Formulation Development and Evaluation of Gastro …jprsolutions.info/files/final-file-58ddc0a3ba2097.92335779.pdf · KEY WORDS: Controlled release, ... limitation, the development

Journal of Pharmacy Research Vol.11 Issue 2 February 2017

Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017,11(2),167-178

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Review Article

ISSN: 0974-6943

Available online throughhttp://jprsolutions.info

*Corresponding author.

Mr.Raghavendra Kumar Gunda M.Pharm

Research Scholar,

School of Pharmaceutical Sciences,

VISTAS, Vels University,

Pallavaram, Chennai,

Tamilnadu, India- 600117.

Formulation Development and Evaluation of

Gastro Retentive Drug Delivery Systems- A Review

Raghavendra Kumar Gunda*1, A.Vijayalakshmi 2

1Research Scholar, School of Pharmaceutical Sciences, VISTAS, Vels University, Pallavaram, Chennai, Tamilnadu, India- 600117.2School of Pharmaceutical Sciences, VISTAS, Vels University, Pallavaram, Chennai, Tamilnadu, India- 600117.

Received on:12-01-2017; Revised on: 19-02-2017; Accepted on: 27-02-2017

ABSTRACT

In recent years many advancement has been made in research and development of Oral Drug Delivery System. Concept of Novel Drug

Delivery System arose to overcome the certain aspect related to physicochemical properties of drug molecule and the related formulations.

Purpose of this review is to compile the recent literature with special focus on Gastro Retentive Drug Delivery Systems to give an update

on pharmaceutical approaches used in enhancing the Gastric Residence Time (GRT). Various approaches are currently used including

Gastro Retentive Floating Drug Delivery Systems(GRFDDS),swelling and expanding system, polymeric bioadhesive systems, modified-

shape systems, high density system and other delayed gastric emptying devices. These systems are very helpful to different problem solve

during the formulation of different dosage form. The present work also focuses on the polymers used in floating drug delivery systems

mostly from natural origin. Floating drug delivery systems are less dense than gastric fluids; hence remain buoyant in the upper GIT for a

prolonged period, releasing the drug at the desired/ predeterminedrate. This review article focuses on the recent technological development

in floating drug delivery systems with special emphasis on the principal mechanism of floatation and advantages of achieving gastric

retention, brief collection on various polymers employed for floating drug delivery systems etc. In addition this review also summarizes the

In –Vitro and In -Vivo studies to evaluate their performance and also their future potential.

KEY WORDS: Controlled release, Floating lag time, Floating duration/ Gastric residence time, Gastro retentive drug delivery systems,

Natural gums, Bioadhesive.

INTRODUCTIONOral administration is the most convenient andpreferred means ofany drug delivery to thesystemic circulation.The effective oraldrugdelivery practice depends on various factors like gastricemptyingprocess, gastrointestinal transit time of dosageform, drug releasefrom dosage form and site ofabsorption of drug[1-3].

Gastric emptying of dosage forms is an extremely variable processand ability to prolong and control the emptying time is a valuableasset for dosage forms, which reside in the stomach for a longerperiod of time than conventional dosage forms.It has been frequentlyobserved thatmany drugs which are easily absorbed atuppergastrointestinal tract (GIT), eliminated quickly in to lowerGIT

because of the peristaltic movement. So it leads toincompleteabsorption of drugs from upper part of GIT. To overcome thislimitation, the development of oralgastro retentive sustained orcontrolled releaseformulations is an attempt to release the drug slowlyatupper GIT to maintain effective drug concentration insystemiccirculation for a prolonged period[3]. Several difficulties are faced indesigning controlled release systems for better absorption and

enhanced bioavailability[4].

Gastroretentive systems can remain in the gastric region for severalhours and hence significantly prolong the gastric residence time ofdrugs. Prolonged gastric retention improves bioavailability, reducesdrug waste, and improves solubility for drugs that are less soluble ina high pH environment. It has applications also for local drug deliveryto the stomach and proximal small intestines.Gastric retention helpsto provide better availability of new products with new therapeuticpossibilities and substantial benefits for patients.

The controlled gastric retention of solid dosage forms may be

achieved by the mechanisms of mucoadhesion, flotation,



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sedimentation (High density), expansion, modified shape systems,or by the simultaneous administration of pharmacological agents

that delay gastric emptying.Several recent examples have beenreported showing the efficiency of such systems for drugs withbioavailability problems[4-6].

