Introduction:
Historically, oral drug administration has been the predominant route for drug delivery. During the past two decades, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate. From a pharmacokinetic point of view, the ideal sustained and controlled release dosage form should be comparable with an intravenous infusion, which supplies continuously the amount of drug needed to maintain constant plasma levels once the steady state is reached.
Although some important applications, including oral administration of peptide and protein drugs, can be used to prepare colonic drug delivery systems, targeting drugs to the colon by the oral route. More often, drug absorption is unsatisfactory and highly variable among and between individuals, despite excellent in vitro release patterns. The reasons for this are essentially physiological and usually affected by the GI transit of the form, especially its gastric residence time (GRT), which appears to be one of the major causes of the overall transit time variability.
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 which drug absorption can occur in the small intestine.
Certain types of drugs can benefit from using gastric retentive devices. These include:
Acting locally in the stomach.
Primarily absorbed in the stomach.
Poorly soluble at an alkaline pH.
Narrow window of absorption.
Absorbed rapidly from the GI tract.
Degrade in the colon.
Gastro retentive Drug Delivery System:
Since the last three decades many drug molecules formulated as Gastro retentive Drug Delivery System (GRDDS) have been patented keeping in view its commercial success. Oral controlled release (CR) dosage forms (DF) have been extensively used to improve therapy of many important medications. The bioavailability of drugs with an absorption window in the upper small intestine is generally limited -with conventional pharmaceutical dosage forms. The residence time of such systems and, thus, of their drug release into the stomach and upper intestine is often short. To overcome this restriction and to increase the bioavailability of these drugs, controlled drug delivery systems, with a prolonged residence time in the stomach, can be used. Incorporation of the drug into a CR-delivery system, which releases its payload in the stomach over a prolonged time period, can lead to significant therapeutic advantages owing to various pharmacokinetic (PK) and pharma co-dynamic aspects.
Gastro retentive dosage forms (GRDFs) are designed to be retained in the stomach for a prolonged time and release their active ingredients and thereby enable sustained and prolonged input of the drug to the upper part of the gastrointestinal (GI) tract. Dosage forms that can be retained in the stomach are called gastro retentive drug delivery systems (GRDDS) . 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. This technology has generated enormous attention over the last few decades owing to its potential application to improve the oral delivery of some important drugs for which prolonged retention in the upper GI tract can greatly improve their oral bio availability and/or their therapeutic outcome.
A major constraint in oral controlled drug delivery is that not all drug candidates are absorbed uniformly throughout the GIT. Some drugs are absorbed in a particular portion of the GIT only or are absorbed to a different extent in various segments of the GIT. Such drugs are said to have an absorption window, which identifies the drug’s primary region of absorption in the GIT. Conventional oral dosage forms provide a specific drug concentration in systemic circulation without offering any control over drug delivery. Whereas Controlled-release drug delivery systems (CRDDS) provide drug release at a predetermined, predictable, and controlled rate. A drug must be in a solubilized and stable form to successfully cross the biological membrane, and it will experience a pH range from 1 to 8 as it travels through the GIT.
Drugs having site-specific absorption are difficult to design as oral CRDDS because 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 (see Figure 1.2 ). This phenomenon drastically decreases the time available for drug absorption after its release and jeopardizes the success of the delivery system.
Figure 2: Drug Absorption in case of (a) conventional dosage form and (b) gastro retentive drug delivery system.
Physiological Consideration and Gastrointestinal motility patterns affecting dosage form retention:
An important requisite for the successful performance of oral CRDDS is that the drug should have good absorption throughout the gastrointestinal tract (GIT), preferably by passive diffusion, to ensure continuous absorption of the released drug. The average time required for a dosage unit to traverse the GIT is 3-4 h, although slight variations exist among various dosage forms (see Table 1.2.1).
