Ms. Julan. U. Desai
But the issue of poor bioavailability (BA) of orally administered drugs is still a challenging one, though extensive advancements in drug discovery process are made 1
Conventional oral dosage forms provide a specific drug concentration in systemic circulation without offering any control over drug delivery. CRDFs or controlled release drug delivery systems (CRDDS) provide drug release at a predetermined, predictable and controlled rate. The de novo design of an oral controlled drug delivery system (DDS) should be primarily aimed at achieving more predictable and increased bioavailability (BA) of drugs.
A major constraint in oral CRDD is that not all drug candidates are absorbed uniformly throughout the gastrointestinal tract. Some drugs are absorbed uniformly throughout the gastrointestinal tract. Some drugs are absorbed in a particular portion of gastrointestinal tract only or are absorbed to a different extent in various segments of gastrointestinal tract. Such drugs are said to have an “ absorption window ”. Thus, only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. After crossing the absorption window, the released drug goes to waste with negligible or no absorption. This phenomenon drastically decreases the time available for drug absorption after it and limits the success of delivery system. These considerations have led to the development of oral CRDFs possessing gastric retention capabilities 2.
One of the most feasible approaches for achieving a prolonged and predictable drug delivery profiles in gastrointestinal tract is to control the gastric residence time(GRT) using gastroretentive dosage forms (GRDFs) that offer a new and better option for drug therapy.
Dosage forms that can be retained in stomach are called gastroretentive drug delivery systems ( GRDDS)3. GRDDS can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches its absorption site thus ensuring its optimal bioavailability.
The stomach is situated in the left upper part of the abdominal cavity immediately under the diaphragm. Its size varies according to the amount of distension: up to 1500 ml following a meal; after food has emptied, a collapsed state is obtained with resting volume of 25-50 ml. The stomach is anatomically divided into 3 parts, fundus, body and antrum (or pylorus). The proximal stomach, made up of fundus and body regions serves as a reservoir for ingested materials while the distal region (antrum) is the major site of mixing motions, acting as a pump to accomplish gastric emptying.
The process of gastric emptying occurs both during fasting and fed states, however the pattern of motility differs markedly in the two states. Two distinct patterns of gastrointestinal motility and secretion exist corresponding to the fasted and fed states. As a result the bioavailability of orally administered drugs will vary depending on the state of feeding.
In the fasted state, it is characterized by an interdigestive series of electrical event and cycle, both through the stomach and small intestine every 2-3 hrs. This activity is called the interdigestive myoelectric cycle or Migrating motor complex (MMC) is often divided into four consecutive phases: basal (Phase I) pre burst (Phase II), burst (Phase III), and Phase IV intervals.
PHASE I the quiescent period, lasts from 30 to 60 mins and is characterized by a lack of secretary, electrical and contractile activity. PHASE II , exhibits intermittent activity for 20-40 min, during which the contractile motions increase in frequency and size. Bile enters the duodenum during this phase, whereas gastric mucus discharge occurs during the latter part of phase II and throughout phase III. PHASE III is a short period of intense large regular contractions, termed “housekeeper waves” that sweep off undigested food and last 10-20 min. PHASE IV is the transition period of 0-5 mins between Phase III & I.
The motor activity in the fed state is induced 5-10 mins after ingestion of a meal and persists as long as food remains in the stomach. The larger the amount of food ingested, the longer the period of fed activity, with usual time spans of 2-6 h, and more typically, 3-4 h, with phasic contractions similar to Phase II of MMC 4 .
When CRDDS are administered in the fasted state, the MMC may be in any of its phases, which can significantly influence the total gastric residence time (GRT) and transit time in gastrointestinal tract.
This assumes even more significance for drugs that have an absorption window because it will affect the amount of time the dosage form spends in the region preceding and around the window. The less time spent in that region, the lower the degree of absorption. On the other hand, in the fed stomach the gastric retention time (GRT) of non disintegrating dosage forms depends mostly on their size and composition and caloric value of food.
From the discussion of the physiological factors in stomach, to achieve gastro retention, the dosage form must satisfy some requirements. One of the key issues is that the dosage form must be able to withstand the forces caused by peristaltic waves in the stomach and constant grinding and churning mechanisms. It must resist premature gastric emptying and once the purpose has been served, it should be removed from the stomach with ease 5 .
Over the last 3 decades, various approaches have been pursued to increase the retention of an oral dosage form in the stomach. These systems include: Bioadhesive systems, swelling and expanding systems, High density systems, Floating systems, Modified systems 1 .
The concept of FDDS was described in the literature as early as 1962. 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.
While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of fluctuations in plasma drug concentration 6 .