Approaches to increase gastric residence time include

High-density systems Bioadhesive or Mucoadhesive systems Swelling and Expanding Systems Superporous Hydrogels Ion Exchange Resins Bioadhesive Liposomal Systems

Raft-forming systems Gas-generating systems Low-density systems (Floating systems /

Hydrodynamically Balanced Systems )

Floating Drug Delivery Systems (GRFDDS)These are the low density systems having their density lesser thanthe gastric fluid (1.004 gm/cm3) and thus remain buoyant in thestomach without affecting the gastric emptying rate for a prolongedperiod. GRFDDS are classified into two major categories[7-13]

.

Effervescent systems/ Gas generating systems

In this system floatability can be achieved by the generation of gasbubbles. They are formulated in such a way that when in contactwith the acidic gastric contents, CO

2 is liberated and gets entrapped

in swollen hydrocolloids, which provides buoyancy to the dosageforms. In vitro, the lag time before the unit floats is < l minute andbuoyancy is prolonged for 8-10 hours. Bilayer or multilayer systemshave also been designed in which drug and excipients can beformulated independently, and the gas generating unit can beincorporated into any of the layers of multiple unit systems, whichavoids the ‘all-or-nothing’ emptying process encountered in singleunit systems[14-15]. It must form a cohesive gel barrier. It should releasecontents slowly to serve as a reservoir[16].

Gas-generating (Effervescent) systems.(a) Bilayer gas-generating systems, with(c) or without (b) semi permeable membrane.

Hydrodynamically balance systems are best suited for drugs havinga better solubility in acidic environment and also for the drugs havingspecific site of absorption in the upper part of the small intestine.To remain in the stomach for a prolonged period of time the dosageform must have a bulk density of less than 1. It should stay in thestomach, maintain its structural integrity, and release drug constantlyfrom the dosage form. HBS are single-unit dosage form, containingone or more gel-forming hydrophilic polymers. Hydroxypropylmethylcellulose (HPMC), hydroxethyl cellulose (HEC), hydroxypropylcellulose (HPC), sodium carboxymethyl cellulose (NaCMC),polycarbophil, polyacrylate, polystyrene, agar, carrageenans or alginicacid are commonly used excipients to develop these systems[17-18].The polymer is mixed with drug and usually administered in a gelatincapsule. The capsule rapidly dissolves in the gastric fluid at bodytemperature and hydration.

Table 1:Polymers and other ingredients used for increasing GRT [19]

Polymers and other ingredients Example

Hydrocolloids (20%-75%) Acacia, Pectin, Chitosan, Agar, Casein, Bentonite,Veegum, HPMC (K4M, K100M and K15M),Gellan gum, Sodium CMC, MC, Calcium alginate,Eudragit S100, Eudragit RL, Propylene foam,Eudragit RS,ethyl cellulose, Polyethylene oxide,β Cyclodextrin, CMC, Polyethylene glycol,polycarbonate, PVA, Sodium alginate, HPC-L,CP 934P, HPC, Eudragit S, Metolose S.M. 100,PVP, HPC-H, HPC-M, HPMC K15, Acrylicpolymer, E4 M and Carbopol.

Inert fatty materials (5%- 75%) Beeswax, fatty acids, long chain fatty alcohols,Gelucires® 39/01 and 43/01.

Effervescent agents Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbonate), CG(Citroglycine).

Release rate accelerants (5%-60%) Lactose, MannitolRelease rate retardants (5%-60%) Dicalcium phosphate, Talc, Magnesium stearateBuoyancy increasing agents (upto80%) Ethyl celluloseLow density material Polypropylene foam powder (Accurel MP

1000®).

Effervesant Layers(Inner and outer sublayer)

Conventional sustainrelease pills)

Swelable membrane layer

H2O

A

B(A) Multiple-unit oral floating drug delivery system.

(B) Working principle of effervescent floating drug delivery



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High-density systems

These systems, which have a density of ~3 g/cm3, are retained in the

rugae of the stomach and are capable of withstanding its peristaltic

movements. Above a threshold density of 2.4–2.8 g/cm3, such

systems can be retained in the lower part of the stomach.

Sedimentation has been employed as a retention mechanism for

pellets that are small enough to be retained in the rugae or 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 rugae 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 the diameter of the pellets. A density close

to threshold density seems necessary for significant prolongation

of gastric residence time. 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/cm3 [20-23].

Swelling and Expanding Systems

Swelling and expanding systems are dosage forms that, after

swallowing, swell to an extent that prevents their exit from the

pylorus[24]. As a result, the dosage form is retained in the stomach

for a long period. These systems may be called ‘plug type systems’,

since they exhibit a tendency to be logged at the pyloric sphincter.