Table-3: Transit trios of various dosage form across the different segment of the GIT.
| Dosage formTable ‘ | Transit time (h) | ||
| Stomach2.7 ± 1,5 | Small intestine3,1 =0.4 | Total5.8 | |
| Peliats | 1.2 ±1,3 | 3.4 ±1,0 | 4.6 |
| Capsules Solution | 0,8 ±1,2 0.3 ± 0,07 | 3,2 ±0,84.1 ±0.5 | 4.0 4.4 |
The complex anatomy and physiology of the GIT, including variations in acidity, bile salts, enzyme content, and the mucosal absorptive surface, significantly influence the release, dissolution, and absorption of orally administered dosage forms. Table II lists the anatomical and physiological features of the GIT.
The intrinsic properties of the drug molecule and the target environment for delivery are the major determining factors in bioavailability of the drug. Factors such as pH, enzymes, nature and volume of secretions, residence time, and effective absorbing surface area of the site of delivery play an important role in drug liberation and absorption, high stomach there are several types of cells that secrete up to 2-3 liters of gastric juice daily. For example, goblet cells secrete mucus, parietal cells secrete hydrochlororic acid, and chief cells secrete pepsinogen. The contraction forces of the stomach churn the chyme and mix it thoroughly with the gastric juice. The average length of the stomach is about 0.2 meter, and the apparent absorbing surface area is about 0.1 m2 (Table 1.2.2)(5). The stomach, the main digestive organ of the body, contains many digestive enzymes and very low pH. The pH of the stomach has been measured from, 1.4 to 2.1.This harsh environment causes the destruction and denaturation of proteins without protection. The pH of the stomach changes when food is present increasing to nearly 4.0.
Physiology of the Stomach:
The Gastrointestinal tract is essentially a tube about nine meters long that runs through the middle of the body from the mouth to the anus and includes the throat (pharynx), esophagus, stomach, small intestine (consisting of the duodenum, jejunum and ileum) and large intestine (consisting of the cecum, appendix, colon and rectum). The wall of the gastrointestinal tract has the same general structure throughout most of its length from the esophagus to the anus, with some local variations for each region. The stomach is an organ with a capacity for storage and mixing. The anteroom region is responsible for the mixing and grinding of gastric contents.
Under fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50ml and contains a small amount of gastric fluid (pH 1–3) and air. The mucus spreads and covers the mucosal surface of the stomach as well as the rest of the GI tract. The GI tract is in a state of continuous motility consisting of two modes, interdigestive motility pattern and digestive motility pattern. The former is dominant in the fasted state with a primary function of cleaning up the residual content of the upper GI tract. The interdigestive motility pattern is commonly called the ‘migrating motor complex’ (‘MMC’) and is organized in cycles of activity and quiescence.
Each cycle lasts 90–120 minutes and consists of four phases. The concentration of the hormone motilin in the blood controls the duration of the phases. In the interdigestive or fasted state, an MMC wave migrates from the stomach down the GI tract every 90–120 minutes. A full cycle consists of four phases, beginning in the lower esophageal sphincter/ gastric pacemaker, propagating over the whole stomach, the duodenum and jejunum, and finishing at the ileum. Phase III is termed the ‘housekeeper wave’ as the powerful contractions in this phase tend to empty the Stomach of its fasting contents and indigestible debris. The administration and subsequent ingestion of food rapidly interrupts the MMC cycle, and the digestive phase is allowed to take place. The upper part of the stomach stores the ingested food initially, where it is compressed gradually by the physic contractions.
The digestive or fed state is observed in response to meal ingestion. It resembles the fasting Phase II and is not cyclical, but continuous, provided that the food remains in the stomach. Large objects are retained by the stomach during the fed pattern but are allowed to pass during Phase III of the interdigestive MMC. It is thought that the sieving efficiency (i.e. the ability of the stomach to grind the food into smaller size) of the stomach is enhanced by the fed pattern or by the presence of food.
The fasted-state emptying pattern is independent of the presence of any indigestible solids in the stomach. Patterns of contractions in the stomach occur such that solid food is reduced to particles of less than 1mm diameter that are emptied through the pylorus as a suspension. The duration of the contractions is dependent on the physiochemical characteristics of the ingested meal.
Generally, a meal of 450kcal will interrupt the fasted state motility for about three to four hours. It is reported that the antral contractions reduce the size of food particles to ?1mm and propel the food through the pylorus. However, it has been shown that ingestible solids ?7mm can empty from the fed stomach in humans.