Fig 2: The mechanism of floating systems
Formulation of this device must comply with the following criteria:
1. It must have sufficient structure to form a cohesive gel barrier.
2. It must maintain an overall specific gravity lower than that of gastric contents (1.004 – 1.010).
3. It should dissolve slowly enough to serve as a drug reservoir.
A list of drugs used in the development of FDDS thus far is given in Table 1:
List of drugs explored for various floating dosage forms 6
Aspirin, Ibuprofen, Tranilast
Diclofenac sodium, Indomethacin, Prednisolone
Diazepam, Furosemide, L-Dopa and Benserazide
Tablets / pills
Amoxycillin Trihydrate, Ampicillin, Diltiazem, p -Aminobenzoic acid, Riboflavin-5’-phosphate, Theophylline, Verapamil HCl
Based on the mechanism of buoyancy, two distinctly different technologies, i.e. noneffervescent and effervescent systems, have been utilized in the development of FDDS.
The most commonly used in noneffervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides, and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene.
One of the approaches to the formulation of such floating dosage forms involves intimate mixing of drug with a gel forming hydrocolloid, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. In addition, the gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier.
Sheth and Tossounian 7 postulated that when such dosage forms come in contact with an aqueous medium, the hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then controls the rate of diffusion of solvent-in and drug-out of the dosage form. As the exterior surface of the dosage form goes into solution, the gel layer is maintained by the immediate adjacent hydrocolloid layer becoming hydrated. As a result, the drug dissolves in and diffuses out with the diffusing solvent, creating a ‘receding boundary’ within the gel structure.
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 to float on the chyme.
Stockwell et al 8 prepared floating capsules by filling with a mixture of sodium alginate and sodium bicarbonate. The systems were shown to float during in vitro tests as a result of the generation of CO 2 that was trapped in the hydrating gel network on exposure to an acidic environment.
The carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel. Moreover, the release of CO 2 helps to accelerate the hydration of the floating tablets, which is essential for the formation of a bioadhesive hydrogel. This provides an additional mechanism (‘bioadhesion’) for retaining the dosage form in the stomach, apart from floatation.
Floating dosage forms with an in situ gas generating mechanism are expected to have grater buoyancy and improved drug release characteristics. However, the optimization of the drug release may alter the buoyancy and, therefore, it is sometimes necessary to separate the control of buoyancy from that of drug release kinetics during formulation optimization.
Gerogiannis and co-workers 9 have described the floating and swelling characteristics of commonly used excipients. From the results of resultant-weight measurements of various excipients, these authors concluded that higher molecular weight polymers and slower rates of polymer hydration are usually associated with enhanced floating behavior. Hence, the selection of high molecular weight and less hydrophilic grades of polymers seems to improve floating characteristics.
The various parameters that need to be evaluated for their effects on GRT of buoyant formulations can mainly be categorized into following different classes:
Galenic parameters: Diametral size, flexibility and density of matrices.
Control parameters: Floating time, dissolution, specific gravity, content uniformity and hardness and friability (if tablets).
Geometrical parameters: Shape.
Physiological parameters: Age, sex, posture, food.
The test for buoyancy and in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37°C. In practice, floating time is determined by using the USP disintegration apparatus containing 900ml of 0.1N HCl as a testing medium maintained at 37°C. The time required to float the HBS dosage form is noted as floating or floatation time 1 .
Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically from the dissolution medium, replenished with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution.
The specific gravity of FDDS can be determined by the displacement method using analytical grade benzene as a displacing medium. The initial (dry state) bulk density of the dosage form and the changes in floating strength with time should be characterized prior to in vivo comparison between floating (F) and nonfloating (NF) units. Further, the optimization of floating formulations should be realized in terms of stability and durability of the floating forces produced, thereby avoiding variations in floating capability that might occur during in vivo studies.
Resultant weight test: An in vitro measuring apparatus has been conceived to determine the real floating capabilities of buoyant dosage forms as a function of time. It operates by measuring the force equivalent to the force F required to keep the object totally submerged in the fluid 10 .
This force determines the resultant weight of the object when immersed and may be used to quantify its floating or nonfloating capabilities. The magnitude and direction of the force and the resultant weight corresponds to the vectorial sum of buoyancy ( F bouy ) and gravity ( F grav ) forces acting on the object as shown in the equation
F = F buoy – F grav
F = d f gV – d s gV = (d f - d s ) gV
F = (df – M / V) gV
in which F is the total vertical force (resultant weight of the object), g is acceleration due to gravity, d f is the fluid density, d s is the object density, M is the object mass, and V is the volume of the object .By convention, a positive resultant weight signifies that the force F is exerted upward and that the object is able to float, whereas a negative resultant weight means that the force F acts downward and that the object sinks. (Figure 3) 1 .