Swelling and controlled release of the drug may be achieved on

contact of the drug delivery system with gastric fluid; the polymer

imbibes water and swells. Extensive swelling of the polymer is the

result of the presence of physical-chemical crosslinks in the

hydrophilic polymer network. The bulk enables gastric retention and

maintains the stomach in a ‘fed’ state, suppressing housekeeper

waves[25,26]. Medicated polymer sheets or swelling balloon hydrogels

are examples of such delivery systems. A balance between the rate

and extent of swelling and the rate of erosion of the polymer is

crucial to achieve optimum benefit and to avoid adverse effects.

They are explained as follows (Non-Effervescent systems)[27].

Colloidal gel barrier systems

These systems incorporate a high level (20-75% w/w) of one or more

gel forming, highly swellable,cellulose type hydrocolloids,

polysaccharides and matrix forming polymers. On coming in contact

withgastric fluid, the hydrocolloids in the system hydrate and form a

colloidal gel barrier around its surface.This gel barrier controls the

rate of fluid penetration into the device and consequent release of

the drug[27].

inside a micro-porous compartment with apertures along its top and

bottom walls. The peripheral walls of the drug reservoir compartment

are completelysealed to prevent any direct contact of the gastric

mucosal surface with the undissolved drug.

Multiparticulate system Floating Beads

In these systems, the dosage of the drug substances is divided on a

plurality of subunit, typically consisting ofthousands of spherical

particles with diameter of 0.05-2.00 mm. Thus multi particulate dosage

forms arepharmaceutical formulations in which the active substance

is present as a number of small independent subunits.To deliver the

recommended total dose, these subunits are filled into a sachet.

Microballons

various approaches are made in delivering substances to the target

site in a controlled release fashion. Oneof such approach is using

polymeric microballoons as carrier for drugs. Hollow microspheres

are known as themicroballoons. Microballoons were floatable in vitro

for 12 hrs, when immersed in aqueous media. Radio graphicalstudies

proved that microballoons orally administered to human were

dispersed in the upper part of stomach andretained there for three hr

against peristaltic movements.

Super porous Hydrogels

In this approach to improve gastric retention time (GRT) super porous

hydrogels of average pore size >100 micro meter, swell to equilibrium

size within a minute due to rapid water uptake by capillary wetting

through numerous interconnected open pores. They swell to a large

size (swelling ratio: 100 or more) and are intended to have sufficient

mechanical strength to withstand pressure by gastric contraction.

This is achieved by co-processing with a hydrophilic particulate

material, croscarmellose sodium. Which forms a dispersed phase

within the continuous polymer matrix during the synthesis

(‘superporous hydrogel composites’). The superporous hydrogel

composites stay in the upper GIT for >24 hours. Recent advances in

the field have led to “superporous hydrogel hybrids”, which are

prepared by adding a hydrophillic or water dispersible polymer that

can be cross-linked after the superporous hydrogel is formed.

Examples of hybrid agents include polysaccharides such as sodium

alginate, pectin and chitosan[28-30].

Ion-Exchange Resins

A coated ion exchange resin bead formulation has been shown to

have gastric retentive properties, which was loaded with bicarbonates.

Ion exchange resins are loaded with bicarbonate and a negatively

charged drug is bound to the resin, resultant beads were thenThis technology is based on the encapsulation of a drug reservoirMicro porous compartment systems



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encapsulated in a semipermeable membrane to overcome the rapid

loss of carbon dioxide. Upon arrival in the acidic environment of the

stomach and exchange of chloride and bicarbonate ions take place.

As a result of this reaction carbon dioxide was released and trapped

in a membrane thereby carrying beads towards the top of gastric

content and producing a floating layer of resin beads in contrast the

uncoated beads, which will sink quickly[31-34].

Bioadhesive or Mucoadhesive Systems

The term “mucoadhesion” is commonly used to describe an

interaction between the mucin layer that lines the entire GIT and a

bioadhesive polymer. Bioadhesive drug delivery systems (BDDS)

are used as a delivery device within the lumen to enhance

drugabsorption in a site specific manner. This approach involves the

use of bioadhesive polymers, which can adhere to the epithelial

surface in the stomach. Thus, they prolong the gastric retention

time[35-36].

Bioadhesion can be explained by[37-38]

The absorption theory

The electron theory

The wetting theory

The diffusion theory

Bioadhesive mechanism

Bioadhesive liposomal Systems

Mucoadhesive liposomal systems are formulated by coating a

polymer to facilitate enteral absorption of poorly absorbed drugs.

Liposomes are generally coated with mucoadhesivepolymers such

as chitosan, carbopol, Carboxymethyl chitin and carboxymethyl

chitosan. The mucoadhesion of the resultant liposomes leads to an

enhanced GRT of the dosage forms[39-40].

