7

CHAPTER II

FLOATING DRUG DELIVERY SYSTEMS: AN OVERVIEW

Oral delivery of the drug is by far the most preferable route of drug delivery due

to the ease of administration, patient compliance and flexibility in the formulations. From

immediate release to site-specific delivery, oral dosage form has really progressed. It is

evident from the recent scientific and patented literature that an increased interest in

novel dosage forms that are retained in the stomach for prolong and predictable period of

time exist today in academic and industrial research groups. Various attempts have been

made to develop gastro retentive delivery systems. For example floating, swelling,

mucoadhesive, and high-density systems have been developed to increases gastric

retention time of the dosage forms. These systems have more flexibility in design of

dosage than conventional dosage form. Several new approaches have been developed

recently to extend gastrointestinal transit time by prolonging residence time in drug

delivery system in the GIT.

The design of oral control drug delivery systems (DDS) should be primarily

aimed to achieve more predictable and increased bioavailibility.1 Nowadays most of the

pharmaceutical scientists are involved in developing the ideal DDS. This ideal system

should have advantage of single dose for the whole duration of treatment and it should

deliver the active drug directly at the specific site. Scientists have succeeded to develop a

system and it encourages the scientists to develop control release systems. Control release

implies the predictability and reproducibility to control the drug release, drug

concentration in target tissue and optimization of the therapeutic effect of a drug by

controlling its release in the body with lower and less frequent dose.2, 3

8

Under certain circumstances prolonging the gastric retention of a delivery system

is desirable for achieving greater therapeutic benefit of the drug substances. For example,

drugs that are absorbed in the proximal part of the gastrointestinal tract 4, and the drugs

that are less soluble or are degraded by the alkaline pH may benefit from the prolonged

gastric retention 5, 6. In addition, for local and sustained drug delivery to the stomach and

the proximal small intestine to treat certain conditions, prolonging gastric retention of

therapeutic moiety may offer numerous advantages including improved bioavailability,

therapeutic efficacy and possible reduction of the dose size.7, 8.

APPROACHES TO GASTRIC RETENTION

Various approaches have been paused to increase the duration of oral dosage form

in the stomach, including floating systems, swelling and expanding systems, modified

shape systems, high density systems and other delayed gastric emptying devices

(Magnetic systems, super porous biodegradable hydro-gel systems).

1. Hydrodynamically balanced systems (HBS) –incorporated buoyant materials enable

the device to float.9, 10

2. Raft systems incorporate alginate gels – these have a carbonate component and, upon

reaction with gastric acid, bubbles form in the gel, enabling floating.9, 10

3. Swelling type of dosage form is such that after swelling; these products swell to the

extent to prevent their exit from the stomach through the pylorus. As a result the dosage

form retain in the stomach for a longer period of time. These systems may be referred to

as “Plug type systems”, since they exhibit tendency to remain logged in the pyloric

sphincters.11

9

4. 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 adhere to

the epithelial surface of the GIT. The proposed mechanism of bio-adhesion is the

formation of hydrogen and electrostatic bonding at the mucus polymer boundary.

5. Modified shape systems are non-disintegrating geometric shapes molded from silastic

elastomer or exuded from polyethylene blends and extended the GTT depending on the

size, shape and flexural modulus of the drug delivery device.

6. High density formulations include coated pellets, 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, zinc oxide, titanium dioxide. This

formulation of high-density pellet is based on assumption that heavy pellets might remain

longer in the stomach, since they position in the lower part of the antrum.12, 13

7. Another delayed gastric emptying approaches 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.

Floating Systems:

Floating systems, first described by Davis in 1968, have bulk density lower than

that of the gastric fluid, and thus remain buoyant in stomach for a prolonged period.

