the recent developments on gastric floating drug … · 2014-04-18 · volume 2, issue 6, 2034...

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Sanjay et al. World Journal of Pharmaceutical Research

THE RECENT DEVELOPMENTS ON GASTRIC FLOATING DRUG

DELIVERY SYSTEMS: AN OVERVEIW Sanjay Dantoriya *, Govind Bhandari, Suresh Chandra Mahajan, Pooja Mishra Mahakal Institute of Pharmaceutical studies, Ujjain (M.P), India.

ABSTRACT

The concept behind the development of novel delivery system in

certain drawback of conventional dosages form and to over come the

certain aspect related to physicochemical properties of drug molecule

and related the formulation development. Controlled release floating

drug delivery system is a promising delivery system for a drug

candidate having limited absorption window sparingly soluble and

insoluble drugs, drugs those locally release in stomach and shows

degradability in colon or poor colonic absorption. This review entitled

the detailed scenario related to floating drug delivery system with their

advantages over the conventional drug delivery system and limitation,

which are helpful in development of dosages form, from the

formulation an technological point of view, the floating drug delivery

system is considerably easy and logical approach. An attempt has been made in this review

article to introduce the readers to the current technological developments in floating drug

delivery system by approaches to design single-unit and multiple unit floating systems ,

physiological and formulation variables which affect the gastric retention ,their classification

and formulation aspects , Micromeritic properties to evaluate the performance and application

of floating system, patented delivery systems , marketed products and the development of a

pharmaceutical dosage forms covered in detail.

Keywords: Floating drug delivery system, Current technology, Single unit, multiple unit,

Gastric evaluation in-vitro and in-vivo, characterization, patent.

World Journal of Pharmaceutical research

Volume 2, Issue 6, 2034-2062. Review Article ISSN 2277 – 7105

Article Received on 29 August 2013, Revised on 18 Sept. 2013,

Accepted on 10 October 2013

*Correspondence for

Author:

Sanjay Dantoriya Mahakal

Institute of Pharmaceutical

studies, Ujjain (M.P), India

[email protected]

om,

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INTRODUCTION

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and

control emptying time is a valuable asset for dosage forms, which reside in the stomach for a

longer period of time than conventional dosage forms. One of such difficulties is the ability to

confine the dosage form in the desired area of the gastrointestinal tract. To overcome this

physiological problem, several drug delivery systems with prolonged gastric retention time

have been investigated. Attempts are being made to develop a controlled drug delivery

system that can provide therapeutically effective plasma drug concentration levels for longer

durations, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug

concentration at steady state by delivering drug in a controlled and reproducible manner [1,2].

Gastro retentive systems can remain in the gastric region for several hours and hence

significantly prolong the gastric residence time of drugs. Prolonged gastric retention

improves bioavailability reduces drug waste and improves solubility of drugs that are less

soluble in high pH environment. Gastric retention to provide new therapeutic possibilities and

substantial benefits from patients. The controlled gastric retention of solid dosage forms may

be achieved by the mechanism of muco adhesion [3,4,5]. floatation, sedimentation, expansion,

modified shape systems or by the administration of pharmacological agents [6,7], that delaying

gastric emptying. Based on these approaches, floating drug delivery systems seems to be the

promising delivery systems for control release of drugs. [8].

Stomach Specific FDDS have a bulk density less than gastric fluids and so remain buoyant in

the stomach without affecting the gastric emptying rate for a prolonged period of time. While

the system is floating on the gastric contents, the drug is released slowly at the desired rate

from the system. After release of drug, the residual system is emptied from the stomach. This

results in an increased GRT and a better control of fluctuations in plasma drug concentration. [39,40].

Basic Gastrointestinal Tract Physiology

(A)Stomach

Basically stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The

proximal part made of fundus and body acts as a reservoir for undigested material, the antrum

is the main site for mixing motions and act as a pump for gastric emptying by propelling

actions [9,10]. Gastric emptying occurs during fasting as well as fed states. The pattern of

motility is however distinct in the 2 states. During the fasting state an inter-digestive series of

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electrical events take place, which cycle both through stomach and intestine every 2 to 3

hours [10-18].

Figure 1: Physiology of stomach

(B). Histology of Stomach [19-21]

This is called the inter-digestive myloelectric cycle or migrating myloelectric cycle (MMC),

which is further divided into following 4 phases as described by Wilson and Washington [21].

Table 1: MMC phases

Phase Time

I (basal phase) Lasts from 40 to 60

minutes

with rare contractions.

II (pre-burst phase) lasts for 40 to 60 minutes with intermittent action potential

and contractions.

III (burst phase) lasts for 4 to 6 minutes intense and regular contractions for

short period.

IV (digestive

motility pattern)

lasts for 0 to 5 minutes continuous contractions

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Figure 2: Motility patterns of the GIT in the fasted state [22-25]

Advantages of Floating drug delivery system

A floating drug delivery system offers numerous advantages over conventional drug delivery

system:

Sustained drug delivery A floating drug delivery system can remain in the stomach for

several hours and the assumed prolongation in the gastric retention is postulated to cause

sustained drug release behavior. [43,44].

Site-specific drug delivery Targeting of drug to stomach appears to be useful for all

substances intended to produce a lasting local action on the gastro duodenal wall. [44].