Raft forming systems

Raft forming systems have received much attention for the drug

delivery for gastrointestinal infections and disorders. Floating Rafts

have been used in the treatment of Gastric esophageal reflux disease

(GERD). The mechanism involved in the raft formation includes the

formation of viscous cohesive gel in contact with gastric fluids,

where in each portion of the liquid swells forming a continuous layer

called a raft. This raft floats on gastric fluids because of low bulk

density created by the formation of CO2. Usually, the system

ingredients includes a gel forming agent and alkaline bicarbonates

or carbonates responsible for the formation of CO2 to make the system

less dense and float on the gastric fluids . Jorgen et al described an

antacid raft forming floating system. The system contains a gel

forming agent (e.g. sodium alginate), sodium bicarbonate and acid

neutralizer, which forms a foaming sodium alginate gel (raft), which

when comes in contact with gastric fluids, the raft floats on the

gastric fluids and prevents the reflux of the gastric contents (i.e.

gastric acid) into the esophagus by acting as a barrier between the

stomach and esophagus[41-42].

FACTORS AFFECTING Gastro Retention Time of Floating Drug

Delivery Systems

The various factors which influence the efficacy of Gastro Retentive

Drug Formulation‘s as a gastro-retentive systems are:

Formulation Factors and Idiosyncratic Factors[27,43]

Formulation Factors

Density

GRT is a function of dosage form buoyancy that is dependent on the

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 floats. Since it is away from the pyloric sphincter, the

dosage unit is retained in the stomach for a prolonged period. Drug

floatation is a function of time and it could least until hydrodynamic

equilibrium is achieved. Dosage forms having larger density then

the gastric content sink at the bottom of the atrium where they settle

and release the active compound in a controlled manner over a

prolonged period of time.

Size

Dosage form units with a diameter of more than 7.5 mm are reported

to have an increased GRT compared with those with a diameter of 9.9

mm. Larger dosage forms tend to have longer gastric retention time

than smaller ones because they are emptied in the digestive phase

(weaker MMC) and also because their passage through the pyloric

sphincter into the small intestine is hindered.

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



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better GRT = 90% to100% retention at 24 hours compared with other

shapes.

Under fasting conditions, the GI motility is characterized by periods

of strong motor activity or the 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.

Viscosity Grade of Polymer:

Drug release and floating properties of GRFDDS are greatly affected

by viscosityof polymers and their interaction. Low viscosity polymers

(e.g., HPMC K100 LV) were found to be morebeneficial than high

viscosity polymers (e.g., HPMC K4M) in improving floating

properties. In addition, adecrease in the release rate was observed

with an increase in polymer viscosity.

Nature of meal

Feeding of indigestible polymers or fatty acids salts can change the

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

gastric emptying rate and prolonging drug release. Type of meal and

its caloric content, volume, viscosity and co-administered drugs affect

gastric secretions and gastric emptying time. The rate of emptying

primarily depends on caloric contents of the ingested meal. It does

not differ for proteins, fats and carbohydrates as longas their caloric

contents are the same. Generally gastric emptying is slowed down

because of increased acidity, osmolarity and calorific values.Gastric

residence time increases in the presence of food, leading to increased

drug dissolution of the dosage form at the most favorable site of

absorption. A GRT of 4-10 hours has been reported after a meal of

fats and proteins.

Frequency of feed

The GRT can be increased by over 400 minutes when successive

meals are given compared with a single meal due to the low frequency

of MMC.

Idiosyncratic Factors

Idiosyncrasy is genetically determined abnormality to a chemical.

The drug interacts with some unique feature of theindividual, not

found in majority of subjects, and produces the uncharacteristic

reaction. The type of reaction isrestricted to individuals with a

particular genotype. It may also depends on-

Gender

their age and race matched female counterparts (4.6±1.2 hours),

regardless of theweight, height and body surface.Mean ambulatory

GRT in males (3.4 ± 0.6 hours) is less compared with their age and

race matched female counter parts (4.6 ± 1.2 hours) regardless of the

weight, height and body surface.

Age

Low gastric emptying time is observed in elderly than do in younger

subjects. Intra subject and inter subjectvariations also are observed

in gastric and intestinal transit time. Elderly people, especially those

over 70 years havea significantly longer GRT. Elderly people,

especially those above 70, have a significantly longer GRT.

Posture

GRT can vary between supine and upright ambulatory states of the

patient

Upright Position:

An upright position protects floating forms against postprandial

emptying because the floatingform remains above the gastric

contents irrespective of its size. Floating dosage forms show

prolonged and morereproducible GRTs while the conventional dosage

form sink to the lower part of the distal stomach from wherethey are

expelled through the pylorus by astral peristaltic movements.