10

Effervescent Systems:

1. Volatile liquid containing systems:

The GRT of a drug delivery system can be sustained by incorporating an

inflatable chamber, which contains a liquid e.g. ether, cyclopentane, that gasifies at body

temperature to cause the inflatation of the chamber in the stomach. The device may also

consist of a bioerodible plug made up of PVA, Polyethylene, etc. that gradually dissolves

causing the inflatable chamber to release gas and collapse after a predetermined time to

permit the spontaneous ejection of the inflatable systems from the stomach.14

2. Gas-generating Systems:

These buoyant delivery systems utilize effervescent reactions between

carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which gets entrapped

in the gellified hydrocolloid layer of the systems thus decreasing its specific gravity and

making it to float over chyme.1, 17, 40 How the dosage form float is shown in the following

figure (Figure- 2.1). 15

Figure- 2.1: The Mechanism of Floating Systems19

11

Non-effervescent systems:

1. Colloidal gel barrier systems

Hydrodynamically balanced system (HBSTM) was first designed by Sheth and

Tossounian in 1975.Such systems contain drug with gel forming hydrocolloids meant to

remain buoyant on stomach contents. This system incorporate a high level of one or more

gel forming highly swellable cellulose type hydrocolloids.e.g.HEC, HPMC, NaCMC,

Polysacchacarides and matrix forming polymer such as polycarbophil, polyacrylates and

polystyrene, incorporated either in tablets or in capsule. On coming in contact with

gastric fluid, the hydrocolloid in the system hydrates and forms a colloidal gel barrier

around the gel surface. The air trapped by the swollen polymer maintains a density less

than unity and confers buoyancy to this dosage form.16

2. Microporous Compartment System

This technology is based on the encapsulation of drug reservoir inside a

Microporous compartment with aperture along its top and bottom wall. The peripheral

walls of the drug reservoir compartment are completely sealed to prevent any direct

contact of the gastric mucosal surface with the undissolved drug. In stomach the

floatation chamber containing entrapped air causes the delivery system to float over the

gastric contents. Gastric fluid enters through the apertures, dissolves the drug, and carries

the dissolved drug for continuous transport across the intestine for absorption.

3. Alginate beads

Multiple unit floating dosage forms have been developed from freeze-dried

calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared

12

by dropping sodium alginate solution in to aqueous solution of calcium chloride, causing

precipitation of calcium alginate. The beads are then separated snap and frozen in liquid

nitrogen, and freeze dried at -40°C for 24 hours, leading to the formation of porous

system, which can maintain a floating force over 12 hours.14, 16

4. Hollow microspheres

Hollow microspheres (microballoons), loaded with ibuprofen in their outer

polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol:

dichloromethane solution of the drug and an enteric acrylic polymer was poured in to an

agitated aqueous solution of PVA that was thermally controlled at 40°C.The gas phase

generated in dispersed polymer droplet by evaporation of dichloromethane formed in

internal cavity in microspheres of the polymer with drug. The microballoons floated

continuously over the surface of acidic dissolution media containing surfactant for greater

than 12 hours in vitro.16

FACTORS AFFECTING GASTRIC RETENTION

Density

Density of the dosage form should be less than the gastric contents (1.004gm/ml).

Size and Shape

Dosage form unit with a diameter of more than 7.5 mm are reported to have an

increased GRT competed to with those with a diameter of 9.9 mm. The dosage form with

a shape tetrahedron and ring shape devises with a flexural modulus of 48 and 22.5

13

kilopond per square inch (KSI) are reported to have better GIT @ 90 to 100 % retention

at 24 hours compared with other shapes.1

Fed or Unfed State

Under fasting conditions, the GI motility is characterized by periods of strong

motor activity or the migrating myoelectric complexes (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.12, 17

Nature of the meal

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.18

Caloric Content

GRT can be increased between 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.16

14

Gender

Mean ambulatory GRT in meals (3.4±0.4 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 19

Elderly people, especially those over 70 years have a significantly longer GRT.20

Posture19

GRT can vary between supine and upright ambulatory states of the patients

Concomitant drug administration

Anticholinergic like atropine and propentheline opiates like codeine and

prokinetic agents like metoclopramide and cisapride.

FORMULATION OF FLOATING DOSAGE FORM

Following types of the ingredients can be incorporated in to HBS dosage form 20

·Hydrocolloids

·Inert fatty materials

·Release rate accelerants

·Release rate retardant

·Buoyancy increasing agents

·Miscellaneous

15

Hydrocolloids

Suitable hydrocolloids are synthetics, anionic or non ionic like hydrophilic gums,

modified cellulose derivatives. e.g. Acacia, pectin, agar, alginates, gelatin, casein,

bentonite, veegum, MC, HPC, HEC, and Na CMC can be used. The hydrocolloids must

hydrate in acidic medium i.e. gastric fluid having pH 1.2.Although the bulk density of the

formulation may initially be more than one, but when gastric fluid enter in the system, it

should be hydrodynamically balanced to have a bulk density of less than one to assure

buoyancy.

