Gastroretentive Drug Delivery Systems: A Promising Approach

Yashomita Mehta¹*, Sunita Nirban¹, Sunil Kumar¹, Kuldeep Malodia¹, Pankaj Rakha² and Manju Nagpal³

¹Lord Shiva College of Pharmacy, Sirsa.

²Rajendra Institute of Technology and Sciences, 4^th mile stone, Hisar Road, Sirsa.

³Chitkara School of Pharmaceutical Sciences, Chitkara University, Barotiwala (HP).

ABSTRACT:

Controlled release drug delivery system (CRDDS) have been most extensively used to improve therapy of certain drugs, but several physiological difficulties faced with CRDDS is the inability to restrain and remain in the gastric region for several hours which limit the bioavailability of drug. Hence drug delivery systems with prolonged gastric residence time (GRT) are an approach to improve bioavailability of drugs, reduction in dose thereby leading to less side/toxic effects. Many approaches have been utilized in the development of gastric retention drug delivery systems (GRDDS) such as floating system, extended system, high density system, superporus system, bioadhesive system, and magnetic system etc. This review also summarizes the in vitro and in vivo studies to evaluate the performance and application of GRDDS. These systems are useful to several problems encountered during the development of a pharmaceutical dosage form.

KEYWORDS: Gastric retention, effervescent, floating, magnetic.

INTRODUCTION:

Oral route remains the most preferred route for the administration of therapeutic agents because low cost of therapy and ease of administration leads to higher level of patient compliance. Over the year, oral dosage forms have been increasingly sophisticated with major role being played by controlled release drug delivery system (CRDDS). Oral controlled drug delivery systems primarily aim to increase the bioavailability, efficacy and minimize adverse effect of the drugs. Drug released from the controlled release drug delivery system (CRDDS) after the ‘absorption window’ has been crossed, goes waste with no or negligible absorption occurring and this phenomenon drastically decreases the time available for drug absorption¹. Oral controlled drug delivery system has not been suitable for variety of important drugs like riboflavin, salbutamol and levodopa etc. These drugs are having narrow absorption window in upper part of gastro intestinal tract (GIT) and degraded in high pH environment which is due to relatively short transit time of the dosage form in these anatomical segments, this resulting in a short absorption phase with lesser bioavailability.

These considerations have led to the development of a unique oral controlled release dosage form with gastroretentive properties. Gastroretentive systems 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. It has application also for local drug delivery to the stomach and proximal small intestine.

Gastroretention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patient².

Suitable Drug Candidate for Gastric Retention³:

§ Drugs that act locally in the stomach e.g. antacids and misoprostol.

§ Drugs that are primarily absorbed from stomach and upper part of GI tract e.g. calcium supplements, chlordiazepoxide and cinnarazine.

§ Drugs with a narrow window of absorption e.g. riboflavin and levodopa, salbutamol.

§ Drugs that degrade in the intestinal or colonic environment e.g. ranitidine HCl and metronidazole.

§ Drugs those are poorly soluble at an alkaline pH.

§ Drugs that have less bioavailability e.g. carvedilol, salbutamol, cefedinir

§ Drugs that have short half life e.g. captopril, famotidine

Factors Affecting Gastric Retention of Dosage Forms:

1. Size of dosage form: 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. In fed conditions, the smaller units get emptied from the stomach during digestive phase and the larger units during housekeeper waves. In most cases, the larger the size of the dosage form, the greater will be the gastric retention time because the larger size would not allow the dosage form to quickly pass through the pyloric antrum in to the intestine.

2. Density of the dosage form: Density plays an important role in determining the location of the delivery systems in the stomach. If density of delivery system is higher than gastric fluids, then it sinks to the bottom of the stomach, while low density systems float on the surface of fluid and hence gastric retention⁴.

3. Fed and Fasted state: During fasting state, the gastrointestinal motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occur every 1.5 to 2 hours, 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 thus increase the drug absorption by allowing it to stay at absorption site for longer time⁵.

4. Fluid volume: The resting volume of the stomach is 25 to 50 ml. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster⁶.