Supine Position:

This position offers no reliable protection against early and erratic

emptying. In supine subjectslarge dosage forms (both conventional

and floating) experience prolonged retention. The gastric retention

offloating forms appear to remain buoyant anywhere between the

lesser and greater curvature of the stomach.

On moving distally, these units may be swept away by the peristaltic

movements that propel the gastric contentstowards the pylorus,

leading to significant reduction in GRT compared with upright

subjects.

Concomitant Intake of Drugs:

Drugs such as prokinetic agents (e.g., metoclopramide and cisapride),

anticholinergics (e.g., atropine or propantheline), opiates (e.g.,

codeine) may affect the performance of GRFDDS. The co-

administration of GI-motility decreasing drugs can increase gastric

emptying time.

Biological factors

Diseases like gastroenteritis, gastric ulcer, pyloric stenosis, diabetes

and hypothyroidism retard gastric emptying. Partial or total

gastrectomy, duodenal ulcer and hypothyroidism promote gastric

emptying rate.Women have slower gastric emptying time than men. Mean

ambulatory GRT in meals (3.4±0.4 hours) is less as compared with



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Advantages of GRFDDS

Increasing the GRT with either of the approaches offers several

advantages such as:

Acidic drug 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.

The Floating systems are advantageous for drugs meant

for local action in the stomach. e.g., antacids.

The GRFDDS are advantageous for drugs absorbed through

the stomach ex: Ferrous salts, Antacids. Improved drug

absorption, because of increased GRT and more time spent

by the dosage form at its absorption site.

Controlled delivery of drugs.Minimizing the mucosal

irritation due to drugs, by drug releasing slowly at controlled

rate.The controlled, slow delivery of drug to the stomach

provides sufficient local therapeutic levels and limits the

systemic exposure to the drug. This reduces side effects

that are caused by the drug in the blood circulation. In

addition the prolonged gastric availability from a site directed

delivery system may also reduce the dosing frequency.

Administration of prolongs release floating dosage forms,

tablet or capsules, will results 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.

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.

As sustained release systems, floating dosage forms offer

various potential advantages. Drugs that have poor

bioavailability because their absorption is limited to upper

GI tract can be delivered efficiently thereby maximizing their

absorption and improving their absolute bioavailability.

Floating dosage forms with SR characteristics can also be

expected to reduce the variability in transit performance. In

addition, it might provide a beneficial strategy for gastric

and duodenal cancer treatment.

The concept of GRFDDS has also been utilized in the development

of various anti- reflux formulations

Disadvantages/Limitations of GRFDDS:

Floating system is not feasible for those drugs that have

solubility or stability problem in G.I. tract.

These systems require a high level of fluid in the stomach

for drug delivery to float and work efficiently.

Drugs showing absorption window at stomach region are

only considered to be better candidates.

Drugs such as Nifedipine, which is well absorbed along the

entire GI tract and also undergo significant first-pass

metabolism, may not be suitable candidates for increasing

the GRT since the slow gastric emptying may lead to reduced

systemic bioavailability. Also there are limitations to the

applicability of GRFDDS for drugs that are irritant to gastric

mucosa.

The dosage form should be administered with a full glass of

water (200-250 ml).

These systems do not offer significant advantages over

the conventional dosage forms for drugs, which are

absorbed throughout the gastrointestinal tract.

The use of large single-unit dosage forms sometimes poses

a problem of permanent retention of rigid large-sized single-

unit forms especially in patients with bowel obstruction,

intestinal adhesion, gastropathy, or a narrow pyloric

opening (mean resting pyloric diameter 12.8 ± 7.0 mm)

POTENTIAL DRUG CANDIDATE FOR GRFDDS

GRFDDS is beneficial for drug candidate which have

stability problems at alkaline pH (captopril, ranitidine HCl,

metronidazole)

Drugs having narrow absorption window in stomach, or

upper part of small intestine

(L-DOPA, p- aminobenzoic acid, furosemide, riboflavin)



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Drugs those are locally active in the stomach (misroprostol,

antacids)

Drugs that exhibit low solubility at high pH values (e.g.,

diazepam, chlordiazepoxide, verapamil)

Drugs that disturb normal colonic microbes (e.g., antibiotics

used for the eradication of Helicobacter pylori, suchas

tetracycline, clarithromycin, amoxicillin)

Table 2: The Potential Candidates for GRFDDS

Formulation Drug candidates

Floating microspheres Aspirin, Griseofulvin, p-nitroaniline,

Ibuprofen, Ketoprofen , Piroxicam,

Verapamil, Cholestyramine,

Theophylline, Nifedipine, Nicardipine,

Dipyridamol , Tranilast and Terfinadine

Floating granules Diclofenac sodium, Indomethacin and

Prednisolone

Films Cinnarizine, Albendazole

Floating tablets and PillsAcetaminophen, Acetylsalicylic acid,

Ampicillin, Amoxycillintrihydrate,

Atenolol, Fluorouracil, Isosorbide

mononitrate, Para- aminobenzoic acid,

Piretanide, Theophylline, Verapamil

hydrochloride, Chlorpheniramine

maleate, Aspirin, Calcium Carbonate,

Fluorouracil, Prednisolone, Sotalol ,

pentoxyfilline and DiltiazemHCl,

Atenolol, ciprofloxacin.