Inert fatty materials

Edible, pharmaceutical inert fatty material, having a specific gravity less than one

can be added to the formulation to decrease the hydrophilic property of formulation and

hence increases the buoyancy. Example: Purified grades of beeswax, fatty acids, long

chain alcohols, glycerides, and mineral oils can be used.

Release rate accelerant

The release rate of the medicament from the formulation can be modified by

including excipients like lactose and/or mannitol. These may be present from about

5-60% by weight.

Release rate retardant

Insoluble substances such as dicalcium phosphate, talc, magnesium strearate

decreased the solubility and hence retard the release of medicaments.

16

Buoyancy increasing agents

Materials like ethyl cellulose, which has bulk density less than one, can be used

for enhancing the buoyancy of the formulation. It may be adapted up to 80 % by weight.

Miscellaneous

Pharmaceutically acceptable adjuvants like preservatives, stabilizers and

lubricants can be incorporated in the dosage forms as per the requirements. They do not

adversely affect the hydrodynamic balance of the systems.

IN VITRO AND IN VIVO EVALUATION OF FLOATING SYSTEMS

Physiological Parameters

Age, sex, posture, food, bioadhesion, health of subject and GIT condition

Galenic Parameter

Diametrical size, flexibility and density of matrices

Control Parameter

Floating time, specific gravity, dissolution, content uniformity, hardness and

friability

Floating time

The test for buoyancy is usually performed in simulated gastric and intestinal

fluid maintained at 37°C.The floating time is determined by using USP dissolution

apparatus containing 900 ml of 0.1 N HCl as the testing medium maintained at 37°C.The

time for which the dosage form floats is termed as the floating or floatation time.1

17

Specific Gravity

Specific Gravity of the floating system can be determined by the displacement

method using benzene as a displacing medium.17, 21

Resultant weight

The 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 force

equivalent to the force F required to keep the object totally submerged in the fluid. 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 Victoria sum of buoyancy (Fbuoy) and gravity

(Fgrav) forces acting on the objects as shown in the equation.

F = Fbuoy – F grav

F = dfgV – dsgV = (df – ds) gV

F = (df – M/V) gV

In which the F is total vertical force (resultant weight of the object), g is the

acceleration due to gravity, df is the fluid density, ds is the object density, M is the object

mass and V is the volume of the object.20

Advantages of Floating Dosage Form 22

1. The Principle of HBS may not be limited to any particular medicament or class of

medicament.

18

2. The HBS formulations are not restricted to medicaments, which are absorbed from

stomach, since it has been found that these are equally efficacious with medicament,

which absorbed from the intestine.

3. Acidic substances like aspirin cause irritation on the stomach wall when come in to

contact with it. Hence HBS formulation may be useful for the administration of aspirin

and other similar drugs.

4. The HBS are advantageous for drugs absorbed through the stomach.e.g. Ferrous salts,

antacids.

5. The efficacy of the medicaments administered utilizing the sustained release principle

of HBS formulation has been found to be independent of the site of particular

medicaments.

6. The HBS are advantageous for drugs meant for local action in the stomach.

e.g.: Antacids.

7. Administration of prolonged release floating dosage forms, tablets or capsules, will

result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid,

would be available for absorption in the small intestine after emptying of the stomach

contents. It is therefore expected that a drug will be fully absorbed from the floating

dosage forms if it remains in the solution form even at the alkaline pH of the intestine.

8. When there is vigorous intestinal movement and a shorted transit time as might occur

in certain type of diarrhea, poor absorption is expected. Under such circumstances it may

be advantageous to keep the drug in floating condition in stomach to get a relatively

better response.

19

Limitations/Disadvantages

These systems require a high level of fluid in the stomach for drug delivery to

float and work efficiently-coat, water.

1. Not suitable for drugs that have solubility or stability problem in GIT.

2. Drugs such as nifedipine which is well absorbed along the entire GIT and which

undergoes first pass metabolism, may not be desirable.

3. Drugs which are irritant to Gastric mucosa are also not desirable or suitable.1

4. The drug substances that are unstable in the acidic environment of the stomach are not

suitable candidates to be incorporated in the systems.1

5. The dosage form should be administered with a full glass of water (200-250 ml).3

6. These systems do not offer significant advantages over the conventional dosage forms

for drugs, which are absorbed through out the gastrointestinal tract.