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

6. Caloric content: The GRT can increase by 4 to 10 hours with a meal that is high in proteins and fats.

7. Posture: Gastro retentive time can vary between supine and upright ambulatory states of the patients.

8. Gender: Mean ambulatory GRT in males (3.4 ± 0.4 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.

9. Age: Elder people, especially those over 70, have a significantly longer GRT⁷.

Techniques of Gastric Retention:

Various techniques have been used to improve the gastric retention of an oral dosage as follows :

Fig1: Techniques of Gastric Retention

Floating drug delivery system: Low density system providing sufficient buoyancy to float over the gastric contents.

High density system: High density systems sediment into the folds of stomach.

Swelling system: Swelling and expanding system in the gastric environment preventing transit from the gastric sphincter.

Bio/Mucoadhesive system: Bioadhesive system enabling the localized retention of the system in the stomach.

Miscellaneous systems: Various other approaches have also been worked out to improve the retention of an oral dosage in stomach, e.g., superporous hydrogels, use of passage delaying agents and magnetic systems.

Floating drug delivery systems: Floating drug delivery systems (FDDS) have a bulk density less than that of the gastric fluids remain buoyant in stomach without affecting gastric emptying rate for a prolong period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate which increases the GRT and a better control on the fluctuation in plasma drug concentration⁸.

Formulation of this device must comply with the following criteria:

§ It must have sufficient structure to form a cohesive gel barrier.

§ It must maintain an overall lower specific gravity than that of the gastric contents.

§ It should dissolve slowly enough to serve as a drug reservoir.

Depending on the mechanism of buoyancy, two distinctly different methods like effervescent and non-effervescent systems have been used in the development of floating drug delivery systems (FDDS).

Non-effervescent FDDS:

In this system contains drugs with gel forming hydrocolloids meant to remain buoyant on stomach contents. This prolongs GRT and maximizes the amount of drug that reaches its absorption site in the solution form and hence ready for absorption. These systems incorporate a high level of one or more gel forming or highly soluble cellulose type hydrocolloids e.g. hydroxyethyl-cellulose (HEC), hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (NaCMC), Polysacchacarides and matrix forming polymers such as polycarbophil, polyacrylates and polystyrene⁹.

Effervescent FDDS:

These are matrix type systems prepared with the help of swellable polymers like methocel, polysaccharides (eg. Chitosan), effervescent components (eg. sodium bicarbonate, citric acid and tartaric acid) or chambers containing a liquid that tends to gasify at body temperature. The optimum ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1⁵. These dosage forms are developed in such a way, when they come in contact with gastric juice in the stomach, CO₂ is liberated and trapped in the swollen hydrocolloids thus, decreasing its specific gravity and making it to float over chyme.

High-density system: Gastric contents have a density close to water (1.004 g cm− 3). When the patient is upright, small pellets of high-density sink to the bottom of the stomach where they become entrapped in the folds of the antrum and withstand the peristaltic waves of the stomach wall. A density close to 2.4-2.8 g cm⁻³ seems necessary for significant prolongation of gastric residence time. Diluents such as Barium Sulphate, Zinc Oxide, Iron powder and Titanium Dioxide must be used to manufacture such high density formulations¹.

Swelling system: These are the dosage forms, which after swallowing swell to an extent that prevents their exit from the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be named as “Plug type systems”, since they exhibit the tendency to remain lodged at the pyloric sphincter. The formulation is designed for gastric retention and controlled delivery of the drug into the gastric cavity. Such polymeric matrices remain in the gastric cavity for several hours even in the fed state. Sustained and controlled drug release may be achieved by selection polymer of proper molecular weight swelling of the polymer retards the drug release. When dosage form comes in contact with gastric fluid, the polymer imbibes water and swells. The extensive swelling of these polymers is due to the presence of physical/ chemical cross-linking in the hydrophilic polymer network, this cross-linking prevent the dissolution of the polymer and hence maintain the physical integrity of the dosage form.

Bio/Mucoadhesive system: These systems bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the GRT of drug by increasing the intimacy and duration of contact of dosage form with the biological membrane¹⁰. The ability to provide adhesion of a drug to the GI wall provides longer residence time in a particular organ site, thereby producing an improved effect in terms of systemic effect. A bio/mucoadhesive substance is a natural or synthetic polymer (eg. polycarbophil, carbopol, lectin, chitosan and gliadin) capable of producing an adhesive interaction with a biological membrane (bioadhesive polymer) or mucus lining of GI mucosal surface (mucoadhesive polymer). The characteristices of a bioadhesive polymer are molecular flexibility, hydrophilic functional groups, specific molecular weight, chain length and conformation¹¹.

