INTRODUCTION:

ORAL DRUG DELIVERY SYSTEM

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms¹. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (Immediate, Sustained or Controlled release) and the design of dosage forms (either solid, dispersion, or liquid), must be developed within the intrinsic characteristics of GI physiology.

The most sophisticated delivery system, the greater is the complexity of these various disciplines involved in the design and optimization of the system. In any case, the scientific framework required for the successful development of an oral drug delivery system consists of a basic understanding of the following three aspects:²

1. The anatomic and physiologic characteristics of the gastrointestinal tract. As shown in Table.

2. Physicochemical, pharmacokinetic and pharmacodynamics characteristics of the drug.

3. Physic mechanical characteristics and the drug delivery mode of the dosage form to be designed

Table 1.1: Anatomic and physiologic characteristics of the gastrointestinal tract³

Region	Surface Area (m2)	pH of The Region	Transit Time
Region	Surface Area (m2)	pH of The Region	Fluid	Solid
GIT	200	1-8	-	-
Stomach	0.1-0.2	1-3.5	50 min.	8 hrs.
Small intestine	4500	5-7.5	2-6 hrs.	4-9 hrs.
Large intestine	0.5-0.1	6.8	2-6 hrs.	3 hrs. to 3 days

Fig 1.1: Gastrointestinal anatomy and dynamics

· Stomach:

The stomach is an organ with a capacity for storage and mixing. Under fasting conditions the stomach is a collapsed bag with a residual volume of 50 mL and contains a small amount of gastric fluid (pH 1-3) and air. The stomach has four main areas: cardia, fundus, body, and pylorus. Within 2-4 hrs after eating a meal the stomach has emptied its contents into the duodenum.³

· Intestine:

The small intestine is a tubular viscous organ and has enormous number of villi on its mucosal surface that create a huge surface area (4500 m²compared to only 0.1-0.2 m²for the stomach). The surface of the mucous membrane of the small intestine possesses about 5 million villi, each about 0.5 to 1 mm long.^3,4

These villi are minute fingerlike projections of the mucosa and have a length of 0.5-1.5 mm, depending upon the degree of distension the intestinal wall and the state of contraction of smooth muscle fibres in their own interiors. Absorption of material occurs by facilitate diffusion, osmosis, and active transport.

The small intestine is the largest section of the digestive tube and it is arbitrarily divided in to three parts. Duodenum (20-30 cm), Jejunum (2-5 m) and the ileum (3-5 m). The duodenum has a pH of 5 to 6 and the lower ileum approaches a pH of 8. ^4,5

1.1 Oral Controlled Drug Delivery:

Oral ingestion is the most convenient and commonly used method of drug delivery. These systems have the obvious advantages of ease of administration and patient acceptance, least sterility constraints and flexibility in the design of dosage form. One would always like to have an ideal drug delivery system that will possess two main properties:⁴

(a). It will be a single dose for the whole duration of treatment.

(b). It will deliver the active drug directly at the site of action.

Unfortunately, such ideal systems are not available. Thus scientists try to develop systems that can be as close to an ideal system as possible.

An oral drug delivery system providing a uniform drug delivery can only partly satisfy therapeutic and biopharmaceutical needs, as it doesn’t take into account the site specific absorption rate within the gastrointestinal tract, therefore there is need for developing delivery system that release the drug at the right time, at the specific site and with the desired rate. Pharmaceutical products designed for oral delivery are mostly immediate release type, which are designed for immediate release of drug for rapid absorption.^4,5,6

Invariably, conventional drug dosage forms do not maintain the drug blood levels within the therapeutic range for an extended period of time. To achieve the same, a drug may be administered repetitively using a fixed dosing interval. This causes several potential problems like saw tooth kinetics characterized by large peaks and troughs in the drug concentration-time curve (Figure 1.2), frequent dosing for drugs with short biologic half-life, and above all the patient noncompliance.

An ideal drug delivery system should aid in the optimization of drug therapy by delivering an appropriate amount to the intended site and at a desired rate. Hence, the delivery system should deliver the drug at a rate dictated by the needs of the body over the period of treatment. By and large, a delivery system may be employed for spatial placement (i.e., targeting a drug to a specific organ or tissue) or temporal delivery (i.e., controlling the rate of drug delivery to the target tissue).^5,6

Figure 1.2: Plasma level profiles following conventional and controlled release dosing.⁴

Controlled release drug administration means not only the prolongation of the duration of drug delivery, similar to the objective in sustained release and prolonged release, but the term also implies the predictability and reproducibility of drug release kinetics. Oral controlled release drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a pre-determined period throughout the course of GI transit.

