INTRODUCTION:
The aim of drug delivery system is to afford a beneficial amount of drug to the appropriate site in the body to attain promptly and then maintain preferred drug concentration. The oral route is increasingly being used for the delivery of therapeutic agents because the low cost of the therapy and simplicity of administration lead to high levels of patient compliance.
These systems have the obvious compensation of ease of administration and patient acceptance. One would always like to have an perfect drug delivery system that will possess two main properties
1. It will be a single dose for the complete extent of treatment
2. It will deliver the active drug directly at the site of action
They are principally used to make sure patient compliance and to get better efficiency of drugs. Increased safety and decreased side effects of drugs help in achieving these objects. Such systems are mainly useful for drugs with narrow therapeutic window where minimum fluctuations in plasma levels are desired. These systems have more flexibility in dosage design than the conventional drug delivery systems.
The current scientific and patent literature shows increased interest in academics and industrial research groups regarding the novel dosage forms that can be retained in the stomach for prolonged and predictable period of time. One of the most possible approaches for achieving a extended and predictable drug delivery profiles in the GI tract is to control the gastric residence time (GRT), using gastroretentive dosage forms (GRDFs). It designed on the basis of one of some approaches like, floating dosage form (formulating low density dosage form that remain buoyant above gastric fluid), high-density dosage forms, and bioadhesive dosage form.
Gastroretention(7,8)
A rational approach to improve bioavailability and improve pharmacokinetic and pharmacodynamic profiles is to maintain the drug reservoir above its absorption area i.e. in the stomach (gastroretention) and to discharge drug in a controlled manner.
The gastroretentive dosage form resides in the stomach for longer period of time than predictable dosage forms. Gastroretentive systems can remain in gastric region for several hours and hence appreciably prolong the gastric retention improves bioavailability, reduces drug waste.
Need For Gastroretention(1,7)
1. Gastroretention is significant for drugs that are degraded in intestine due to alkaline pH.
2. It is also vital for drugs that should act locally in the stomach like antacids.
3. Drugs that are unsteadily absorbed due to uneven gastric emptying time.
4. Gastroretention is predominantly useful for the treatment of peptic ulcers caused by H.pylori infections.
5. If the drugs are inadequately soluable in intestine due to alkaline pH, gastric retention may increase.
6. Solubility before they are emptied, resulting in enhanced bioavailability.
Advantages of Gastroretentive Delivery System(9,10)
1. Gastroretentive systems are beneficial in improving gastrointestinal absorption of drugs with narrow absorption windows.
2. Such systems are useful for drugs that are best absorbed in the stomach. e.g. albuterol.
3. Gastroretention maintains the steady beneficial levels over a prolonged period and thus reduction in fluctuation in therapeutic levels minimizing the risk of resistance particularly in case of antibiotics. e.g. beta lactum antibiotics (penicillins)
4. Retention of drug delivery systems in the stomach prolonges generally gastrointestinal transit time thereby rising bioavailability of system intended for once-a-day administration e.g. Ofloxacin
Basic Gastrointestinal Tract Physiology(11)
Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for integration motions and act as a pump for gastric emptying by propelling action.
Gastric emptying occurs during fasting as well as fed states. The example of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical measures take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.(12)
1. Phase I (basal phase) lasts from 40 to 60 minutes with unusual contractions.
2. Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and occurrence also increases steadily.
3. Phase III (burst phase) lasts for 4 to 6 minutes. It includes extreme 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.(13)
4. Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.
Behind the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises incessant contractions as in phase II of fasted state. These contractions consequence in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is postponed resulting in hold back of gastric emptying rate.(14) Scintigraphic studies influential gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to fundamentally two complications, that of short gastric residence time and impulsive gastric emptying rate. (Fig. 1)
Fig. 1: Regions of Stomach (141)
Factors Affecting Gastric Retention (Gastric Emptying Time)(15,16,17)
Particle Size:
To pass through the pyloric valve into the small intestine the particle size should be in the range of 1to2 mm.
Type of Meal and Caloric Content:
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. Increase in caloric value slows down gastric emptying time. If we take liquids in larger amount, in fasted conditions, faster the emptying time & if take in fed condition, emptying time can be Increased If we take solids, in fasted condition, solids emptied quickly & in In fed condition, emptying time can be significantly increased.