Advantages of Gastroretentive Drug Delivery Systems¹²:

1. Enhanced bioavailability: The bioavailability of various drugs (e.g. riboflavin and levodopa) in GRDFs is significantly enhanced in comparison to administration of CR polymeric formulations.

2. Minimized drug degradation at the colon: Gastric retention of the drug occurs with GRDFs that minimizes the amount of drugs reaches the colon and hence prevents the degradation of drug that degraded in the colon.

3. Reduced frequency of dosing: For drugs with a relatively short biological half-life, sustained and slow input from CR-GRDF may result in reduced frequency of dosing which improves patient compliances and there by improves therapy also.

4. Targeted therapy for local ailments: The prolonged and sustained administration of the drug from GRDF to the stomach may be advantageous for local therapy in the stomach and small intestine. Thus, therapeutic drug concentrations may be attained locally in the upper gastro intestinal tract.

5. Reduced fluctuation of plasma 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.

6. Extended time over critical (effective) concentration: The sustained mode of administration enables extension of time over a critical concentration and thus enhances the pharmacological effects and improves the clinical outcomes.

7. Site specific drug delivery: A floating dosage form is feasible approach especially for those drugs which have limited absorption sites in upper small intestine. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic level and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency.

Limitations of Gastroretentive Drug Delivery Systems:

§ FDDS requires a sufficiently high level of fluid in the stomach for the system to float therein and work efficiently. This problem can be overcome by coating the dosage form with bioadhesive polymer which adhere to gastric mucosa¹³ or administering dosage form with a glass full of water (200-250 ml) with frequent meals.

§ Bioadhesion in the acidic environment and high turnover of mucus may raise questions about the effectiveness of this technique.

§ Gastric retention of high density systems in the antrum part under the migrating waves of the stomach is questionable.

§ GRDFs are not suitable for drugs that may cause gastric lesion e.g. non-steroidal-anti-inflammatory drugs.

§ GRDFs are not suitable for drugs that are unstable in the acidic environment and absorbed throughout the gastrointestinal tract.

Table 1: Gastroretentive products available in the market¹⁴

Brand Name	Active Ingredient(s)
Cifran OD	Ciprofloxacin
Madopar	L-DOPA and Benserazide
Valrelease	Diazepam
Topalkan	Aluminum -magnesium antacid
Almagate FlatCoat	Aluminum -magnesium antacid
Liquid Gavison	Aluminium hydroxide,
Conviron	Ferrous sulfate
Cytotec	Misoprostal

Table 2: Commonly used drug in formulation of gastro retentive dosages forms¹⁵

Dosage Forms	Drugs
Floating Tablets	Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Captopril, Cinnerzine, Chlorpheniramine maleate, Ciprofloxacin, Diltiazem, Fluorouracil, Isosorbide, dinitrate, Isosorbid mononitrate, p-Aminobenzoic acid(PABA), Prednisolone, Nimodipine, Sotalol, Theophylline,, Verapamil
Floating Capsules	Chlordiazepoxide HCl, Diazepam, Furosemide, L-DOPA and Benserazide, Nicardipine, Misoprostol, Propranolol, Pepstatin
Floating Microspheres	Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen, Terfenadine, Tranilast
Floating Granules	Diclofenac sodium, Indomethacin, Prednisolone
Powders	Several basic drugs
Films	Cinnerzine

Evaluation Parameters of gastroretentive dosage form:

1. Total floating time: The test for buoyancy or floating time is determined by using the USP dissolution apparatus containing 900 ml of 0.1 N HCl simulated gastric or intestinal fluids as the testing medium maintained at 37^oC. The time for which the dosage form floats is termed as the floating or floatation time⁸.

