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*P.Dhaneshwar1, P.Stephen2, A.N.RAJALAKSHMI1
1* Department of Pharmaceutics,
College of pharmacy,
Mother Theresa Post Graduate & Research Institute Of Health Sciences, Puducherry, India
2 Sai mirra innopharm pvt ltd,
Ambattur, Chennai, India

Drug absorption in the gastrointestinal tract is a highly variable process and prolonging gastric retention of the dosage form extends the time for drug absorption. Novel drug delivery system overcomes the physiological problems of short gastric retention through various approaches including floating drug delivery systems (FDDS), these systems float due to bulk density less than gastric fluids and so, remain buoyant in the stomach for a prolonged period of time, releases the drug slowly at the desired rate from the system and increase the bioavailability of narrow absorption window drugs. This review entitles the applications of sustained release effervescent floating bilayer tablets, suitable for sustained release of those drugs incompatible with floating constituents over an extended period of time for better patient compliance and acceptability. The purpose of this paper is to review the principle of sustained release effervescent floating drug delivery system, current technology used in the development of same as well as summarizes the applications, advantages, methodology, evaluation methods and future potential for sustained release effervescent floating bilayer tablets


PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 5, Issue 8

Received On: 04/04/2017; Accepted On: 24/04/2017; Published On: 01/08/2017

How to cite this article: Dhaneshwar P, Stephen P, Rajalakshmi AN;Sustained release effervescent floating bilayer tablets - A review of Novel Approach; PharmaTutor; 2017; 5(8);32-40

Oral route  is  the  most  convenient  and  preferred  means  of  drug  delivery  to  the systemic  circulation  due  to its ease of administration, patient compliance, least sterility constraints and flexible design of dosage forms. However, the development process is presented with several physiologic difficulties, such as an inability to restrain and localize the drug delivery system within desired regions of the gastrointestinal tract (GIT), an unpredictable gastric emptying rate that varies from person  to  person,  a brief  gastrointestinal  transit time  and  the  existence  of  an absorption window in the upper small intestine for several drugs.

Depending upon the physiological state of the subject and the design of the pharmaceutical formulation, the emptying process can last from a few minutes up to12 hr. This variability, in turn, may lead to unpredictable bioavailability and times to achieve peak plasma levels, since the majority of drugs are preferentially absorbed in the upper part of the small intestine. The relatively brief gastric emptying time (GET) in humans, which normally averages 2 to 3 hr through the major absorption zone (stomach or upper part of the intestine), can result in incomplete drug release from the drug delivery system (DDS) leading to diminished efficacy of the administered dose.

In addition, some drugs display region specific absorption which is related to differential drug solubility and stability in different regions of GIT, as a result of changes in environmental pH, degradation by enzymes present in the lumen of the intestine or interaction with endogenous components such as bile. Active transport mechanisms for drugs involving carriers and pump systems have been also well described. These drugs show absorption window, which signifies the region of GIT where absorption primarily occurs.
Drugs released from sustained/controlled release systems, after absorption window has been crossed, go waste with negligible absorption which indicates that absorption window can limit the bioavailability of orally administered compounds and can be a major obstacle to the development of sustained/controlled release drugs. Therefore, it would be beneficial to develop sustained release formulations which remain at the absorption site for an extended period of time.

One of the feasible approaches for achieving prolonged and predictable drug delivery profile in GIT is to control gastric retention time (GRT) of the formulation. Dosage forms with prolonged GRT, i.e., Gastro Retentive Dosage Forms (GRDFs), will overcome the problems of simple sustained release dosage forms.


Gastro Retentive Dosage Forms (GRDFs)
GRDFs are dosage forms which prolong the retention time of a drug in the GIT, thereby improving the oral bioavailability of the drug.  
Over the past three decades, the pursuit and exploration of devices designed to be retained in the upper part of the gastrointestinal  (GI) tract has advanced  consistently  in terms of technology and  diversity, encompassing a variety of systems and devices such as floating  systems,  raft  systems,  expanding systems,  swelling  systems, bioadhesive systems and low-density  systems.

Gastric retention will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.  Also longer residence time in the stomach could be advantageous for local action in the upper part of the small intestine, for example treatment of peptic ulcer disease. Furthermore, improved bioavailability is expected for drugs that are absorbed readily upon release in the GI tract. These drugs can be delivered ideally by slow release from the stomach.