While developing a controlled release system one has to overcome basically three areas of challenges:

1. To develop a suitable system that delivers drug at a therapeutically effective rate at a predetermined site for a certain period of time required.

2. To develop a system that can be easily targeted to the site of action or the site of absorption and would reside there for sufficient period of time so as to release the drug in the vicinity of the site.

3. The drug should be delivered in such a way so that there is minimum first pass metabolism.^6,7

Controlled release drug delivery system attempts to sustain drug blood concentration at relatively constant and effective levels in the body by spatial placement (i.e., targeting a drug to a specific organ or tissue) or temporal delivery (i.e., controlling the rate of drug delivery to the target tissue). Thus controlled release drug delivery system offer various advantages viz. reduce blood level fluctuations, minimize drug accumulation, employ less total drug, improve patient compliance, and minimize local and systemic side effects.^6,7,8

1.1.1 Controlled Drug Delivery can leads to:⁹

i. Sustained drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body.

ii. Localized drug action by spatial placement of a controlled release system (usually rate controlled) adjacent to or in the diseased tissue or organ.

iii. Target drug action by using carriers or chemical derivatization to deliver drugs to a particular target cell type.

1.1.2. Merits of Controlled Drug Delivery:¹⁰

i. Decreased incidence and/or intensity of adverse effects and toxicity.

ii. Better drug utilization.

iii. Controlled rate and site of release.

iv. More uniform blood concentrations.

v. Improved patient compliance.

vi. Reduced dosing frequency.

vii. More consistent and prolonged therapeutic effect.

viii. A greater selectivity of pharmacological activity.

1.1.3. Demerits of Controlled Drug Delivery:¹¹

i. Increased variability among dosage units.

ii. Stability problems.

iii. Toxicity due to dose dumping.

iv. Increased cost.

v. More rapid development of tolerance.

vi. Need for additional patient education and counseling.

1.1.4. Factors influencing the design of controlled release products: ^12,13,14

Different variables to be considered for design of controlled release products are-

a. Physicochemical properties of drugs: A range of physicochemical properties of drugs such as solubility, stability, partition co-efficient, and protein binding contribute in a major way to designing of controlled release products.

b. Route of administration: Some routes of administration exert a negative influence on the drug efficacy especially during chronic administration and therefore route of administration should be taken into account. Many physiological constraints imposed by particular route, that is GI motility, blood supply, first pass metabolism and sequestration of small foreign particles by the liver and spleen influence the performance of controlled release systems.

c. Acute/Chronic therapy: Expected length of drug therapy to achieve cure or control of ailment is an important factor in design of controlled release products like development of one year contraceptive implant represents a different case than does an antibiotic treatment for acute microbial attack.

d. Target site: Untoward side effects can be minimized by delivering the maximum fraction of applied dose reaching the target site. This can be partially attained by localized delivery or use of novel carriers.

e. The patient: Condition of patient, whether patient in ambulatory or bed ridden, obese or gaunt, old or young etc. can affect the design of controlled release systems. A depot intramuscular injection of drug or implant performs in a different manner in an ambulatory patient.

f. The diseased state: Patho-physiological stage of subject plays important part in design of suitable controlled release delivery system. For e.g. in hepatic failure oral delivery of drugs should be stopped and in many circumstances unique manifestation of the disease can be taken as an advantage.

1.1.5. Classification of Oral controlled drug delivery systems:^15,16,17

Oral controlled drug delivery systems can be broadly classified on the basis of their mechanism of drug release. Primarily, controlled release is achieved by diffusion, degradation and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release systems. Diffusion occurs when bioactive agent passes through the polymer, which forms the building block of controlled release system.