Volume:
The resting volume of stomach is 25 to 50 ml. Volume of liquid administered affects gastric emptying time. When volume is large, the emptying is faster.
Biological Factors:
In case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males Stress increases gastric emptying rates.
Size of Dosage Form:
Timmermans and Andre studied the effect of size of floating and non floating dosage forms on gastric emptying. Dosage form having a diameter of more than 7.5 mm show better gastric residence time.(18)
Compared with one having 9.9mm.Garg and Sharma reported that tetrahedron-and ring-shaped. devices have better gastric residence time as compared with other shapes.
Density of Dosage Form:
A buoyant dosage form having a density of less than that of the gastric fluids floats (approximately less than 1). Since it is awayFrom the pyloric sphincter the dosage unit is retained in the stomach for prolonged time.
Different Techniques of Gastroretntion(19,20,21)
1 Floating Systems
2 Swelling & Expanding Systems
3 Bioadhesive Systems
4 High Density Systems
Approaches to Design Fdds:
1 Single –Unit Dosage Form
2 Multiple-Unit Dosage Form
1 Single-Unit Dosage Form:
The globular shells apparently having lower density than that of gastric fluid can be used as a carrier for drug for its controlled release.
In coated shells popcorn, poprice, and polystyrol have been exploited as drug carriers. Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to undercoat these shells. These are further coated with a drug-polymer mixture. The polymer of choice can be either ethylcellulose or hydroxypropyl cellulose depending on the type of release desired. Finally, the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.
Fluid-filled floating chamber type of dosage forms includes incorporation of a gas-filled floatation chamber into a microporous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. The other two walls in contact with the fluid are sealed so that the undissolved drug remains therein.(22)
Hydrodynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastro intestinal tract and aid in enhancing the absorption. Such systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine
Disadvantages of Single-Unit Dosage Form:
The single-unite dosage forms are sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation.
It also experiences “all or none” pattern.
Multiple-Unit Dosage Form:
The purpose of designing Multiple-unit dosage form may be to distribute uniformly the drug content within gastric content, gradually lasting effects & reduced variability in absorption with lower probability of dose dumping.
Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine, and polyalkylcyanoacrylate. Spherical polymeric microsponges, also referred to as “microballoons,” have been prepared. Microspheres have a characteristic internal hollow structure and show an excellent in vitro floatability. In Carbon dioxide–generating multiple-unit oral formulations several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described in the recent patent literature. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded.(23)
Floating Drug Delivery System:
Floating Drug Delivery System (FDDS) is one of the techniques of Gastroretention. The concept of FDDS was first described in the literature as early as 1968, when Davis disclosed a method for overcoming the difficulty experienced by some person of chocking while swallowing medicinal pills.
Floating Drug Delivery System offer numerous advantages over other gastric retention systems. These have a bulk density lower than gastric fluids & thus remain buoyant in stomach without affecting gastric emptying rate for prolonged period of time. While system is floating on gastric contents, drug is released slowly at desired rate from stomach.(24) (Fig. I)
Non-Effervecent Floating Dosage Form:
Non-effervescent FDDS are based on mechanisms of swelling of polymer or bioadhesion to mucosal layer in gastrointestinal tract.
The most commonly used excipients in these dosage forms are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonates, polyacrylate, polymethacrylate, such as chitosan and carbopol.
One of the approaches to formation of such floating dosage forms involves intimate mixing of drug with gel forming hydrocolloids, which swell in contact with gastric fluid after oral administration and maintain a relative integrity of shape and bulk density of less than unity within the outer gelatinous barrier.
The air trapped by swollen polymer confers buoyancy to these reservoirs for sustained drug release since through gelatinous barrier. In addition, the gel structure acts as the reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier.(25)
Limitations of Fdds:
1. One of the disadvantages of floating systems is that they require a sufficiently high level of fluids in the stomach for the drug delivery dosage form to float therein and to work efficiently.
2. Floating systems are not feasible for those drugs that have solubility or stability problem in gastric fluids and for drugs those are irritant to the gastric mucosa.