Application of Floating Drug Delivery System 5

• Recent study indicated that the administration of Diltiazem floating tablets twice a

day may be more effective compared to normal tablets in controlling the B.P. of

hypertensive patients.

• Modular® HBS containing L-Dopa and Benserazide, here the drug was absorbed

over a period of 6-8 hours and maintained substantial plasma concentration for

Parkinsonian patients. Cytotech®- containing Misoprostol, a synthetic

prostaglandin –EL analogue, for prevention of gastric ulcer caused by non-

steroidal anti-inflammatory drugs (NSAIDS).

20

• As it provides high concentration of drug within gastric mucosa, it is used to

eradicate H.pylori (a causative organism for chronic gastritis and peptic ulcers).

• 5-fluorouracil has been successfully evaluated in the patients with stomach

neoplasm.

• Developing HBS dosage form for tacrin provide better delivery systems and

reduced its GI side effects.

• Treatment of gastric and duodenal ulcer.

Future Potential

• Floating dosage form offers various future potential as evident from several recent

publications. The reduced fluctuations in the plasma level of drug results from

delayed gastric emptying.

• Drugs that have poor bioavailability because of their limited absorption to the

upper gastrointestinal tract can be delivered efficiently thereby maximizing their

absorption and improving their absolute bioavailability.

• Buoyant delivery system considered as a beneficial strategy for the treatment of

gastric and duodenal cancers.

• The floating concept can also be utilized in the development of various anti-reflux

formulations.

• Developing a controlled release system for the drugs, which are potential to treat

the Parkinson’s disease.

21

• To explore the eradication of Helicobacter pylori by using the narrow spectrum

antibodies.

22

Table 2.1: Commercial Gastroretentive Floating Formulations 3, 23, 24

Name Type and Drug Remarks

Madopar HBS

(PropalHBS)

Floating capsule, Levodopa and

benserazide Floating CR capsules

Valrelease 34 Floating capsule, Diazepam Floating Capsules

Topalkan Floating Antacid, aluminum and

magnesium mixture

Effervescent floating liquid

alginate preparation

Amalgate Float Coat 35 Floating antacid,

Floating gel Floating dosage form

Conviron Ferrous sulphate Colloidal gel forming FDDS

Cifran OD Ciprofloxacin (1 gm) Gas generating floating form

Cytotech Misoprostol (100 mcg/200 mcg) Bilayer floating capsule

Liquid Gaviscone Mixture of alginate

Suppress gastro esophageal

reflux and alleviate the heart

burn

23

TABLE 2.2: SUMMARY OF THE RESEARCH WORK ON GRDDS

S.

No. DRUG POLYMERS TYPE RESULT REFERENCE

1.

Theophylline

Agar and Light

mineral oil Floating tablets

Controlled

Release

25

2.

Frusemide

HPMC, Lactose DC

Modified

Release Dosage

Form

Improved

bioavailability

and Drug

absorption

26

3.

Sulpride

Carbopol 934 P

Modified

Release Dosage

Form

Sustained

Released and

extending oral

bioavailability

27

4. Chlorpheniramine

Maleate Eudragit RL Matrix Tablet

Controlled

Release 28

5. Chlorpheniramine

Maleate

Calcium alginate,

PVA

Multi unit

system

Enhanced

floating

property.

29

6. Tetracycline HPMC and

Polythene oxide

Triple Layer

Tablets

Controlled

Release

30

7. Metronidazole

HPMC and

Polyethylene Oxide

Triple Layer

Tablets

Controlled

Release 31

24

8. Metronidazole

Cellulose

Derivatives and

Starch Derivatives

Capsules

Sustained

Release

32

9. Amoxycillin

Alginate and

Amylose

Floating

Alginate Beads

Sustained

Release 33

10. Pentoxyfilline HPMC K4M

Matrix Floating

Tablets

Sustained

Release 34

11. Captopril

HPMC 4000 and

HPMC 5000 cps and

Carbopol 934 p

Floating

Tablets

Controlled

Release 35

12. Pentoxyphilline

HPMC 4000 and

HPMC 5000 cps and

Carbopol 934 p

Floating Matrix

Tablets

Sustained

Release 36

13. Ketoprofen

Eudragit S100 (ES)

and Eudragit (RL)

