GASTRORETENTIVE DRUG DELIVERY SYSTEM: AN APPROACH TO ENHANCE GASTRIC RETENTION FOR PROLONGED DRUG RELEASE

Received on 03 November, 2013; received in revised form, 19 December, 2013; accepted, 26 February, 2014; published 01 April, 2014

GASTRORETENTIVE DRUG DELIVERY SYSTEM: AN APPROACH TO ENHANCE GASTRIC RETENTION FOR PROLONGED DRUG RELEASE

Ankur Raj Sharma* and Afroz Khan

Jaypee University of Information Technology, Waknaghat-173 234, Himachal Pradesh, India

ABSTRACT: Oral route has been the most convenient and accepted route of drug delivery. Owing to tremendous curative benefits of the oral controlled release dosage forms are being preferred as the interesting topic in pharmaceutical field to achieved improved therapeutics advantages. Gastroretentive drug delivery system is novel drug delivery systems which has an upper hand owing to its ability of prolonged retaining ability in the stomach and thereby increase gastric residence time of drugs and also improves bioavailability of drugs. Attempt has been made to summarize important factors controlling gastroretentive drug delivery systems. This review covers the advantages, disadvantages, marketed preparation and some patents of gastroretentive drug delivery system and represents the floating and non-floating gastroretentive system and also highlights some of the current gastroretentive approaches. Recent approaches to increase the gastric residence time of drug delivery systems include bioadhesive systems, floating systems (low density systems), non-floating systems (high density systems) , magnetic systems, swelling systems, unfoldable and expandable systems, raft forming systems and superporous systems, biodegradable hydrogel systems.

Gastroretentive Drug Delivery System (GRDDS), Gastric Residence Time, (GRT), Physiology of Stomach, Floating and Non- Floating Systems

INTRODUCTION:Owing to tremendous curative benefits of the oral controlled release dosage forms are being preferred as the interesting topic of research over the past 3 decades ¹. The much obvious interest in this scenario is owing to its two fold advantage. Primarily, the oral controlled release dosage forms have the potential to upkeep an effective concentration in system for a longer duration.

Secondly, it is helpful in providing easy dosage administration to the patient, that further provides patient compliance on the part of the patient and ultimately providing an array of options in the final formulation. But the benefits are yet obstructed by the knock of short gastric retention time (GRT) and the unpredictable rapid gastric rate may cause partial drug release in the absorption zone of the patient’s body hence, hampering the efficiency of the dosage. It has caused the awaited development in oral gastroretentive drug delivery systems (GRDDS) ².

An unaccustomed drug delivery system of gastroretentive dosage form has evolved. It has an upper hand owing to its ability of prolonged retaining ability in the stomach. This improves the gastric residence span of drugs in stomach. This elongated retention ability provides more benefits which may be enumerated as: improving activity span for short half-life drugs, bioavailability of drugs, exclusion of side effects, reduction in dosage periodicity, saving drugs owing to former benefit, improves solubility for drugs that are less soluble in a high pH environment, optimized therapy and ultimately easy compliance on the part of the patient ^{3, 4}.

Recent approaches to increase the gastric residence time of drug delivery systems include bioadhesive systems, floating systems (low density systems), non-floating systems (high density systems), magnetic systems, swelling systems, unfoldable and expandable systems, raft forming systems and superporous systems, biodegradable hydrogel systems ⁵.

Basic Gastrointestinal Tract Physiology: The stomach primarily aims at processing and transporting food. The stomach provides for short term food reservation and quick consumption of relatively large meal. The primary substantial metabolism of enzymes is promoted in stomach of proteins. The peristalsis of stomach mix up and grind consumed food with secretions of the stomach, turning food in simplified liquid form. The liquefied bulk is transported to the small intestine for further digestion ⁶.

The human anatomy categorises stomach in three main parts: fundus, body and antrum (pylorus). The proximal portion referred to as fundus and the body functions as storage for undigested food. The antrum provides for the main site for mixing motions and acts as gastric emptying pump by propeller actions ⁷.

Both the fasting and fed states cause gastric emptying. However the two states are varied upon pattern of motility. In this phenomenon, series of electric events takes place in cycles via stomach and intestine every 2 to 3hous ⁸. There occurs a phenomenon of interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is divided in 4phases as given by Wilson and Washington ⁶. The 4 phases are enumerated below and also shown in Figure 1.