Recent Trends: Gastro Retentive Drug Delivery
Size-increasing drug delivery system
Systems unfolding in the stomach: Gastric retention of a highly swellable, gastro retentive drug delivery system
Systems unfolding in the stomach:
Tetrahedron-shaped drug delivery system formed by assembling two components: silastic corners and erodible arms.
A) The device significantly swells on contact with gastric fluids (to a few hundred times of the original volume); B – D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contraction slips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach.
Density controlled drug delivery system Floating system
Inherent low density
Low density due to swelling
Low density due to gas formation and entrapment
ELEMENTARY OSMOTIC PUMP
Single layer tablet: Drug core (water soluble drug with or without excipients)
Semi permeable membrane with a drilled orifice
Water imbibitions by the core because of osmotic action results in drug dissolution, which is released at a controlled rate through the orifice
Not suitable for water insoluble drugs
Examples: Sudafed 24 hours (Pseudoephedrine); Volmax (Salbutamol)
Available marketed products
Alpress™ LP (prazosin)
Cardura® XL (doxazosin mesylate)
Concerta® (methylphenidate HCl) CII
Covera-HS®(verapamil)
Ditropan XL® (oxybutynin chloride)
DynaCirc CR® (isradipine)
Efidac 24® (chlorpheniramine)
Glucotrol XL® (glipizide)
Sudafed® 24 Hour (pseudoephedrine)
Procardia XL® (nifedipine)
Volmax® (albuterol)
Extended release formulation of Methylphenidate
Indicated for the treatment of attention Deficit Hyperactivity Disorder (ADHD)
Immediate-release overcoat provides a rapid onset of action (1-2 hours).
Controlled release of methylphenidate in the morning hours helps avoid the troughs seen with immediate-release products.
Higher concentration of methylphenidate released in the early afternoon provides
A smooth effect through the early evening hours.
Extended release formulation of Methylphenidate
Challenges in Oral Drug Delivery
Oral: easily administered formulations
Stomach: gastric retention platforms
Intestine: formulations for improved absorption of poorly soluble drugs and high molecular weight drugs
Colon: colon targeted drug delivery systems
Challenges in Oral Drug Delivery
Oral: easily administered formulations
One-third of the population has pill swallowing difficulties.
Orally disintegrating tablets provides a suitable solution.
Bio-adhesive Buccal Tablets for avoiding FPM
In-situ gelling formulation for dental therapy
Stomach: gastric retention platforms
Many drugs get absorbed only in upper small intestine.
Designing such molecules as once-daily formulations are elusive for these molecules. Thus GI retention platforms had emerged.
One of the major challenges in developing gastric retention device is overcoming the house keeping waves particularly in the fasted state.
Approaches for making gastric retention platforms
Low density microspheres with bioadhesive coats
Moderately swelling matrix systems
Bioadhesives
Super swelling hydrogel systems
Intestine: formulations for improved absorption of poorly soluble drugs and high molecular weight drugs
Lack of sufficient solubility pose as major problem in oral drug delivery
The other problem is delivering protein peptides due to their instability in GI environment
Technologies for improving drug solubility
Solid dispersions
Nanocrystals and nanoparticles
Polymeric micelles
Self emulsifying systems
Colon: colon targeted drug delivery systems
Promising delivery of acid and enzymes labile substances thorough colon made this delivery route popular
Further local delivery to colon in certain disease state is essential
Technologies for improving drug solubility
Modified enteric coating
Biodegradable swellable polymers
PH-controlled systems
Time delayed systems
WINDOW OF ABSORPTION
SPATIAL GI PHYSIOLOGY
DELIVERY
ORAL DELIVERY OF MACROMOLECULES
COST
LOW PERMEABILITY DRUGS (BCS III / IV)
ORAL MACROMOLECULAR DELIVERY
Eligen Technology (Emisphere technologies Ltd.)