Many drugs  categorized  as once-a-day  delivery  have  been  demonstrated  to have  suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended  release  development  challenging. Therefore, a system designed for longer gastric retention will extend the time within high drug absorption can occur in the small intestine. Certain types of drugs can benefit from using gastric retentive devices. These include:

Drugs acting locally in the stomach: Drugs that are primarily absorbed in the stomach: Drugs those are poorly soluble at an alkaline pH: Drugs with a narrow window of absorption: Drugs absorbed rapidly from the GI tract and Drugs that degrade in the colon.

Basic physiology of the gastrointestinal tract
Anatomically the stomach is divided into three regions: fundus, body, and antrum (pylorus).The  proximal  part  made  up  of  fundus  and  body  acts  as  a  reservoir  for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions [Desai S, 1984].

Gastric emptying occurs  during  fasting  as  well  as  fed  states. The pattern of motility is however  distinct in the two states. During the fasting state an interdigestive series of electrical  events take place,  which  cycle both through  stomach  and intestine  every  2  to  3  hours  [Vantrappen GR  et  al,  1979]. This  is  called  the  interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases [Wilson CG et al, 1989].

A. Phase I (basal phase) lasts from 40 to 60 min with rare contractions

B. 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.

C. 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.

D. Phase  IV  lasts for  0  to  5  minutes  and  occurs  between  phases  III  and  I  of 2 consecutive cycles.
After 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 continuous contractions as in phase II of fasted state.  These contractions result 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 delayed resulting in slowdown of gastric emptying rate (Bolton S et al, 1989).

Under physiological condition, the gastric absorption of most drugs is insignificant as a result of its limited surface area (0.1 - 0.2 m2) covered by a thick layer of mucous coating, the lack of villi on the mucosal surface, and the short residence time of most drug in the stomach. Rapid gastric emptying, also called dumping syndrome, occurs when undigested food empties too quickly into the small intestine. Stomach emptying is a coordinated function by intense peristaltic contractions in the antrum.

At the same time, the emptying is opposed by varying degrees of resistance to passage of chyme at the pylorus. The rate depends on pressure generated by antrum against pylorus resistance.

Factors affecting gastric retention
1. Density
The density of a dosage form also affects the gastric emptying  rate. A buoyant dosage form having a density of less than that of the gastric fluids (1.004 gm/ml) floats.
2. Size and shape
To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm (Wilson CG and Washington N, 1989). Dosage form unit with a diameter of more than 7.5 mm are reported to have an increased GRT compared to those with a diameter  of 9.9 mm. The dosage  form with a shape tetrahedron  and ring shape devices with a flexural modulus of 48 and 22.5 kilopond per square inch (KSI) are reported to have better GIT (90 to 100 %) retention at 24 hours compared  with other shapes.
3. Fasting or fed state
Under fasting conditions, the GI motility is characterized  by periods  of strong motor activity or the Migrating Myoelectric Cycles (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 (Talukder R et al, 2004).
The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn’t get time  to produce sufficient  acid  when  the liquid  empties  the stomach;  hence  generally basic drugs have a better chance of dissolving in fed state than in a fasting state.
Studies have  revealed  that  gastric  emptying  of  a  dosage  form  in  the  fed  state  can  also  be influenced  by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves.
4. Nature of the meal
The rate of gastric emptying depends  mainly  on viscosity,  volume,  and caloric content  of  meals. Nutritive  density of  meals  helps  determine  gastric  emptying  time. However, increase  in  acidity  and  caloric value slows  down  gastric  emptying  time. 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 (Xu WL et al; 1991).
5. Effect of liquid, digestible solid and indigestible solid type food
It has been demonstrated using radio labeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (>1 mm) indigestible objects from stomach was dependent   upon interdigestive   migrating myoelectric cycle. When liquid   and digestible solids are present in the stomach, it contracts ~3 to 4 times per minute leading to the movement of the contents through partially opened pylorus. Indigestible  solids larger  than  the  pyloric  opening  are propelled  back  and several  phases  of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible  solids. Studies  have  shown  that the gastric residence time (GRT) can be significantly increased under the fed conditions since the MMC is delayed.
6. Biological factors
Biological factors such  as age,  body  mass  index  (BMI),  gender, posture and diseased  states  (Diabetes,  Chron’s  disease)  influence  gastric  emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. GRT can very between supine and upright ambulatory states of the patients [Mojaverian P et al; 1998]. Stress increases gastric emptying rates while depression slows it down.
7. Frequency of feed
The  gastro  retentive  time  can  increase  by  over  400  minutes  when  successive meals are given compared  with a single meal due to the low frequency  of MMC [Jain NK, 2004].
8. Gender
Mean ambulatory GRT in meals (3.4 hours) is less compared with their age and race-matched female counterparts (4.6 hours), regardless of the weight, height and body surface.
9. Volume of liquids
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 faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids.
10. Effect of size of floating and non floating dosage
The  effect  of size  of floating  and non  floating  dosage  forms  were  studied  on gastric emptying and concluded that the floating units remained buoyant on gastric fluids. These are less likely to be expelled  from the stomach  compared  with the non floating units,  which  lie  in  the  antrum  region  and  are  propelled   by  the  peristaltic   waves. (Timmermans J and Andre JM, 1994)