Floating Capsules Chlordiazepoxide hydrogen chloride,

Diazepam , Furosemide, Misoprostol, L-

Dopa, Benserazide, Ursodeoxycholic

acid and Pepstatin, and Propranolol

Formulation of Floating Dosage Form

The following types of the ingredients can be incorporated in to

GRFDDS

Hydrocolloids

Inert fatty materials

Release rate accelerants

Release rate retardant

Buoyancy increasing agents

Miscellaneous

Hydrocolloids:

Suitable hydrocolloids are synthetic, anionic or non-ionic like

hydrophilic gums, modifiedcellulose derivatives. e.g., Acacia, pectin,

agar, alginates, gelatin, casein, bentonite, veegum, MC, HPC, HEC,

and SCMC can be used. The hydrocolloids must hydrate in acidic

medium i.e., gastric fluid is having pH 1.2.Althoughthe bulk density

of the formulation may initially be more than one, but when gastric

fluid is enter in the system, itshould be hydro-dynamically balanced

to have a bulk density of less than one to assure buoyancy.

Table 3: Polymers and their Applications in GRFDDS19,27

Name of Pharmaceutical A Application in GRFDDSthe polymer pplications

Pec tin Adsorbent, Pectin gel beads have beenemulsifying agent, shown to be an effectiveGelling agent, medium for controlling thethickening agent, release of a drug within thestabilizing agent. gastrointestinal (GI) tract.

Acacia Emulsifying and Used in novel tabletsuspending agent, formulations and modifiedbinder, viscosity- release tabletsenhancer

Agar Emulsifying agent, It has been investigated in astabilizing agent, number of experimentalsuppository base, pharmaceutical applicationssuspending agent, including as a Sustainedtablet binder, release agent in gels, beads,thickening agent, microspheres, and tablets.viscosity-increasingagent

Ge la t in Coating agent, Low-molecular-weightfilm-former, gelatin has been investigatedGelling agent, for its ability to enhance thesuspending agent, dissolution of orallytablet binder, ingested drugs. Ibuprofen–viscosity-increasing gelatin micro pellets haveagent. been prepared for the

controlled release of thedrug.

Alginic Acid Stabilizing agent, Alginate gel beads capablesuspending agent, of floating in the gastricsustained release cavity have been prepared,adjuvant, tablet binder, the release properties oftablet disintegrant, which were reported to beViscosity increasing applicable for sustainedagent release of drugs, and for

targeting the gastric mucosa.C hito s an Coating agent, Chitosan has been processed

disintegrant, into several pharmaceuticalfilmformer, forms including gels, films,mucoadhesive, binder, beads, microspheres, tabletsviscosity-increasing and coatings for liposomes.agent.

Ethylcellulose Coating agent, Studies have also suggestedflavoring fixative, ethylcellulose for use inTablet binder, floating microparticlestablet filler, viscosity- Based on low-density foamIncreasing agent. powder, for gastro retentive

drug delivery systemsPolycarbophil Adsorbent, Floating-bioadhesive

bioadhesive, microspheres coated withControlled release poly carbophil have beentablet binder, found to be a useful gastroemulsifying agent, retentive drug deliverythickening agent, system for the treatment ofsuspending agent. Helicobacter pylori.

So d ium Alkalizing agent, Sodium bicarbonate hasbicarbonate therapeutic agent. been used as a gas-forming

agent in alginate raftsystems and in floating,controlled-release oraldosage forms of furosemideand cisapride.

Inert fatty materials:Edible, pharmaceutical inert fatty material, having a specific gravity



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less than one can beadded to the formulation to decrease the

hydrophilic property of formulation and hence increases the

buoyancy e.g.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 includingexcipient like lactose and/or mannitol. These

may be present from about 5-60 % by weight. (Super Disintegrant)

Release rate retardants:

Insoluble substances such as di-calcium phosphate, talc, magnesium

stearate decreases thesolubility and hence retard the release of

medicaments.