Fig 3: Effect of resultant weight during buoyancy on the floating tendency of FDDS.
The crossing of the zero base line by the resultant weight curve from positive toward negative values indicates a transition of the dosage form from floating to nonfloating conditions. The intersection of lines on a time axis corresponds to the floating time of the dosage form.
The in vivo gastric retentivity of a floating dosage form is usually determined by gamma scintigraphy or roentgenography. Studies are done both under fasted and fed conditions using F and NF (control) dosage forms. It is also important that both dosage forms are non disintegrating units, and human subjects are young and healthy.
As mentioned earlier, drug absorption from oral controlled release (CR) dosage forms is often limited by the short GRT available for absorption.
However, HBS type dosage forms can retain in the stomach for several hours and therefore, significantly prolong the GRT of numerous drugs. .
These special dosage forms are light, relatively large in size, and do not easily pass through pylorus, which has an opening of approx. 0.1– 1.9 cms.
A floating dosage form is a feasible approach especially for drugs which have limited absorption sites in upper small intestine.
The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels 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.
The eradication of Helicobacter pylori requires the administration of various medicaments several times a day, which often results in poor patient compliance. More reliable therapy can be achieved by using GRDDS. Floating alginate beads have been used for the sustained release of Amoxycillin trihydrate. Thus, it can be expected that the topical delivery of antibiotic through a FDDS may result in complete removal of the organisms in the fundal area due to bactericidal drug levels being reached in this area, and might lead to better treatment of peptic ulcer.
As sustained release systems, floating dosage forms offer various potential advantages. Drugs that have poor bioavailability because their absorption is limited to upper GI tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavalabilities.
Floating dosage forms with SR characteristics can also be expected to reduce the variability in transit performance. In addition, it might provide a beneficial strategy for gastric and duodenal cancer treatment.
The concept of FDDS has also been utilized in the development of various anti- reflux formulations. Floating systems are particularly useful for acid soluble drugs, drugs poorly soluble or unstable in intestinal fluids, and those which may undergo abrupt changes in their pH dependent solubility due to food, age and disease states.
· They require a sufficiently high level of fluids in the stomach for the drug delivery buoyancy, to float therein and to work efficiently.
· Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluid.
· Drugs such as Nifedipine, which is well absorbed along the entire GI tract and which undergoes significant first- pass metabolism, may not be desirable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailability.
· Also there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.
Dosage forms with a prolonged GRT will bring about new and important therapeutic options. They will significantly extend the period of time over which drugs may be released and thus prolong dosing intervals and increase patient compliance beyond the compliance level of existing CRDFs. Many of the “Once-a-day” formulations will be replaced by products with release and absorption phases of approximately 24 hrs. Also, GRDFs will greatly improve the pharmacotherapy of the stomach itself through local drug release leading to high drug concentrations at gastric mucosa which are sustained over a large period. Finally, GRDFs will be used as carriers of drugs with the “absorption window”.
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Ms. Julan. U. Desai, Dr. Mrs. Jolly. R. Parikh, Rajesh.H.Parikh
Ms. Julan. U. Desai is currently working as a Lecturer, Department of Pharmaceutics, at Anand Pharmacy College, Anand, Gujarat, India. She completed her D.Pharm, B.Pharm and M.Pharm from A. R. College of Pharmacy, Vallabh Vidyanagar, Gujarat, India with top rank in all the three disciplines. She was ranked top in the B.Pharm Entrance Test (BET) all over Gujarat in 2001. Her area of interest in research includes the novel oral drug delivery systems.
Mailing address: Ms. Julan. U. Desai
102, Shri Ramvatika Aptt., B/h Raghuvir Chambers, Bakrol Road, Vallabh Vidyanagar, Gujarat - 388120.
E-mail ID : email@example.com
Dr Jolly R Parikh is currently working as Assistant Professor and Head, Department of Pharmaceutics & Pharmaceutical Technology, at the A R College of Pharmacy, Vallabh Vidyanagar, Gujarat; India. She is the Chairman Board of studies in Pharmaceutics & Pharmaceutical Technology at the Sardar Patel University, VallabhVidyanagar. She has about 20 years of teaching experience. She is currently guiding M.Pharm & PhD students in the research area of New Drug Delivery systems.
Rajesh.H.Parikh is currently working as Professor with the Department of Pharmaceutics & Pharmaceutical Technology of Ramanbhai Patel College of Pharmacy, Education Campus, Changa-388 421, Gujarat, India. He is also providing his services as a Principal of the college. He earned his B.Pharm and M.Pharm from The M.S.University of Baroda and PhD from the Gujarat University. His research area of interest includes fast dissolving oral dosage forms and particle engineering for pharmaceutical applications