the range of 1-2 mm. The pH of the stomach in fasting state and fed state are 1.5 - 2.0 and 2.0 - 6.0 respectively. A large volume of waste administrated in oral dosage form raises the pH of the stomach con-tents to 6 - 9. The rate of gastric emptying depends mainly on viscosity, volume and caloric contents of meals. It does not make any difference whether the meal has high protein, fat or carbohydrate contents as long as the caloric content is the same while there is decrease in gastric emptying time by increasing acidity and caloric value.⁵Other factors influences such as biological factors which includes age, body mass, index, gender, posture and diseased states (Hepatic failure, Diabetes, Chronis’ disease). In case of elderly persons gastric emptying is slowed down. Females have slower gastric emptying rates than that of males. Stress increases the gastric emptying rates whereas depression slows it down. Volume of liquids administered also effects the gastric emptying time. Larger the liquid content, faster the emptying. Several formulations parameters can affect the gastric residence time such as Size, Shape, Density, Diameter etc, of the dosage unit which affects gastric emptying. Out of all ring-shaped devices have better gastric rates when compared to all other shapes. For-mutations having a diameter more than 7.5mm shows better gastric residence time compared with preparations having 9.9mm. Density of a dosage form influences the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids. So, the unit is retained in the stomach for a pro-longed period. Out of all the floating drug delivery system formulations are having reliable gastric emptying patterns due to free distribution of the drug through-out the GIT when compare to single unit formulations.⁶

Gastric motility:

Gastric motility is controlled by a complex set of neural and hormonal signals. Nervous control originates from the enteric nervous system as well as parasympathetic (predominantly vogues nerve) and sympathetic systems. A large battery of hormones has been shown to influence gastric motility- for e.g. both gastrin and cholecystokinin act to relax the proximal stomach and enhance contractions in the distal stomach. The bottom line is that the patterns of gastric motility likely are a result from smooth muscle cells integrating a large number of inhibitory and stimulatory signals. Liquid readily pass through the pylorus in spurts, but solids must be reduced to a diameter of less than 1-2mm before passing pyloric gatekeeper. The gastric volume is important for dissolution of the dosage form in vivo. The resting volume of the stomach is 25-50ml. There is a large difference in gastric secretion of normal and achlorhydric individuals. Gastric pH also has pronounced effect of absorption of drug from delivery system. The pH of fasting stomach is 1.2-.2.0 and in fed condition 2.0-6.0.⁷

Drug used in formation of FDDS: -

Floating microspheres – Aspirin, Griseofulvin, p-nitroaniline, Ibuprofen, Ketoprofen.

Piroxicam, Verapamil, Cholestyramine, Theophylline, Nifedipine, Nicardipine, Dipyridamole.

Floating granules- Diclofenac sodium, Indomethacin and Prednisolone Films– Cinnarizine Albendazole.

Floating tablets and Pills - Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxycillin trihydrate, Atenolol, Fluorouracil, Isosorbide mononitrate, Para-amino benzoic acid, Pertained, Theophylline, Verapamil hydrochloride, Chlorpheniramine maleate, Aspirin, Calcium Carbonate, Fluorouracil, Prednisolone, Sotalol, pentoxifylline and Diltiazem HCl.

Floating Capsules - Chlordiazepoxide hydrogen chloride, Diazepam, Furosemide,

Misoprostol, L-Dopa, Benderizines, Ursodeoxycholic acid and Pepstatin, and Propranolol.⁸

Classification of floating drug delivery system:

A. Single Unit Floating Dosage Systems

a) Effervescent Systems (Gas-generating Systems)

b) Non-effervescent Systems

B. Multiple Unit Floating Dosage Systems

a) Non-effervescent Systems

b) Effervescent Systems (Gas-generating Systems)

c) Hollow Microspheres

C. Raft Forming Systems

A. Single Unit Floating Dosage Systems:

a) Effervescent Systems (Gas-generating Systems): These buoyant systems utilised matrices prepared with swellable polymers like HPMC, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifiers at body temperature. Then optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethyl cellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach.⁹

b) Non-effervescent Systems: This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. These systems may be referred to as the ‘plug-type systems’ since they have tendency to remain lodged near the pyloric sphincter. One of the formulation methods of such dosage forms involves the mixing of drug with a gel, which swells in contact with gastric fluid after oral

Administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Examples of this type of FDDS include colloidal gel barrier.¹⁰

B. Multiple Unit Floating Systems:

In spite of extensive research and development in the area of HBS and other floating tablets, these systems suffer from an important drawback of high variability of gastrointestinal transit time, when orally administered, because of their all-or-nothing gastric emptying nature. In Order to overcome the above problem, multiple unit floating systems were developed, which reduce the inter subjective variability in absorption and lower the probability of dose-dumping. Reports have been found on the development of both non-effervescent and effervescent multiple unit systems. Much research has been focussed and the scientists are still exploring the field of hollow microspheres, capable of floating on the gastric fluid and having improved gastric retention properties.¹¹

a) Non-effervescent Systems:

No much report was found in the literature on non-effervescent multiple unit systems, as compared to the effervescent systems. However, few workers have reported the possibility of developing such system containing indomethacin, using chitosan as the polymeric excipient. A multiple unit HBS containing indomethacin as a model drug prepared by extrusion process is reported. A mixture of drug, chitosan and acetic acid is extruded through a needle, and the extrudate is cut and dried. Chitosan hydrates and floats in the acidic media, and the required drug release could be obtained by modifying the drug-polymer ratio.