1. Phase I- Basal phase, lasts from 30 to 60 minutes with rare contractions and is characterized by a lack of secretory, electrical, and contractile activity.
2. Phase II- Preburst phase, lasts for 20 to 40 minutes with intermittent contractions, during which contractile motions increase in frequency and size.
3. Phase III- Burst phase, lasts for 10 to 20 minutes with intense and regular contractions for short period, termed housekeeper waves that sweep off undigested food.
4. Phase IV lasts for 0 to 5 minutes and is the transition period between Phases III and I.

FIGURE 1: MOTILITY PATTERN IN GIT

Upon food being ingested, the stomach motions vary fasted to fed state. It’s termed as digestive motility pattern and constitutes regular peristalsis as in phase II of the state of fast. This incredibly reduces food size (to less than 1mm), propelling food towards pylorus. The gastric emptying rate is delayed during fed state onset of MMC, causing slowdown of gastric emptying rate ⁹.

Why there is need of GRDDS? There occurs a quick elimination of certain drugs, that have been absorbed from the gastrointestinal tract (usually having short half-lives), from circulatory system due to which frequent dosing is required. To sort out this matter, innovative method gastroretentive drug delivery systems are incorporate.

They have efficient plasma drug concentration thereby reduce dosing frequency. Another highlight of this system is that it effectively reduces variations in plasma drug concentration by delivering the drug in a controlled and reproducible fashion ¹⁰. The rationale for the use of GRDDS is shown in Figure 2.

FIGURE 2: RATIONALE FOR THE USE OF GRDDS¹¹

Advantages of GRDDS ¹²:

1. Increase in bioavailability and curative efficiency of drugs and economic usage of dosage.
2. Minimised factor of risk in resistance in antibiotics owing to stabilised therapeutic levels over prolonged periods removing fluctuations.
3. Optimised release in case of short half-life drugs, causes flip flop pharmacokinetics and also ensures patient compliance with reduced dosage frequency.
4. They are advantageous against drawbacks of the gastric retention time (GRT) as well as the gastric emptying time (GET). The system remains buoyant on gastric fluid because of lower bulk density than gastric fluids.
5. These are efficient in repairing stomach and small intestine related problems. Its attributed to the fact that gastroretentive drug delivery sustains drug release and hence, avail local therapy in these organs.
6. This method provides with a systematic and controlled drug delivery system which minimises chances of drug over exposure at the diseased site.
7. Providing a narrow curative index, the gastroretentive dosage forms minimises variance in concentrations of drugs and effects.
8. This system provides higher efficiency due to reduced counter activity by body.
9. As the system provides with controlled rates of fluctuation, a wider array is provided for selectivity in receptor activation.

Disadvantages of GRDDS ^{13, 14, 15}

1. Need for increased level of fluids in the stomach.
2. Unsuitable for such drugs as:

• Problematic with solubility in gastric fluid
• Causing G.I irritation
• Inefficient in acidic environment

1. Drugs intended for selective release in the colon.
2. Unpredictable adherence owing to state of constant renewal of mucus wall of stomach.
3. GRDDS is fed into the system after the meal as time of stay in stomach depends on digestive state.
4. The ability of the drug to remain in the stomach depends upon the subject being positioned upright.
5. Hydrogel based swelling system takes longer time to swell.
6. Upon multiple administrations, size increasing drug delivery systems pose the threat to life owing to possible hazard of permanent retention in stomach.
7. Superporous systems having drawback like problematical storage of much easily hydrolysable, biodegradable polymers.

Suitable and unsuitable drugs candidates for GRDDS: Suitable and unsuitable drugs candidates for GRDDS are listed in Table 1 and Table 2 respectively.