Gastric emptying and problems
Major adversity encountered through the oral route is the first pass effect, which leads to reduce systematic availability of a large number of a drug. These problems  can  be  exacerbated  by alteration  in  the  gastric  emptying  that  occur  due to factors such as age, race, sex and disease states, as they may seriously affect the release of a drug from DDS. It is therefore desirable to have a Controlled release product that exhibits  an  extended,  GI  residence  and  a  drug  release  profile  independent  of patient related variables.

Requirement of Gastric retention
From the discussion of the physiological factors in the stomach, it must be noted that, to achieve gastric retention, the dosage form must satisfy certain 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 the constant contractions and grinding and churning mechanisms. To function as a gastric retention device, it must resist premature gastric emptying. Furthermore, once its purpose has been served, the device should be removed from the stomach with eases.

Drug candidates for gastric retention
Various drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous and controlled manner.
Potential drug candidates for gastroretentive drug delivery systems include: drugs that are locally active in the stomach (e.g. misoprostol, antacids etc.); drugs that have narrow absorption window in gastrointestinal tract (e.g. L-DOPA, Para-aminobenzoic acid, Furosemide, Riboflavin, Salbutamol [Swarbrick, 2007; Shinde et al, 2010]); drugs that are unstable in the intestinal or colonic environment (e.g. captopril, ranitidine HCl, metronidazole.); drugs that disturb normal colonic microbes (e.g. antibiotics against Helicobacter pylori) and drugs that exhibit low solubility at high pH values (e.g. diazepam, chlordiazepoxide, verapamil HCl).

Approaches for gastric retention
Hydro dynamically balanced systems (HBS) –incorporated buoyant materials enable the device to float. Raft systems incorporate alginate gels – these have a carbonate component and, upon reaction with gastric acid, bubbles  form in the gel, enabling  floating [Whitehead  L et al, 1996; Iannuccelli V et al; 1998].

Swelling type of dosage  form is such that after swelling,  this product  swells to extent  that prevents  their exit  from the stomach through  the pylorus. As a result,  the dosage form retained in the stomach for a longer period of time. These systems may be referred to as a “Plug type system”, since they exhibit tendency to remain logged in the pyloric sphincters (Bolton S et al, 1989).

Bioadhesive  or  mucoadhesive  systems  are  used  to  localize  a  delivery  device within the lumen and cavity of the body to enhance the drug absorption process in a site - specific  manner.  The approaches  involve  the use of bioadhesive  polymers  that  can be adhered to the epithelial surface of the GIT. The proposed mechanisms of bioadhesive are the  formation  of hydrogen  and  electrostatic  bonding  at  the  mucus  polymer  boundary [Jimenez-Castellanos NR et al, 1993].

Modified shape systems are  non-disintegrating  geometric  shapes  molded  from silastic elastomer or extruded from polyethylene blends and extended the GET depending on the size, shape and flexural modulus of the drug delivery device.

High-density formulations include coated pallets, and have density greater than that of the stomach content (1.004 gm/cm3). This is accomplishing  by coating the drug with a heavy  inert  material  such  as  barium  sulphate,  ZnO,  titanium  dioxide.  This formulation of high-density pellet is based on assumption that heavy pellets might remain longer in the stomach, since they are position in the lower part of the antrum [Talukder R et al, 200]).

Another delayed gastric emptying approach of interest include sham feeding of digestible polymers or fatty acid salts that charges the motility pattern, of the stomach to a fed stage thereby decreasing the gastric emptying rate and permitting considerable prolongation of the drug release.



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