Oral controlled drug delivery systems can be broadly classified on the basis of their mechanism of drug release into: ¹⁷

1. Dissolution-controlled release

a) Encapsulation dissolution control

b) Matrix dissolution control

2. Diffusion-controlled release

a) Reservoir devices

b) Matrix devices

3. Ion exchange resins

4. Osmotic controlled release

5. Gastro retentive systems

1.2 Gastroretentive Systems:^18,19,20

Variability in GI transit time is a concern for oral controlled drug delivery systems. A major constraint in oral controlled release drug delivery is that not all the drug candidates are absorbed uniformly throughout the GIT (gastrointestinal tract). Some drugs are absorbed in a particular portion of GI tract only or absorbed to a different extent in various segments of GI tract. Such drugs are said to have an absorption window. Thus only the drugs which are released in the preceding region and in close vicinity to the absorption window are available for absorption. After crossing the absorption window, the release drug goes to waste with negligible or no absorption. Thus the time available for drug absorption drastically decreases.

Drugs with a narrow absorption window in the GI tract are particularly susceptible to variation in both bioavailability and times to achieve peak plasma levels. Also most of the drugs are sparingly soluble or insoluble in gastric fluids. In these type of drugs dissolution is directly related to time available for solubilization and thus in such cases gastric retention time or transit time becomes significant factor for drug absorption.

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. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. One of the most feasible approaches for achieving and predictable drug delivery profile in GIT is to control the GRT so that gastric emptying process can be extended from few minutes to 12 hr using GRDF’s that offers new and better option for drug therapy. Gastro retentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. Furthermore, other drugs, such as isosorbidedinitrate, that are absorbed equally well throughout the GIT will not benefit from incorporation into a gastric retention system.^19,20

Gastrointestinal motility and Gastric emptying:^21,22

Gastric emptying occurs during fasting as well as fed states. It is characterized by a distinct cycle of electromechanical activity known as the interdigestive myoelectric cycle or migrating myoelectric cycle (MMC). Each cycle lasts 90-120 minutes and consists of 4 phases. The concentration of hormone motilin in the blood controls the duration of the phases. In the interdigestive or fasted states, an MMC wave migrates from the stomach down the GI tract every 90-120minutes.^21,22A full cycle consists of 4 phases, beginning in the lower oesophagul sphincter/gastric pacemaker, propagating over the whole stomach, the duodenum and jejunum, and finishing at the ileum. Phase-III is termed as ‘housekeeper wave’ as the powerful contractions in this phase tends to empty the stomach of its fasting contents and indigestible debris. The administration and subsequent ingestion of food rapidly interrupts the MMC cycle, and the digestive phase is allowed to take place. The upper part of the stomach stores the ingested food initially, where it is compressed gradually by the phasic contraction.

The fasted-state emptying pattern is independent of the presence of any indigestible solids in the stomach. Patterns of contractions in the stomach occur such that solid food is reduced to particles of less than 1mm diameter that are emptied through the pylorus as a suspension. The duration of contractions is dependent on the physiochemical characteristics of the ingested meal.²³

The size of the stomach varies according to the amount of distension. In fed conditions it spreads up to 1500 ml. while under the fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50 ml containing a small amount of gastric fluid (pH 1-3) and air. The mucus spreads and covers the mucosal surface of the stomach as well as the rest of the GIT. The GIT is in a state of continuous motility consisting of two modes, interdigestive motility pattern and digestive motility pattern. The former is dominant in the fasted state with a primary function of cleaning up the residual content of the upper GI tract. The interdigestive motility pattern is commonly called the ‘migrating motor complex’ (MMC) and is organized in cycles of activity and quiescence.²⁴

The series of events cycle through both the stomach and intestine every two to three hours which is divided into 4 consecutive phases.²⁵

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.

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

Figure 1.3: Motility pattern in GIT

Generally, a meal of approximately 450 kcal will interrupt the fasted state motility for about 3-4 hours. It is reported that the antral contractions reduce the size of food particles to≤1 mm and propel the food through the pylorus. However, it has been shown that indigestible solids≤7 mm can empty from the fed stomach in humans.²⁶

Table1.2: Features of Upper GIT²⁶

Section	Transit time (h)	pH	Absorbing surface area (m2)	Absorption pathway
Stomach	Variable	1-4	0.1	Passive, active, aqueous channel transport
Small intestine	3±1	5-7.5	120-200	Passive, active, aqueous channel transport, facilitated transport, ion pair transport, enterocytosis, carrier mediated transport.