b) Effervescent Systems (Gas-generating Systems):

Kuraet al reported sustained release floating granules containing tetracycline hydrochloride. The granules are a mixture of drug granulates of two stages A and B, of which A contains 60 parts of HPMC, 40 parts of polyacrylic acid and 20 parts of drug and B contains 70 parts of sodium bicarbonate and 30 parts of tartaric acid. 60 parts by weight of granules of stage A and 30 parts by weight of granules of stage B are mixed along with a lubricant and filled into capsule. In dissolution media, the capsule shell dissolves and liberates the granules, which showed a floating time of more than 8 h and sustained drug release of 80% in about 6.5 h. Floating Incapsula’s of Pepstatin having a diameter of 0.1-0.2mm has been reported by Umezawa.¹²

c) Hollow Microspheres:

Hollow microspheres are considered as one of the most promising buoyant systems, as they possess the unique advantages of multiple unit systems as well as better floating properties, because of central hollow space inside the microsphere. The general techniques involved in their preparation include simple solvent evaporation, and solvent diffusion and evaporation. The drug release and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers such as polycarbonate, Eudragit and cellulose acetate were used in the preparation of hollow microspheres, and the drug release can be modulated by optimizing the polymer quantity and the polymer-plasticizer ratio.¹³

C. Raft Forming Systems:

Raft forming systems have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and disorders. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of CO2. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids described an antacid raft forming floating system. The system contains a gel forming agent (e.g. alginic acid), sodium bicarbonate and acid neutralizer, which forms a foaming sodium alginate gel (raft) when in contact with gastric fluids. The raft thus formed floats on the gastric fluids and prevents the reflux of the gastric contents (i.e. gastric acid) into the oesophagus by acting as a barrier between the stomach and oesophagus. A patent assigned to Reckitt and Colman Products Ltd., describes a raft forming formulation for the treatment of helicobacter pylori (H. Pylori) infections in the GIT. The Composition contained drug, alginic acid, sodium bicarbonate, calcium carbonate, mannitol and a sweetener. These ingredients were granulated, and citric acid was added to the granules. The formulation produces effervescence and aerates the raft formed, making it float.¹⁴

Advantages of floating drug delivery system:

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

These advantages include:

1. Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.

2. Controlled delivery of drugs.

3. Delivery of drugs for local action in the stomach.

4. Minimizing the mucosal irritation due to drugs, by drug releasing slowly at controlled rate.

5. Treatment of gastrointestinal disorders such as gastro-oesophageal reflux.

6. Simple and conventional equipment for manufacture.

7. Ease of administration and better patient compliance.

8. Site-specific drug delivery.¹⁵

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

10. FDDS are advantageous for drugs meant for local action in the stomach eg: Antacids

11. 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.

12. 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.

13. 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.

14. Controlled delivery of drugs. Minimizing the mucosal irritation due to drugs, by drug releasing slowly at controlled rate.

15. Treatment of gastrointestinal disorders such as gastro oesophageal reflux.

16. Ease of administration and better patient compliance.

17.Site-specific drug delivery.¹⁶

Disadvantages of floating drug delivery system:

1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids.

2. Drugs such as Nifedipine, which is well absorbed along the entire GI tract and which undergo significant first-pass metabolism, may not be suitable candidates for FDDS since the Slow gastric emptying may lead to reduced systemic bioavailability. Also, there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.

3. One of the disadvantages of floating systems is that they require a sufficiently high level of fluids in the stomach, so that the drug dosages form float therein and work efficiently.

4. These systems also require the presence of food to delay their gastric emptying.

5. Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted.

6. Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery systems.

7. Gastric emptying offloading for Ms in supine subjects may occur at random and becomes highly dependent on the diameter and size. Therefore patients should not be dosed with floating forms j u s t before going to bed.¹⁷

8. Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted.

9. Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery systems.

10 High variability in gastric emptying time due to its all or non-emptying process.

11 Gastric emptying of floating forms in supine subjects may occur at random and becomes highly dependent on the diameter and size. Therefore patients should not be dosed with floating forms just before going to bed.¹⁵

Polymers and other ingredients used in floating drug delivery system:

1. Polymers: The following polymers used in preparations of floating drugs-

HPMC K4 M, Calcium alginate, Eudragit S100, Eudragit RL, Propylene foam, Eudragit RS, ethyl cellulose, poly methyl methacrylate, Methocel K4M, Polyethylene oxide, β Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate, PVA, Polycarbonate, Sodium alginate, HPC-L, CP 934P, HPC, Eudragit S, HPMC, Metoloe S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4 M and Carbopol.

2. Inert fatty materials (5% - 75%): Edible, inert fatty material having a specific gravity of less than one can be used to decrease the hydrophilic property of formulation and hence increase buoyancy. E.g. Beeswax, fatty acids, long chain fatty alcohols, Gelucires 39/01 and 43/01.

3. Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbonate, CG (Citroglycine).

4. Release rate accelerants (5%-60%): eg. lactose, mannitol.

5. Release rate retardant’s (5%-60%): eg. Dicalcium phosphate, talc, magnesium stearate.

6. Buoyancy increasing agents (upto 80%): eg. Ethyl cellulose.

7. Low density material: Polypropylene foam powder (Accrual MP 1000).¹⁸

CONCLUSION:

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. FDDS promises to be a potential approach for gastric retention. Although there are number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique. Worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.

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Received on 17.02.2022 Modified on 15.04.2022

Asian J. Pharm. Tech. 2022; 12(3):272-276.

DOI: 10.52711/2231-5713.2022.00044