3. Gastric emptying of floating dosage forms in supine subjects may occur at becomes highly dependent on the diametric size. Therefore, patients cannot be dosed with floating dosage forms just before going to bed.(26)
Classification of Floating Drug Delivery System (FDDS)(1,10, 26,)
Based on mechanism of buoyancy, two distinctly different technologies has been utilized in the development of FDDS,
1 Effervescent Floating Dosage Form
2 Non-Effevescent Floating Dosage Forms
Effervescent Floating Dosage Forms:
These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, e.g., sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms.
Evaluation of Polymers(27)
The excipients used in FDDS are evaluated for their,
1. Floating characteristics (Resultant Weight Force i.e. FRW)
2. Swelling characteristics (Gravimetric method)
The test media used for evaluation of polymers are,
1. Deionised water (air free)
2. Simulated meal medium (S.M.M.)
Evaluation of Floating Dosage Form (10,27,34,43,44,89,134,135,136,137,138,139)
The evaluation of floating dosage forms is done in vivo and in vitro.
The various parameters that need to be evaluated include,
1. Floating Lag Time (FLT)
2. Total Floating Time (TFT)
3. Dissolution profiles
4. Specific gravity
5. Content uniformity
6. Hardness
7. Friability (in case of solid dosage forms)
Applications of Floatng 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 are summarized
as follows.
Sustained Drug Delivery System:
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 systems. 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.
Recently 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).
Similarly a comparative study between the Madopar HBS and Madopar standard formulation was done and it was shown that the drug was released up to 8 hours in vitro in the former case and the release was essentially complete in less than 30 minutes in the latter case.(28)
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, e.g., riboflavin and furosemide.
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.(29)
A bilayer-floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced.
Absoption 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.
A significant increase in the bioavailability 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%).
Miyazaki et al conducted pharmacokinetic studies on floating granules of indomethacin prepared with chitosan and compared the peak plasma concentration and AUC with the conventional commercially available capsules. It was concluded that the floating granules prepared with chitosan were superior in terms of decrease in peak plasma concentration and maintenance of drug in plasma.(30)
Ichikawa et al developed a multiparticulate system that consisted of floating pills of a drug (p- amino benzoic acid) having a limited absorption site in the gastrointestinal tract. It was found to have 1.61 times greater AUC than the control pills.
The absorption of bromocriptine is limited to 30% from the gastrointestinal tract, however an HBS of the same can enhance the absorption. It was also studied that if metoclopramide is co delivered with bromocriptine, the side effects associated with high doses of bromocriptine can be prevented and the dosage from becomes therapeutically more potential.
In few cases the bioavailability of floating dosage form is reduced in comparison to the conventional dosage form. In a recent study 3 formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The bioavailability of the two gastroretentive preparations with sustained release characteristics was significantly decreased when compared with the immediate-release tablet. This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations.(31)
CONCLUSION:
Oral ingestion is the most convenient and commonly used method of drug delivery. Patients best accept conventional dosage forms but there are some limitations of these dosage forms like frequent dosing, increase chances of missing dose of drug etc. So these limitations focused attention on controlled- and sustained release dosage forms.
Gastroretention is one of the techniques for sustained-release. In recent years scientific and technological advancement have been done in research and development of gastroretentive drug delivery system. The Floating Drug Delivery System (FDDS) is the best technique to achieve gastroretention. FDDS have low bulk density than gastric fluids and thus remain buoyant in stomach. A perfect system, which will be retained in the stomach for longer time, has not yet been developed but some formulations show more bioavailability than the existing. The FDDS are useful for drugs with slow and incomplete intestinal absorption. Although there are some difficulties in manufacturing of FDDS, large numbers of companies are focusing towards commercializing this technique.
ACKNOWLEDGEMENT:
Author are thankful to Gourishankar college of D pharma, Limb Satara for providing valuable help and authors are also Thankful Mr. Raje V.N, Principal, Gourishankar college of D pharma, Limb, Satara for providing necessary guidance for this work.
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Received on 25.10.2018 Modified on 18.11.2018
Accepted on 20.12.2018 © A&V Publications All right reserved
Asian J. Res. Pharm. Sci. 2019; 9(2):91-96.
DOI: 10.5958/2231-5659.2019.00014.6