Factors affecting gastric retention ^27,28,29

There are several factors that can affect gastric emptying (and hence GRT) of an oral dosage form. These factors include density, size, and shape of dosage form, concomitant intake of food and drugs such as anticholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine) and prokinetic agents (e.g., metoclopramide, cisapride), and biological factors such as gender, posture, age, body mass index, and disease states (e.g., diabetes, Crohn’s disease).

Density:

It plays important role in determining the location of the drug delivery system and affects the gastric emptying rate. If the dosage form is of higher density than that of gastric content, then it will sink to the bottom of the stomach while the low density drug delivery system will remain buoyant on the surface of gastric fluid. In both the systems dosage form remains away from the pyloric sphincter, thus it retains in stomach for longer duration. A density of less than 1.0 gm/cm³ is required to exhibit floating property. ²⁸

Size: The size of the dosage form is another factor that influences gastric retention. The mean gastric residence times of non-floating dosage forms are highly variable and greatly dependent on their size, which may be small, medium, and large, units. Studies have revealed that the small size tablets leave the stomach during the digestive phase while the large size tablets are emptied during the housekeeper waves.²⁹

Fed or Unfed State:

Food intake, the nature of the food, caloric content, viscosity, volume and frequency of feeding have a profound effect on the gastric retention of dosage forms. The presence or absence of food in the stomach influences the GRT of the dosage form. Usually, the presence of food increases the GRT of the dosage form and increases drug absorption by allowing it to stay at the absorption site for a longer time that is there is significant prolongation of gastric emptying after meal (~4 hr). Volume of liquid administration also affects the gastric emptying. The resting volume of the stomach is 25 to 50 ml when volume is large the emptying is large. Studies have shown that the gastric emptying time of floating and non-floating single units is shorter in fasted subjects.³⁰

Age and Gender:

It has been found that gastric emptying is slow in elderly person and women, while it is faster in young person and men.³¹

Posture:

There is no significant difference in the mean GRT for individuals in upright, ambulatory and supine state. On the other hand, in upright position, the floating systems floated to the top of gastric contents and remained for a longer time, showing prolonged GRT. But the non-floating units settled to the lower part of stomach and underwent faster emptying as a result of peristaltic contractions, and the floating units remained away from the pylorus. However, in supine position, the floating units are emptied faster than non-floating units of similar size.³²

Stress:

It is also one of the reasons which can increase the gastric emptying rate while depression slows it down.³³

1.3. Floating Drug Delivery Systems:

The floating drug delivery systems float in the stomach after its administration. Floating drug delivery systems is the important approach to achieve gastric retention to obtain sufficient drug bioavailability. Floating drug delivery system is based on the gastroretentive drug delivery systems. Floating drug delivery systems are mainly dependent upon the different type of polymers and role of polymer.³⁴

Gastric emptying of dosage form is extremely variable process and ability to prolong and control the emptying time. Gastric transit time is valuable asset for dosage forms, which reside in the stomach for a long period of time than conventional dosage form.

Conventional oral dosage forms such as tablets, capsules provide specific drug concentration in systemic circulation without offering any control over drug delivery and also cause great fluctuations in plasma drug levels. Many attempts have been made to develop sustained release preparations with extended clinical effects and reduced dosing frequency.^35,36

Floating systems are low density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuation.³⁷

FDDS can be divided into non-effervescent and gas-generating (effervescent) system.^38,39,40

1.3.1. Non-Effervescent Floating Dosage Form: ^41,42,43

The non-effervescent FDDS works on the mechanism of polymer swelling, bioadhesion of the polymer to mucosal layer of GI tract, gel forming hydrophilic polymers, low density materials etc. The most commonly used excipients for the preparations of non-effervescent FDDS are gel forming or swellable cellulose type hydrocolloids, polysaccharides and the matrix forming polymers like polyacrylates, polymethacrylates, polycarbonates, polystyrenes and bioadhesion polymers like chitosan and carbopols, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates. This system can be further divided into 4 sub-types:

a) Hydro-dynamically balanced system (HBS)/Colloidal gel barrier systems:⁴⁴

Sheth and Tossounian first designated this HBS. These are single-unit dosage forms, containing one or more gel-forming hydrophilic polymers. Hydroxy propyl methyl cellulose (HPMC) is the most common used excipient, although hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), sodium carboxy methyl cellulose (NaCMC), agar, carrageenans or alginic acid are also used. These systems incorporate high levels (20 to 75 % w/w) of one or more gel forming highly swellable cellulose type hydrocolloids either in tablets or capsules. When such a system comes in contact with the gastric fluid, the hydrochloride in the system hydrates and forms a colloidal gel barrier around its surface.