CLEC Crosslinked Enzyme Crystals (Altus Pharmaceuticals)
Hydroance (Lipocene Inc.) [Lipid based formulations]
Oral Insulin Developments
Salient Features of Upper Gastrointestinal Tract: Table No.1
| Section | Length (m) | Transit time (h) | pH | Microbial count | Absorbing surface area (m2) | Absorption pathway |
| Stomach | 0.2 | Variable | 1-4 | <103 | 0.1 | P, C, A |
| Small Intestine | 6-10 | 3 ± 1 | 5-7.5 | 103 – 1010 | 120-200 | P, C, A, F, I, E, CM |
P – Passive diffusion C – Aqueous channel transport
A – Active transport F – Facilitated transport
I – Ion-pair transport E – Entero-or pinocytosis
CM – Carrier mediated transport
Different Features of Stomach
Gastric pH: Fasted healthy subject 1.1 ± 0.15
Fed healthy subject 3.6 ± 0.4
Volume : Resting volume is about 25-50 ml
Gastric secretion: Acid, pepsin, gastrin, mucus and some enzymes about 60 ml with approximately 4 mmol of hydrogen ions per hour.
Effect of food on Gastric secretion: About 3 liters of secretions are added to the food. Gastro intestinal transit time Figure No.1
Requirements for Gastric Retention:
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 ease.
Need For Gastro Retention:
Drugs that are absorbed from the proximal part of the gastrointestinal tract (GIT).
Drugs that are less soluble or are degraded by the alkaline pH they encounters at the lower part of GIT.
Drugs that are absorbed due to variable gastric emptying time.
Local or sustained drug delivery to the stomach and proximal Small intestine to treat certain conditions.
Particularly useful for the treatment of peptic ulcers caused by H. Pylori Infections.
Advantages of Gastro retentive Delivery Systems:
Improvement of bioavailability and therapeutic efficacy of the drugs and possible reduction of dose e.g. Furosemide
Maintenance of constant therapeutic levels over a prolonged period and thus reduction in fluctuation in therapeutic levels minimizing the risk of resistance especially in case of antibiotics. e.g. b-lactam antibiotics (penicillin’s and cephalosporin’s)
Retention of drug delivery systems in the stomach prolongs overall.
Gastrointestinal transit time thereby increasing bioavailability of sustained release delivery systems intended for once-a-day administration. E.g. Ofloxacin
Enhanced bioavai liability and enhanced first-pass biotransformation.
Sustained drug delivery/reduced frequency of dosing.
Targeted therapy for local ailments in the upper GIT.
Reduced fluctuations of drug.
Extended time over critical (effective) concentration.
Site specific drug delivery.
Limitations of the Techniques of Gastro retention:
More predictable and reproducible floating properties should be achieved in all the extreme gastric conditions.
The floating systems in patients with achlorhydria can be questionable in case of swellable systems, faster swelling properties are required and complete swelling of the system should be achieved well before the gastric emptying time.
Bioadhesion in the acidic environment and high turnover of mucus may raise questions about the effectiveness of this technique. Similarly retention of high density systems in the antrum part under the migrating waves of the stomach is questionable.
Not suitable for drugs that may cause gastric lesions e.g. Non- steroidal anti inflammatory drugs. Drugs that are unstable in the strong acidic environment, these systems do not offer significant advantages over the conventional dosage forms for drugs that are absorbed throughout the gastrointestinal tract.
The mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.
In all the above systems the physical integrity of the system is very important and primary requirement for the success of these systems.
Factors Affecting Gastric Retention:
Density: GRT is a function of dosage form buoyancy that is dependent on the density.
Size: Dosage form units with a diameter of more than 7.5mm are reported to have an increased GRT compared with those with a diameter of 9.9mm.
Shape of dosage form: Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes.
Single or multiple unit formulation: Multiple unit formulations show a more Predictable release profile and insignificant impairing of performance due to failure of units, allow co- administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.
Fed or unfed state: under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (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.
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 astric emptying rate and prolonging drug release.
Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats.
Frequency of feed: the GRT can increase by over 400 minutes, when successive meals are given compared with a single meal due to the low frequency of MMC.
Gender: Mean ambulatory GRT in males (3.4±0.6 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.
Age: Elderly people, especially those over 70, have a significantly longer GRT.
Posture: GRT can vary between supine and upright ambulatory states of the patient.
Concomitant drug administration: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride.