TABLE 1: POTENTIAL DRUG CANDIDATES FOR GRDDS ¹⁶

TABLE 2: UNSUITABLE DRUG CANDIDATES FOR GRDDS ¹⁷

Factors controlling GRDDS ^{9, 18, 19}: Factors controlling GRDDS are shown in Figure 3 and some of the factors are enumerated below:

FIGURE 3: FACTORS CONTROLLING GRDDS

1. Density: Dosage form with lower density in the gastric content can float to the surface while high density sink to the bottom of the stomach. Suitable density required for floating property is less than 1.0 gm/ cm³
2. Size: Size should be more than 7.5 mm in diameter.
3. Shape: Either round or spherical shaped dosage form exhibit better property related to other shapes.
4. Single or multiple unit formulation: Multiple units are desirable due to foretell release profile.
5. Fed or Unfed State: Gastric retention time is less during fasting condition due to rise in gastric motility
6. Nature of Meal: High amount of fatty acid and other indigestible polymers slow down the gastric retention time due to variation in gastric motility
7. Frequency of Feed: Low frequency of migrating myoelectric complex (MMC) contributes to GRT upto 400 times which inturn depends on the frequency of food intake
8. Caloric Content: A high protein and fat rich diet can increase GRT by 4 to 10h.
9. Gender: Males have greater GRT than females
10. Age: GRT is more in geriatric patients and less in neonates and children. Age above 70 (>70) exhibit longer GRT.
11. Posture: GRT can vary between supine and upright ambulatory states of the patient.
12. Disease State: Gastric disease such as diabetes, chron’s disease, hypothyroidism, hyperthyroidism, duodenal ulcers etc fluctuates the GRT
13. Concomitant Intake of Drug: Combination of some drugs along with gastric motility enhancers or depressants, affect GRT

Approaches for GRDDS: The following methods have been devised to improve period of retainment of oral dosage form in the stomach viz. floating system, swelling and expanding system, bioadhesive system, high density system and other delayed gastric emptying devices ¹⁰. It is shown in Figure 4 and classification of GRDDS is shown in Figure 5.

FIGURE 4: APPROACHES FOR GRDDS

1. Floating Systems: An optimised level of drug bioavailability can be reached by judicious gastric retention. The floating drug delivery system is a novel approach for the same. It is needed for drugs that have an absorption window in the stomach or in the upper small intestine ²¹. This method does not affect the rate of gastric emptying over a prolonged time. It is a low density approach (lower than gastric fluid). Hence remain buoyant in the stomach releasing the drug slowly. The emptying of residual system is followed by the drug release, from the stomach. Thus occurs an increased gastric retention time (GRT) and improved control over fluctuating plasma drug concentration ¹³. The pre-requisites for floating drug delivery system are ²¹:
   1. Slow content release to act as reservoir.
   2. Specific gravity should be maintained lower than gastric contents (1.004 – 1.01 gm/cm3)
   3. It must form a cohesive gel barrier.

FIGURE 5: CLASSIFICATION OF GRDDS ^{10, 20}

Mechanism of Floating Drug Delivery Systems: The slow drug release is accompanied with requisite rate during the system flow on the gastric contents. The release is followed by removal of the residual system from the stomach. But, along with the appropriate level of floating force (F), minimum levels of gastric contents are needed to permit achievement of buoyancy retention principle and also to keep dosage form buoyant over meal surface. In the literature an apparatus has been described that measures the kinetics of floating force. Its operation constitutes of measuring a force equivalent to F (with respect to time) which keeps the object submerged.

As depicted in Figure 6, the presence of force F in a higher positive side makes the object flow better. This apparatus optimizes FDDS and prevents its drawbacks unforeseeable intragastric buoyancy capability variations, related to stability and durability ²².

F = F _buoyancy - F _gravity

= (D_f - D_s) gv

Where, F= total vertical force, D_f = fluid density, D_s = object density, v = volume and g = acceleration due to gravity.

FIGURE 6: MECHANISM OF FLOATING DRUG DELIVERY SYSTEMS, GF: GASTRIC FLUID, CO₂: CARBON DIOXIDE

Based on the buoyancy mechanism, floating systems are classified as follows:

1. Effervescent systems
2. Non-effervescent systems

1. Effervescent Systems (Gas Generating Systems): Gas bubble generation helps to achieve floatability. The swellable polymers viz. methylcellulose and chitosan and various effervescent compounds, e.g. sodium bicarbonate, tartaric acid and citric acid, help in creating matrix type of such systems ²³. They are created in a manner that upon contact with gastric contents CO₂ is released finally entrapping in swollen hydrocolloids, that makes dosage forms buoyant ¹³.