The Hydro-dynamically balanced system must comply with following three major criteria:

1. It must have sufficient structure to form cohesive gel barrier.

2. It must maintain an overall specific density lower than that of gastric contents.

3. It should dissolve slowly enough to serve as reservoir for the delivery system.

Figure 1.4: Intragastric floating tablet.

Figure 1.5: Hydrodynamically Based System (HBS).

b) Microporous compartment system.⁴⁵

Harrigan described a floating system, known as an intragastric floating drug delivey device. This technology is comprised of encapsulation of a drug reservoir inside a micro porous compartment with pores along its top and bottom surfaces. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric mucosal surface with undissolved drug. In stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the pores, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption. The micro porous compartment system is shown in Figure 1.6

Figure 1.6: Microporous intra-gastric floating drug delivery device.

c) Alginate beads⁴⁶

Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter were prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing a precipitation of calcium alginate. These beads were then separated; snap frozen in liquid nitrogen and freeze-dried at–40ºC for 24 hr, leading to formation of porous system that maintained floating force for over 12 hr. They were compared with non-floating solid beads of same material. The latter gave a short residence time of 1 hr, while floating beads gave a prolonged residence time of more than 5.5 hr. Floating systems comprising of calcium alginate core separated by an air compartment from a membrane of calcium alginate or a calcium alginate/polyvinyl alcohol have also been developed.

d) Hollow Microspheres^47,48

Hollow microspheres (micro balloons), loaded with ibuprofen in their outer polymer shells were prepared by novel emulsion solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer were poured into an agitated aqueous solution of polyvinyl alcohol that was thermally controlled at 40^oC. The gas phase was generated in dispersed polymer droplet by evaporation of dichloromethane formed an internal cavity in microsphere of polymer with drug. These micro balloons floated continuously over surface of acidic solution media that contained surfactant, for greater than 12 hrin vitro.

Figure 1.7: Mechanism of micro balloon formation by emulsion-solvent diffusion method.

1.3.2. Effervescent systems ^49,50,51

A drug delivery system can be made to float in the stomach by incorporating a floating chamber, which may be filled with vacuum, air or inert gas. The gas in floating chamber can be introduced either by volatilization of an organic solvent or by effervescent reaction between organic acids and bicarbonate salts.⁴⁹

a) Volatile liquid containing systems:

These devices are osmotically controlled floating systems containing a hollow deformable unit that can be converted from a collapsed to an expanded position and returned to collapse position after an extended period of time. A deformable system consists of two chambers separated by an impermeable, pressure responsive, movable bladder. The first chamber contains the drug and the second chamber contains volatile liquid such as cyclopentane or ether that vaporizes at physiological temperature to produce a gas, enabling the drug reservoir to float.⁵⁰

Figure 1.8: Gastro inflatable drug delivery device

Intra-gastric, osmotically controlled drug delivery system consists of an osmotic pressure controlled drug delivery device and an inflatable floating support in bioerodible capsule. When the device reaches the stomach, bioerodible capsule quickly disintegrates to release the drug delivery system⁵¹. The floating support is made up of a deformable hollow polymeric bag containing a liquid that gasifies at body temperature to inflate the bag. (Figure 1.9).

Figure 1.9: Intragastric osmotic controlled drug delivery system.

b) Gas generating systems:

These buoyant delivery systems utilize matrices prepared with swellable polymers such as Methocel or polysaccharides, e.g., chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage form to float on the chyme. The carbon dioxide generating components may be intimately mixed within the tablet matrix, in which case a single-layered tablet is produced, or a bilayered tablet may be compressed which contains the gas generating mechanism in one hydrocolloid containing layer and the drug in the other layer formulated for a SR (sustained release) effect.⁵²

Figure 1.10: (a) Gas generating effervescent tablet (b) Gas generating bi-layer tablet and (c) Bi-layered tablet with semi-permeable coat.

Figure 1.11: Multiple unit oral floating dosage systems

Figure 1.12: Stages of floating mechanism.