Buoyancy Increasing agents:

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

can be used forenhancing the buoyancy of the formulation. It may

be adapted up to 80 % by weight.

Table 4: List of Marketed Products with increased GRT44

Brand name Drug (dose) Company, country Dosage form

Madopar® Levodopa(l00mg), benserazide(25mg) Roche Products, US Floating controlled release capsuleValrelease® Diazepam (15mg) Hoffmann-La Roche, US Floating capsuleLiquid Gaviscon® Al. hydroxide (95mg), Mg. carbonate (358mg) GlaxoSmithKline, India Raft-forming liquid alginate preparationTopalkan® Aluminium-magnesium antacid Pierre Fabre Drug, France Floating liquid alginate preparationConviron® Ferrous sulphate Ranbaxy, India gel-forming floating systemCifran OD® Ciprofioxacin (500mg & 1g) Ranbaxy, India Gas-generating floating tabletOflin OD® Ofloxacin (400mg) Ranbaxy, India Gas-generating floating tabletCytotec® Misoprostol (100ng) Pharmacia, US Bilayer floating capsule

Miscellaneous:

Pharmaceutically acceptable adjuvant like preservatives, stabilizers,

and lubricants can beincorporates in the dosage forms as per the

requirements. They do not adversely affect the hydrodynamic balance

of the systems. A list of Polymers and their Applications in GRFDDS

are given in Table 3.

Evaluation of Floating Drug Delivery System:

Evaluation of a formulation and parameters to be evaluated is a critical

aspect in formulation technology. Aschematic on evaluation of

GRFDDS is shown as in Schematic Diagram.

Evaluation of Powder Blend as per general Pharmacopoeial

specifications such as Angle of Repose, Bulk Density, Tapped

Density, Hausners Ratio, Compressibility Index etc.

Evaluation of Floating Tablets

Pharmacopoeial Tests

Hardness[46]

The hardness of the tablets was tested by diametric compression

using a Monsanto Hardness Tester. A tablet hardness of about 2-4

Kg/cm2 is considered adequate for mechanical stability.

Friability[46]

The friability of the tablets was measured in a Roche Friabilator. 20

Tablets were taken, Weighed and Initial weight was noted (W0) are

dedusted in a drum for a fixed time (100 Freefalls, in a Roche Friabilator)

and weighed (W) again. Percentage friability was calculated from the

loss in weight as given in equation as below. The weight loss should

not be more than 1 %

Friability (%) = [(Initial weight- Final weight) / (Initial weight)] x

100

Content Uniformity[46]

In this test, 20 tablets were randomly selected and the percent drug

content was determined, the tablets contained not less than 85% or

not more than 115% (100±15%) of the labeled drug content can be

considered as the test was passed.Schematic Diagram of Evaluation of Floating Drug Delivery System



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Assay[47]

The drug content in each formulation was determined by triturating

20 tablets and powder equivalent to average weight was dissolved

in 100ml of 0.1N Hydrochloric acid by sonication for 30 min. The

solution was filtered through a 0.45μ membrane filter, diluted suitably

and the absorbance of resultant solution was measured

spectrophotometrically at λmax of API( nm) using 0.1 N Hydrochloric

acid as blank .

Thickness[46]

Thickness of the all tablet formulations were measured using

verniercalipers by placing tablet between two arms of the

verniercalipers.

In-Vitro Buoyancy Studies[48-49]

The tablets were placed in a 100-mL beaker containing 0.1N HCl. The

time required for the tablet to rise to the surface and float was

determined as floating lag time.

Buoyancy (%) = Wf /W

f+W

s*100

Where, Wfand W

s are the weights of floating and settled

microspheres respectively.

In-Vitro Dissolution Study[50-51]

The In-vitro dissolution study for the Floating tablets were carried

out in USP XXIII type-II dissolution test apparatus (Paddle type)

using 900 ml of 0.1 N HCl as dissolution medium at 50 rpm and

temperature 37±0.5°C. At predetermined time intervals, 5 ml of the

samples were withdrawn by means of a syringe fitted with a pre-filter,

the volume withdrawn at each interval was replaced with same

quantity of fresh dissolution medium. The resultant samples were

analyzed for the presence of the drug release by measuring the

absorbance at λmax of API( nm) using UV Visible spectrophotometer

after suitable dilutions. The determinations were performed in

triplicate (n=3)

Kinetic modelling of drug release[52-57]

The dissolution profile of all the formulations was fitted in to zero-

order, first-order, Higuchi and Korsmeyer-peppas models to ascertain

the kinetic modelling of drug release.