These systems are further classified as below:

1. Volatile Liquid Containing System: This system comprises of dual chambers having an impermeable, pressure responsive, movable bladder separation. The former chamber has drugs and the latter has volatile liquid. To sustain the GRT of a drug delivery system an inflatable chamber has to be incorporated, that carries a liquid e.g. ether, cyclopentane. It turns to gaseous form at body temperature causing inflatation of the chamber in the stomach. It may contain a biodegradable plug, made of polyvinyl alcohol, polyethylene, etc. This plug gradually dissolves making the chamber release gas and to collapse after a specific duration to allow spontaneous release of the inflatable systems from the stomach. The drug continues to release as the device inflates ²⁴.

These systems are further classified as below:

1. Intragastric floating gastrointestinal drug system.
2. Inflatable gastrointestinal delivery system
3. Intragastric-osmotically controlled drug delivery system
4. Floating capsules
5. Floating pills
6. Floating system with ion exchange resins
7. Non- effervescent Systems: The Non- effervescent floating dosage forms have swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymeth-acrylate, and polystyrene ²⁵. Its creation has a simplistic approach i.e. mixing of drug with the gel, followed by swelling by coming in contract with gastric fluid after oral administration and thus maintaining a relative integrity of shape and keeping a bulk density less than one (<1) ^{25, 26}. The dosage form gains its buoyancy owing to air trapped in the swelled up matrix. This swollen up matrix reserves drug and maintains sustained drug release via gelatinous mass ²⁵. Hydroxylpropyl methyl cellulose (HPMC), polyacrylate, polyvinyl acetate, carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates, are the most commonly used excipients ²⁶.

1. Matrix Tablets: It can be formulised in a single layer matrix table by implementing bicarbonates in the matrix forming hydrocolloid gel agent or in a dual layer matrix along with gas generating matrix together as an individual layer. The drug acts as the second layer. There is a possibility of triple layer matrix tablet. However now the gas generating matrix is one layer and rest two are drug layers ¹⁰.
2. Gas Generating Systems

These systems are further classified as below:

1. Hydrodynamically balanced systems
2. Microballoons / hollow microspheres
3. Alginate beads
4. Layered tablets

1. Single layered floating tablets
2. Double layered floating tablets

Table 3 enlists examples of commonly used drugs in formulation of different forms of GRDDS.

TABLE 3: COMMONLY USED DRUGS IN FORMULATION OF GRDDS

2. Non-floating Systems: Non- floating systems are class of gastroretentive drug delivery systems which do not float but remain in the stomach for a prolonged time period. These systems are further classified as below and some of them are described in Table 4.

1. Bioadhesive systems
2. Swelling systems
3. High density systems
4. Expandable systems
5. Magnetic systems
6. Raft forming system
7. Superporous hydrogel systems

Gastroretentive Drug Delivery System: Review from previous studies: Review from previous studies of GRDDS is listed in Table 5.

Marketed products and patents of GRDDS: Marketed products and patents of some gastroretentive drug delivery systems are listed in Table 6 and Table 7 respectively.

TABLE 4: NON-FLOATING SYSTEMS

TABLE 5: REVIEW FROM PREVIOUS STUDIES OF GRDDS

TABLE 6: COMMERCIALLY AVAILABLE MARKETED PRODUCTS OF GRDDS

TABLE 7: PATENTS FOR GRDDS ^49-60

CONCLUSION: Gastroretentive drug delivery system have emerged as an efficient means of prolonged retaining ability in the stomach and thereby increase gastric residence time of drugs and also improves bioavailability of drugs. Inspite of number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focussing towards commercializing this technique. Number of commercial products and patents issued in this field are evident of it.

ACKNOWLEDGEMENT: We would like to express our heartfelt thanks to our beloved parents for their blessings, our teacher’s and friends/classmates for their help and wishes for the successful completion of this review article.

DECLARATION OF INTEREST: The author reports no declaration of interest.

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    Sharma AR and Afroz Khan: Gastroretentive Drug Delivery System: An approach to enhance Gastric retention for prolonged drug release. Int J Pharm Sci Res 2014; 5(4): 1095-06.doi: 10.13040/IJPSR.0975-8232.5(4).1095-06

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