Biological factors: Diabetes and Crohn’s disease.
Suitable drug candidates for Gastro retention:
In general, appropriate candidates for CRGRDF are molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of
Narrow absorption window in GI tract e.g., riboflavin and levodopa.
Primarily absorbed from stomach and upper part of GI tract, e.g., calcium supplements, chlordiazepoxide and cinnarazine.
Drugs that act locally in the stomach, e.g., antacids and misoprostol.
Drugs that degrade in the colon, e.g., ranitidine HC1 and metronidazole.
Drugs that disturb normal colonic bacteria, e.g., amoxicillin trihydrate.
Type of Gastro retentive Techniques:
Various drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have a lower level of side effects and provide their therapeutic effects without the need for repeated dosages or with a low dosage frequency. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited.
In the exploration of oral controlled release drug administration, one encounters three areas of potential challenge.
Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment.
Modulation of gastro intestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for prolonged period of time to maximize the delivery of a drug dose.
Minimization of hepatic first pass elimination: If the drug to be delivered is subjected to extensive hepatic first pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.
Several techniques, including floating, swelling, inflation, and adhesion have been explored to increase the gastro retention of dosage forms {see Figure lb).
Bio/Mucoadhesive System
Floating Drug Delivery System
Swelling System
Expandable System
High-density System.
Figure 5: Classification Gastro retentive drug delivery system.
Different Techniques of Gastric Retention:
Various techniques were used to encourage gastric retention of an oral dosage form. Floating systems have low bulk density, so that they can float on the gastric juice in the stomach.2–4 the problem arises when the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to float on. Different techniques used for gastric retention mentioned below: See figure No.2
Hydrodynamically balanced systems (HBS)
Effervescent systems
Low-density systems
Raft systems incorporate alginate gels
Bioadhesive or mucoadhesive systems
Bio/Mucoadhesive Drug Delivery System:
Definition:
Bioadhesion is an interfacial phenomenon in which two materials, at least one of which is biological are held together by means of interfacial forces, when the associated biological system is mucous, it is called mucoadhesion. Mucoadhesive drug delivery system prolong the residence time of the dosage form at the site of application or absorption and facilitate an intimate contact of the dosage form with the underline absorption surface and thus contribute to improved and or better therapeutic performance of the drug.
The mucosal layer lines a number of regions of the gastrointestinal (GI) tract, the airways, the ear, nose, and the eye. These represent potential site for attachment of any bioadhesive system, and hence, .the mucoadhesive drug delivery system includes the following:
Buccal delivery system
Oral delivery system
Vaginal delivery system
Rectal delivery system
Nasal delivery system
Ocular delivery system
Mucoadhesives are the swellable or non-swellable, synthetic or natural polymers that interact with the mucosal layer covering the mucosal epithelial surface and mucin that prolong the residence time of dosage form at the site of absorption or application and facilitate the intimate contact of dosage form with the underlying absorption surface. Mucoadhesive polymers are used in the design of oral sustained release tablets in order to prolong the residence time in the GI tract and their duration of drug action.
Floating Drug Delivery:
The floating sustained release dosage forms present most of the characteristics of hydrophilic matrices and are known as ‘hydrodynamically balanced systems’ (‘HBS’) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gelled barrier at the outer surface. The drug is released progressively from the swollen matrix, as in the case of conventional hydrophilic matrices. These forms are expected to remain buoyant (3- 4 hours) on the gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric contents. Many results have demonstrated the validity of the concept of buoyancy in terms of prolonged GRT of the floating forms, improved bioavailability of drugs and improved clinical situations. These results also demonstrate that the presence of gastric content is needed to allow the proper achievement of the buoyancy retention principle. Among the different hydrocolloids recommended for floating form formulations, cellulose ether polymers are most popular, especially hydroxypropyl methylcellulose’s. Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy.