1.3.3. Advantages of Floating Drug Delivery:^53,54

· Sustained drug delivery/reduced frequency of dosing:

The drugs having short biological half-life, a sustained and slow input from FDDS may result in a flip-flop pharmacokinetics and it reduces the dose frequency. This feature is associated with improved patient compliance and thus improves the therapy.

· Reduced fluctuations of drug concentration:

The fluctuations in plasma drug concentration are minimized, and concentration-dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index. That makes it possible to obtain certain selectivity in the elicited pharmacological effect of drugs that activate different types of receptors at different concentrations.

· Improved receptor activation selectivity:

FDDS reduces the drug concentration fluctuation over a critical concentration and thus enhances the pharmacological effects and improves the clinical outcomes.

· Enhanced first-pass biotransformation:

When the drug is presented to the metabolic enzymes (cytochrome P-450, in particular CYP-3A4) in a sustained manner, the pre-systemic metabolism of the tested compound may be considerably increased rather than by a bolus input.

· Minimized adverse activity at the colon: Retention of the drug in GRDF at stomach minimizes the amount of drugs that reaches the colon and hence prevents the degradation of drug that degraded in the colon

· Site specific drug delivery:

A floating dosage form is a widely accepted approach especially for drugs which have limited absorption sites in upper small intestine.

· Enhanced bioavailability:

The bioavailability of some drugs (e.g. riboflavin and levodopa) CR-GRDF is significantly enhanced in comparison to administration of non-GRDF CR polymeric formulations.

· Targeted therapy for local ailments in the upper GIT:

The prolonged and sustained administration of the drug from FDDS to the stomach may be useful for local therapy in the stomach.

· Extended time over critical (effective) concentration:

The sustained mode of administration enables extension of the time .^53,54

1.3.4 Disadvantages: ⁵⁵

· Drugs which are irritant to gastric mucosa are also not desirable or suitable.

· The dosage form should be administered with a full glass of water (200-250 ml).

· These systems require a high level of fluid in the stomach for drug delivery to float and

· Work efficiently-coat, water.

· Not suitable for drugs that have solubility or stability problem in GIT.

· Drugs such as Nifedipine which is well absorbed along the entire GIT and which undergoes first pass metabolism, may not be desirable ^55,56

1.3.5 Mechanism of Floating Systems:

Floating drug delivery systems (FDDS) have a 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.

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 gastric content needed to allow the proper achievement of the buoyancy retention principle, 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. The object floats better if F is on the higher positive side. This apparatus helps 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.^57,58

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.

Fig 1.13. MECAHNISM OF FLOATING DRUG DELIVERY SYSTEM

1.3.6 Drug Candidates Suitable for FDDS ^59,60 :

a. Drugs those are unstable in the intestinal or colonic environment (e.g. captopril,

2. Ranitidine HCl, metronidazole).

3. Drugs that exhibit low solubility at high pH values (e.g. diazepam, chlordiazepoxide, verapamil).

4. Drugs that have narrow absorption window in GIT (e.g. L-DOPA, Para amino benzoic acid, furosemide, riboflavin).

5. Drugs that disturb normal colonic microbes (e.g. antibiotics used for the eradication of Helicobacter pylori, such as tetracycline, clarithromycin, amoxicillin).

6. Drugs those are locally active in the stomach (e.g. misroprostol, antacids).

1.3.7 Factors Affecting Floating Drug Delivery System:^61,62

1. Caloric Content:

GRT can be increased between 4 to 10 hours with a meal that is high in proteins.

2. Nature of the meal:

Feeding of indigestible polymers of fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging the drug release.

4. Size and Shape:

Dosage form unit with a diameter of more than 7.5 mm are reported to have an increased GRT competed to with those with a diameter of 9.9 mm.

The dosage form with a shape tetrahedron and ring shape devises with a flexural modulus of 48 and 22.5 kilopond per square inch (KSI) are reported to have better GIT for 90 to 100 % retention at 24 hours compared with other shapes.

5. Fed or Unfed State:

Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complexes (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.