Floating

Microparticles

Sustained

Release 37

14. Riboflavin

Calcium and low

Methoxylated

Pectin(LMP),

Sodium alginate

Floatable

Multiparticulate

System

Sustained

Release 38

15. Tetracycline

Calcium and low

Methoxylated

Pectin(LMP) and

Sodium Alginate

Floatable

Multiparticulate

system

Sustained

Release 39

Methotrexate Calcium and Low Floatable Sustained 40

25

16. Methoxylated

Pectin(LMP),

Sodium Alginate

Multiparticulate

system

Release

17. Prednisolone

Chitosan H and

Chitosan L

Floating

Granules

Sustained

Release 40

18. Pepstatin PVP and HPMC

Floating Mini

Capsules

Extended

Gastric

Retension

41

19.

Anhydrous

Cholestryamine

Alginic acid,

Sodium alginate,

Citric acid , and

Sodium bicarbonate

Ion Exchange

Resin

Controlled

Release 42

20. Furosemide

Β-Cyclodextrins,

HPMC 4000,

HPMC 100 and

CMC

Floating

Bilayer Tablets

Increase in

bioavailability 43

21. Polyvinyl Lactams Polyacrylates

Expandable

Tablets

Sustained

Release 44

22. Ciprifloxcin

Sodium alginate,

Xanthum gum,

Crosslinked PVP

Tablets Sustained

Release 45

23. Ciprofloxacin

HPMC K4M, Avicel

PH 101

Matrix Floating

Tablets

Prolonged

gastric residual

time

46

26

24. Nicardipine Hydrocolloids

Floating

Capsules

Sustained

Release 47

25. Captopril

HPMC(4000 and

15000 cps) and

Carbopol 934p

Floating

Tablets

Sustained

Release 48

26. Amoxycillin

Alginate

Floating

Alginate Beads

Prolonged

buoyancy and

high drug

loading

efficiency

49

27. Ketoprofen

Eudragit S100 and

Eudragit RL

Floating

Microparticles 50

28. Ketoprofen

Eudragit S, Ethyl

cellulose and

PMMA

Floating

Micropraticles

Enhanced

release rates

51

29. Nimodipine

HPMC, PEG 6000,

Poloxamee-188

Floating

Tablets

Sustained

Release 52

30. Piroxicam Polycarbonate Floating

Microspheres

Sustained

Release and

Increased

Bioavailability

53

31.

P-Amino Benzoic

acid Polycarbonate

Miltiparti-

-culate system

(floating pills)

Enhancing 1.61

times

bioavailability

54

27

32. Tetracycline HPMC and PEO Triple Layer

Tablets

Sustained

Release 55

33.

Metronidazole

HPMC and PEO Triple Layer

Tablets

Sustained

Release 56

34. Clarithromycin HPMC and PEO Triple Layer

Tablets

Sustained

Release 57

35. Riboflavin HPMC and PEO Microballoon Sustained

Release 58

36. Diltiazem Hcl Gleucire 43101

Multi unit

Floating

Systems

Extended

Gastric

Retension

59

37. Rantidine Hcl

Guargum, Xanthum

gum and HPMC Tablets

Sustained

Release 60

38. Norfloxacin

Hydroxypropyl

Methylcellulose and

Xanthan gum.

Floating

Tablets

Gastroretentive

Drug Delivery 61

39

Dipyridamole Polyethylene oxide

(PEO)

Floating

Osmotic Pump

System

Gastroretentive

Drug Delivery 62

28

40. Amlodipine

besylate

HPMC K100 M,

HPMC K15 M,

Carbapol 934

Effervescent

Floating Tablet

Extended

Gastric

Retention

63

41. Clarithromycin HPMC K4 M,

HPMC K15 M

Floating

Tablets

Controlled

Release 64

42. Domeperidone HPMC and PEO Floating Matrix

Tablets

Prolonged

gastric residual

time

65

43. Famotidine Methocel K100 and

Methocel K15M

Floating

Tablets

Prolonged

gastric residual

time

66

44.

Metformin

Hydrochloride Ethyl Cellulose

Floating

Microspheres

Gastroretentive

Drug Delivery 67

45. Rosiglitazone

Maleate

HPMC K4 M,

HPMC K15 M

Floating-

Bioadhesive

Tablets

floatation and

bioadhesion to

prolong

residence in the

stomach

68

29

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