Gastroretentive Drug Delivery System : An Overview

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Mr. Shinde Anilkumar J

Mr. Shinde Anilkumar J

Several approaches have been proposed to retain the dosage forms in the stomach. These methods include bioadhesive system, swelling system and expanding system and floating system.

In fact the buoyant dosage unit enhances gastric residence time( GRT) without affecting the intrinsic rate of emptying. Unfortunately floating devices administered in a single unit form ( Hydrodynamically balanced system) HBS are unreliable in prolonging the GRT owing to their ‘ all- or- nothing’ emptying process and, thus they may causes high variability in bioavailibity and local irritation due to large amount of drug delivered at a particular site of the gastrointestinal tract.

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.1

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.2

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 categorised 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.3

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.

Physiology Of The Stomach:

The Gatrointestinal tract is essentially a tube about nine metres long that runs through the middle of the body from the mouth to the anus and includes the throat (pharynx), oesophagus, 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 Gatrointestinal tract has the same general structure throughout most of its length from the oesophagus to the anus, with some local variations for each region. The stomach is an organ with a capacity for storage and mixing. The antrum 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 organised in cycles of activity and quiescence.4

Gastro intestinal Motility pattern

Physiology of Gastrointestinal

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 oesophageal 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 phasic 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. 5

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. 6

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.TableNo.1

Salient Features Of Upper Gastrointestinal Tract: TableNo.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:7

·  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 Gastroretentive Delivery Systems:8

·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 (penicillins and cephalosporins)

·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

Limitations Of The Techniques Of Gastroretention:

More predictable and reproducible floating properties should be achieved in all the extreme gastric conditions.

1.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.

2.  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.

3.  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.

 4. The mucus on the walls of the stomach is in a state of constant renewal, resulting in

 unpredictable adherence.

5.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:9

1.Density: GRT is a function of dosage form buoyancy that is  dependent on  the density.

2.Size: Dosage form units with a diameter of more than 7.5mm are reported to have an

ncreased GRT compared with those with a diameter of 9.9mm.

3. 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.

4.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.

5.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.

6.Nature of meal: feeding of indigestible polymers or fatty acid salts can change the

motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate

and  prolonging drug release.

7.Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in   

proteins and fats.

8.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.

9.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.

10.Age: Elderly people, especially those over 70, have a significantly longer GRT.

11.Posture: GRT can vary between supine and upright ambulatory states of the patient.

12.Concomitant drug administration: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide  and cisapride.

13.Biological factors: Diabetes and Crohn’s disease.

Different Techniques Of Gastric Retention:10

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:

Floating Drug Delivery:11, 12

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 methylcelluloses. Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy.13,14

Parallel to formulation studies, investigations have been undertaken in animals and humans to evaluate the intragastric retention performances of floating forms. These assessments were realised 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 utilised matrices prepared with swellable polymers like methocel, 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 ethylcellulose. 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 hydroxypropyl methylcellulose (HPMC) and floating systems based on ion exchange resin technology, etc.16

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.17

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.18

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 Gastroretentive Dosage Forms:19, 20

Evaluation for gastroretention 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.21

Future Prospects:22

While the control of drug release profiles has been a major aim of pharmaceutical research and development in the past two decades, the control of GI transit profiles could be the focus of the next two decades and might result in the availability of new products with new therapeutic possibilities and substantial benefits for patients. Soon, the so-called ‘once-a-day’ formulations may be replaced by novel gastroretentive products with release and absorption phases of approximately 24 hours.

References:

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9. P. Grubel et al, Gastric emptying of non-digestible solids in the fasted dog., J.Pharm.Sci.,1987, 76, 117 –122.

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11.S. Desai and S. Bolton, “A Floating Controlled Release Drug Delivery System: In  vitro–In vivo Evaluation”, Pharma. Res., 1993, 10 (9) 1321-325.

12.B. M. Singh and K. H. Kim, “Floating drug delivery systems: an approach to controlled drug delivery via gastric retention”, J.  Control. Rel., 2000, 63, 235–259.

13.J. Timmermans and A. J. Moes, “Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules: new data for reconsidering the   controversy”, J. Pharm. Sci., 1994, 83, 8–24.

14.J. Timmermans and A. J. Moes, “How well do floating dosage forms float?”, Int. J.Pharm.,1990, 62, 207–216.

15.P. R. Seth and J. Tossounian, The hydrodynamically balanced system HBSTM: A novel drug deliverysystem for oral use, Drug Dev.Ind. Pharm. 1984,10, 313–339.

16.P. G Yeole., S. Khan, V. F Patel., Floating drug delivery systems: Need and development., Indian. J. Pharm. Sci. 2005, 67(3),265 – 272.

17.N. R. Jimenez-Castellanos, H. Zia and C. T. Rhodes, “Mucoadhesive drug Delivery Systems”, Drug Dev. Ind. Pharm. 1993, 19, 143.

18.D. E. Chickering, J. S. Jacob and E. Mathowitz, “Bioadhesive microspheres II: Characterisation and evaluation of bioadhesion  involving hard, bioerodible polymers and soft tissue”, Reactive Polymers, 1995, 25, 189–206.

19.V. Iannuccelli, G. Coppi, R. Sansone and G. Ferolla, “Air-compartment Multiple-unit System for Prolonged Gastric Residence, Part II. In vivo  Evaluation”, Int. J. Pharma., 1998, 174 (1–2),55– 62.

20.I. R. Wilding and S. P. Newman, “Giving Decisions More Precisions in Drug Development: Use of Radionuclide Imaging,” Drug Dev. Syst. &Scie., 2001, 1 (1) 5–10.

21.J. Chen, W. E. Blevins, H. Park and K. Park, “Gastric Retention Properties of Superporous Hydrogel Composites”, J. Control. Rel., 2000,  64 (1–3), 39–51.

22.K. Cremer, Drug delivery: Gastro- remaining dosage forms., Pharm.J. 1997, 259, 108.

About Authors:

Mr. Shinde Anilkumar J

Mr. Shinde Anilkumar J
Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Kolhapur. (M.S), Pin-4160 13.

Dr. More Harinath N

Dr. More Harinath N.
Principal, Bharati Vidyapeeth College of Pharmacy, Kolhapur. (M.S), Pin-4160 13

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