In-Vivo Evaluation for Gastro-Retention:

X-ray/ Gamma Scintigraphy:

X ray/Gamma Scintigraphy is a very popular evaluation parameter

for floatingdosage form nowadays. It helps to locate dosage form in

the gastrointestinal tract (GIT), by which one can predictand correlate

the gastric emptying time and the passage of dosage form in the GIT.

Here the inclusion of aradio opaque material into a solid dosage form

enables it to be visualized by X rays. Similarly, the inclusion of a

emitting radionuclide in a formulation allows indirect external

observation using a camera or scintiscanner. Incase of scintigraphy,

the rays emitted by the radionuclide are focused on a camera,

which helps to monitor thelocation of the dosage form in the GIT.

TheFormulated Tablets (TranilastEudragit S (BaSO4) Isardipine

(HPMC) system)and for In-Vivo studies two healthy male volunteers

administered hard gelatin capsules packed with microballons (1000

mg) with 100 mL water. X-ray photographs at suitable intervals were

taken[58-60].

Two phases: Phase I (fasted conditions): Five healthy volunteers

(3 males and 2 females) in an open randomized crossover design,

capsules ingested in sitting position with 100 mL of tap water.

Phase II (fed states): Four subjects received normal or MR capsules

in a crossover design after standard breakfast. Venous blood samples

were taken in heparinized tubes at predetermined time intervals after

dosing.

In-Vivo behavior of coated and uncoated beads, prepared floating

beads was monitored using a single channel analyzing study in 12

healthy human volunteers of mean age 34 yrs by Gamma

scintigraphy[31].

Tablet density

Tablet density is an important parameter for floating tablets. The

tablet would floats only when its density is less than that of gastric

fluid (1.004). The density is determined using following

relationship[61]

V = r2hd =m/v

v = volume of tablet (cc)

r = radius of tablet (cm)

h = crown thickness of tablet (g/cc)

m = mass of tablet

FOR MULTIPLE UNIT DOSAGE FORMS (MICROSPHERES/

MICROBALLONS) [60]

In case of multiparticulate drug delivery systems, differential scanning

calorimeter (DSC), particle size analysis, flow properties, surface

morphology, mechanical properties and x-ray diffraction studies are

performed.

Size and shape evaluation

The particle size and shape plays a major role in determining solubility

rate of the drugs and thus potentially its bioavailability. The particle

size of the formulation can be determined using Sieve analysis, Air

elutriation analysis, Photo analysis, Optical microscope, Electro



167-178

résistance counting methods, Sedimentation techniques, Laser

diffraction methods[31,62].

Morphology and surface topographyThe surface topography and structures were determined usingscanning electron microscope (SEM) operated with an accelerationvoltage of 10k.v, Contact angle meter, Atomic force microscopy

(AFM), Contact profiliometer[62].

Percentage drug entrapment

Percentage entrapment efficiency was reliable for quantifying the

phase distribution of drug in the pre-pared formulations. The drug is

extracted by a suitable method, analyzed and is calculated from:

PDE = Practical Drug Loading /Theoretical Drug Loading * 100

FUTURE POTENTIAL AND CONCLUSION

The development of GRFDDS products is currently one of the most

important challenges in pharmaceutical research. From the above

review we conclude that GRFDDS products by virtue of formulation

and product design provide drug release in a modified form distinct

from that of the conventional dosage forms mainly at stomach region,

aptly applicably to drugs showing absorption at stomach site. The

physicochemical properties of the drug, polymer and the drug to

polymer ratio govern the release of drug from the formulation. The

use of one kind of polymer or another can affect the release kinetics,

the presence of burst effect and the mechanisms involved in the

release. Natural polymers have been used significantly in designing

and synthesis of novel drug delivery systems because of their

biodegradable, biocompatible, ecofriendly nature and vast

availability. Hence these natural polymers will expand the scope of

new drug delivery systems in the future. With proper selection of

natural polymers and their blending with other polymers better

floating dosage forms with improved floating lag time, floating

duration and drug release can be achieved. The use of Natural

Polymers can be a good replacement for synthetic polymers in the

Formulation development of controlled release floating dosage forms,

Formulations prepared by such renewable and eco-friendly plant

resources can be considered as promising floating matrix forming

agents to bring about sustained release action with site specific

delivery for improved bioavailability. FDDS approach may be used

for various potential active agents with narrow absorption window,

e.g. antiviral, antifungal and antibiotic agents (sulphonamides,

quinolones, penicillins, cephalosporins, aminoglycosides and

tetracyclines).

The kinetic study of drug release helps in obtaining meaningful

parameters which are employed for comparative purposes and relating

the release parameter with important parameters such as

bioavailability which further aids in studying the influence of

formulation factors on the drug release for optimization.

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