2. Floating forces: The density can express the fact that an object will float or not, this does not reflect the magnitude of floating forces produced by the object. Moreover, a single density determination made before immersion does not enable one to foresee the floating force evalution of the dosage form. Therefore, an in vitro measuring apparatus has been conceived for determining the real floating capabilities exhibited by buoyant dosage forms as a function of time. It operates by measuring the force equivalent to F required to maintain the object totally submerged in the fluid. As shown in Figure 2 from a partial schematic view of apparatus, a linear transmitter device (FTD) perform the double function of maintaining the object in chosen fluid medium and of transmitting the reacting force F, of either upward or downward direction, to the electromagnetic measuring module of a weighing balance where it is connected. This force determines the resultant weight of the object in immersed conditions and may be used for the quantification of its floating or non-floating capabilities. The magnitude and direction of the force and hence the resultant weight, corresponds to vector sum of buoyancy (F_buoy) and gravity (F_grav) forces acing on the object.

F = F_buoy - F_grav ... (1)

F = D_fg.V - D_sg.V = (D_f - D_s) g.V …(2)

F = (D_f – M/V) g.V …(3)

Where, F is total vertical force (resultant weight of the object), D_f = fluid density, D_s = object density, V = volume, M = object mass and g = acceleration due to gravity.

Fig. 2: Determination of Floating Force¹⁶

By convention, a positive resultant weight signifies force F exerted vertically upwards and that the object is able to float, whereas a negative resultant weight means that the force F acts vertically downwards and that the object sinks¹⁶.

3. Bioadhesive strength: The bioadhesive strength of a polymer can be determined by measuring the force required to separate the polymer specimen sandwiched between the layers of either an artificial (e.g., cellophane) or biological (e.g., rabbit stomach tissue) membrane. This force can be measured by using a modified precision balance or an automated texture analyzer¹⁷.

4. Weight gain or Water uptake¹⁸: The swelling behavior of dosage form can be measured either by studying its dimensional changes, weight gain or water uptake. The study is conducted by immersing the dosage form in the simulated gastric fluid at 37^oC. The dimensional changes can be measured in terms of increase in the tablet diameter and/or thickness at regular interval of time. Water uptake (WU) is measured in terms of % weight gain as given by the eqn 4:

WU = (W_t - W_o) × 100/W_o …..(4)

Where, W_t = Weight of the dosage form at time t; W_o = Initially weight

Gastroretention:

γ-emitting radioisotopes as radiomarkers, compounded into GRDFs are used for evaluation of GI transit times in healthy volunteers¹⁹. A small amount of stable isotope e.g., Samarium Oxide (¹⁵²Sm) is compounded into GRDFs during its preparation. Prior to study, the dosage form is irradiated in a neutron source to convert the isotope into γ-emitting material e.g., ¹⁵³Sm²⁰. Then emitted rays can be imaged using a “gamma camera” of scintillation counter, combined with a computer to process the image and thereby the dosage form can be tracked in the GIT. A major advantage of this technique is its high safety profile, as it is accompanied by relatively low doses of radiation.

Drug release studies:

Drug release studies are performed using the USP dissolution apparatus. Samples are withdrawn periodically, with replacement and then analyzed for their drug content after an appropriate dilution. The major requirement for the dissolution test is to allow a dosage form to sink to the bottom of the vessel before the rotation of the paddle. In case of floating GRDDS, this can be accomplished by attaching a small, loose piece of non-reacting material such as few turns of wire helix, around the dosage form that would otherwise float. However, this method can inhibit the three-dimensional swelling process of the dosage form and consequently affect the drug release from the formulation²¹.

CONCLUSION:

GRDDS, comprised mainly of floating, bioadhesive, and swellable systems, have emerged as an efficient means of enhancing the BA and controlled delivery of drugs that exhibit an absorption window. These systems achieve this by retaining the dosage form in the gastric region, from where the drug is presented at the absorption window. This ensures maximal absorption of the drug for the desired period. Finally, while the control of drug release profiles has been a major aim of pharmaceutical research and development in the past two decades, the control of GI transit profiles could be the focus of the next two decades and might result in the availability of new products with new therapeutic possibilities and substantial benefits for patients. Soon, the so-called ‘once-a-day’ formulations may be replaced by novel gastroretentive products with release and absorption phases of approximately 24 hours.

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Received on 17.12.2010

Modified on 21.12.2010

Accepted on 17.01.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(1): Jan.-Feb. 2011, 01-06