6. Density:

Density of the dosage form should be less than the gastric contents (1.004gm/ml).⁶²

1.4 EVALUATION PARAMETERS OF STOMACH SPECIFIC FDDS

1. Weight variation:

Uniformity of Weight according to Indian pharmacopoeia, 20 tablets are selected at random, weight together and individually for the determination of weight of tablets. The mean and standard deviations are calculated⁶³

2. Hardness

Hardness or tablet crushing strength (fc ), is the force required to break a tablet in a diametric Compression is measured using Monsanto tablet hardness tester. It is expressed in kg/cm². ⁶⁴

3. Thickness:

Thickness and diameter of ten tablets are measured using vernier calipers.⁶⁵

4. Friability

The friability test was carried out in Roche Friabilator. Ten tablets are weighted (Wo) initially and put in a rotating drum. Then the tablets are subjected to 100 falls of 6 in. height. After completion of rotation, the tablets are weighed (W) again. % Weight loss or friability (f)=(1-w/ w0)×100 ⁶⁶

5. Disintegration time

In vitro disintegration time is determined using disintegration test apparatus. For this, a tablet is placed in each of the six tubes of the apparatus and one disc was added to each tube. The time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured⁶⁷

6. Buoyancy time

A tablet is introduced in to the beaker containing 100ml of 0.1N HCL. The time taken by the tablet to come up to the surface and floated is taken as the buoyancy time. An average of three determinations from of batch is taken for the floating forms⁶⁸.

7. Floating time and dissolution:

The test for floating time measurement is usually performed in stimulated gastric fluid or 0.1mole.lit HCl maintained at 37⁰C. It is determined by using USP dissolution apparatus containing 900 ml of 0.1mole lit HCl as the dissolution medium at 37⁰C. The time taken by the dosage form to float is termed as floating lag time and the time for which the dosage form floats is termed as the floating or flotation time.⁶⁹

8. Drug release:

Dissolution tests are performed using the dissolution apparatus. Samples are withdrawn periodically from the dissolution medium with replacement and then analyzed for their drug content after an appropriate dilution⁷⁰.

1.5. Application of Floating Drug Delivery Systems:

Floating drug delivery offers 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 can be summarized as follows^70,71

1. Absorption Enhancement:

Drugs that have poor bioavailability because of site specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption e.g. a significantly increase in the bio-availability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX-long product (29.5%) ^71,72.

2. Site-Specific Drug Delivery:

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine (Riboflavin and Furosemide) e.g.: Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets ⁷³.

3. Sustained Drug Delivery:

HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems⁷³

These systems have a bulk density of<1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited e.g.: Sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo.

The formulation compared with commercially available MICARD capsules using rabbits. Plasma concentration time curves showed a longer duration for administration (16 hours) in the sustained release floating capsules as compared with conventional MICARD capsules (8 hours)⁷⁴.

1.6. Polymers used for development of floating drug delivery:

Tablets: Cellulosic hydrocolloids-HPMC, HPC, HEC, MC, NaCMC.

Gel-forming hydrocolloids and matrix former-Carbopol, Carrageenan, Gum guar, Gum Arabic, Sodium alginate, Polyethylene oxide, Polyvinyl lactam Polyarcylates, Polyvinyl acetate.

Capsule :

Cellulosic hydrocolloids-HPMC, HPC, HEC, NaCMC.

Gel-forming hydrocolloids and matrix former-Sodium alginate, Carbopol, Agar.

Microsphere/microparticles:

Cellulose derivative-Ethyl cellulose.

Gel-forming hydrocolloids and matrix former-Eudragit, Polycarbonate, Polyacrylate, Polymethacrylate, Polystyrene, Chitosan, Gelatin, Alginate, Gelucir⁷⁵.

Table 1.3 Marketed preparation of GRDDS.⁷⁵

Name	Drug	Type
Madopar	Levodopa and Benserazide	HBS capsule
Valrelease	Diazepam	Tablet
Topalkan	Mixture of aluminium and magnesium salts	Tablet
Amalgate float coat	Antacid	Floating capsule
Conviron	Ferrous sulphate	Colloidal gel forming tablet
Cifran OD	Ciprofloxacin	Gas generating floating tablet
Cytotech	Misoprostol	Bilayer floating capsule
Liquid Gaviscon	Mixture of alginic acid and sodium bicarbonate	Liquid dosage form
Metformin GR	Metformin	Floating swellable tablet

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Received on 21.07.2018 Modified on 19.08.2018

Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 220-232.

DOI: 10.5958/0975-4377.2018.00034.4