Parallel to formulation studies, investigations have been undertaken in animals and humans to evaluate the intragastric retention performances of floating forms. These assessments were realized either indirectly through pharmacokinetic studies with a drug tracer, or directly by means of X-ray and gamma scintigraphic monitoring of the form transit in the GI tract. When a floating capsule is administered to the subjects with a fat and protein meal, it can be observed that it remains buoyant at the surface of the gastric content in the upper part of the stomach and moves down progressively while the meal empties. The reported gastric retention times range from 4 to 10 hours. Pharmacokinetic and bioavailability evaluation studies confirm the favourable incidence of this prolonged gastric residence time.15
Gas-Generating Systems:
These buoyant systems utilized matrices prepared with swellable polymers like methodical, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethyl cellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach.
Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropy methylcellulose (HPMC) and floating systems based on ion exchange resin technology, etc.
Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol®, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates. Table No.2 & Table No.3
Drugs Reported To Be Used In the Formulation Of Floating Dosage Forms: Table No.2
| Sr.No. | Dosage forms | Drugs |
| 1. | Floating microspheres | Aspirin, Griseofulvin, p-nitroaniline, Ibuprofen, Terfinadine and Tranilast |
| 2. | Floating granules | Diclofenac sodium, Indomethacin and Prednisolone |
| 3. | Films | Cinnarizine |
| 4. | Floating Capsules | Chlordiazepoxide hydrogen chloride, Diazepam, Furosemide, Misoprostol, L-Dopa, Benserazide, Ursodeoxycholic acid and Pepstatin |
| 5. | Floating tablets and Pills | Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxycillin trihydrate, Atenolol, Diltiazem, Fluorouracil, Isosorbide mononitrate, Para- aminobenzoic acid, Piretamide, Theophylline and Verapamil hydrochloride |
Marketed preparation: Table No.3
| Sr.No. | Drug | Brand name |
| 1. | Diazepam Floating capsule | Valrelease® |
| 2. | Benserazide and L-Dopa | Madopar® |
| 4. | Aluminium – Magnesium antacid | Topalkan® |
| 5. | Antacid preparation | Almagate Flot-Coat® |
Bioadhesive:
This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach. The original concept of bioadhesive polymers as platforms for oral controlled drug delivery was to use these polymers to control and to prolong the GI transit of oral controlled delivery systems for all kinds of drugs. Whereas bioadhesion has found interesting applications for other routes of administration (buccal, nasal, rectal and vaginal), it now seems that the controlling approach of GI transit has been abandoned before having shown any significant clinical outcome.
According to in vivo results obtained in animals and in humans, it does not seem that mucoadhesive polymers are able to control and slow down significantly the GI transit of solid delivery systems. Attention should be paid to possible occurrence of local ulcerous side effects due to the intimate contact of the system with mucosa for prolonged periods of time. The continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seems to limit the potential of mucoadhesion as a gastroretentive force.
High Density Systems:
Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in fold also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8 – 25 hours, depending more on density than on diameter of the pellets. Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by up to 1.5–2.4g/cm-3.
Swelling and Expanding Systems:
These dosage forms are larger than the pyloric opening and so are retained in the stomach. There are some drawbacks associated with this approach. Permanent retention of rigid large-sized single-unit forms can cause bowel obstruction, intestinal adhesion and gastroplasty.
It can be referred as Plug-Type systems Polymers in the systems swell at a very faster rate and with higher degree to form a swollen matrix of which size is greater than that of the pylorus. The rate and extent of swelling are important parameters. The rate of swelling and rate of erosion are also important. The integrity of the system is also crucial to prevent the disintegration of the system and to withstand the powerful waves from the stomach.
Evaluation of Gastro retentive Dosage Forms:
Evaluation for gastro retention is carried out by means of X-ray or gamma scintigraphic monitoring of the dosage form transit in the GI tract. The modern technique of gamma scintigraphy now makes it possible to follow the transit behaviour of dosage forms in human volunteers in a non-invasive manner.
Conclusions:
In the field of gastric retention, we have seen that there are many obstacles that need to be overcome in order to be able to claim true gastric retention. Considering the advantages for improved delivery of drugs, some companies have undertaken the considerable task of developing these types of devices, some with success and others with failure due to the unpredictability of the human GI tract. However, we are as close as we have ever been to seeing a greater transition of gastric retention devices from developmental level to the manufacturing and commercial stage.
ning dosage forms., Pharm.J. 1997,259,108.