Pharmacokinetic advantage In addition, with the total gastrointestinal transit duration is

increased, a greater amount of drug may be delivered and thus the relative bioavailability

will consequently be increased

Targeted therapy for local ailments in the upper GIT The prolonged and sustained

administration of the drug from GRDF to the stomach may be advantageous for local

therapy in the stomach and small intestine. eg. Antibiotic for Helicobacter pylori based

ulcer, Antacid.

Reduced counter-activity of the body Slow input of the drug into the body was shown

to minimize the counter activity leading to higher drug efficiency.

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Minimized adverse activity at the colon Retention of the drug in the GRDF at the

stomach minimizes the amount of drug thatreaches the colon. Thus, undesirable activities

of the drug in colon may be prevented.

Enhanced bioavailability The bioavailability of riboflavin CR-GRDF is significantly

enhanced in comparison to the administration of non-GRDF CR polymeric formulations. [45, 46, 47].

Disadvantages of floating drug delivery system [48-50]

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-coat, water. The drugs that are significantly absorbed through out

gastrointestinal tract, which undergo significant first pass metabolism, are only desirable

candidate.

Some drugs present in the floating system causes irritation to gastric mucosa.

Three major requirments of FDDS are [48-50]

It must form a cohesive gel barrier.

It must maintain specific gravity lower than gastric contents (1.004-1.01g//c).

It should release contents slowly to serve as a reservoir.

Criteria for selection of drug candidate for FDDS [51]

Desirable half-life If the drug has a short half-life of less than 2 hours, the dosage form

may contain a prohibitively large quantity of the drug.

High therapeutic index Drugs with low therapeutic index are not suitable for

incorporation in controlled release formulations. e.g. Digitoxin.

Small dose the dose of a drug in the conventional dosage form is high, its suitability as a

candidate for controlled release is seriously undermined

Aqueous solubility Drugs with aqueous solubility make good candidates for controlled

release dosage form.

Stability to wide pH range, GI enzymes and flora Stability of the drug in the GI

contents is important to ensure a complete and reproducible drug input into the body.

Typically the drug must be stable in the pH range of 1 to 8.

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First pass clearance Delivery of the drug to the body in desired concentration is

seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism,

when administered in controlled release form. Saturable hepatic metabolism may render a

drug unsuitable because systemic availability for such drug is highly reduced when the

input rate is small.

Drugs Those Are Unsuitable For Gastroretentive Drug Delivery Systems [27,31]

Drugs that have very limited acid solubility e.g. phenytoin etc.

Drugs that suffer instability in the gastric environment e.g. erythromycin etc.

Drugs intended for selective release in the colon e.g. 5- amino salicylic acid and

corticosteroids etc.

Mechanism of floating systems [52]

While the system is floating on the gastric the drug is released slowly at the desired rate from

the system. After release of drug, the residual system is emptied from the stomach However

besides a minimal gastric content needed to allow the proper achievement of the buoyancy

retention principle, a minimal level of floating force (F) is also required to keep the dosage

form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a

novel apparatus for determination of resultant weight has been reported in the literature. The

apparatus operates by measuring continuously the force equivalent to F (as a function of

time) that is required to maintain the submerged object. The object floats better if F is on the

higher positive side. This apparatus helps in optimizing FDDS with respect to stability and

durability of floating forces produced in order to prevent the drawbacks of unforeseeable

intra gastric buoyancy capability variations19.

F = F buoyancy - F gravity = (Df - Ds) gv---1

Where, F= total vertical force,

Df =fluid density,

Ds = object density,

v = volume and

g = acceleration due to gravity.

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Figure 5: Different mechanisms of floating systems

Classification of FDDS [10]

A. Single Unit Floating Dosage Systems

a) Effervescent Systems (Gas-generating Systems)

b) Non-effervescent Systems B. Multiple Unit Floating Dosage Systems

a) Non-effervescent Systems

b) Effervescent Systems (Gas-generating Systems)

c) Hollow Microspheres

d). Raft Forming Systems

Types of floting drug delivery system

Based on the mechanism of buoyancy, two distinctly different technologies have been

utilized in the development of FDDS

(A). Non-Effervescent FDDS [57, 58, 59]

The Non-effervescent FDDS is based on mechanism of swelling of polymer or bioadhesion

to mucosal layer in GI tract. The most commonly used excipients in noneffervescent FDDS

are gel forming or highly swellable cellulose type hydrocolloids, hydrophilic gums,

polysaccharides and matrix forming materials such as polycarbonate, polyacrylate,

polymethacrylate, polystyrene as well as bioadhesive polymers such as Chitosan and

carbopol.

The various types of this system are as:

(1). Colloidal gel barrier systems

Hydro-dynamically balanced system (HBS) of this type contains drug with gel forming or

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swellable cellulose type hydrocolloids, polysaccharides and matrix forming polymers. They

help in prolonging the GI residence time and maximize drug reaching its absorption site in

the solution form ready for absorption. These systems incorporate high levels (20 to 75 %

w/w) of one or more gel forming highly swellable cellulose type hydrocolloids e.g.

Hydroxyethyl cellulose, hydroxyropyl cellulose, hydroxyropyl methyl cellulose, sodium

carboxymethylcellulose incorporated either in tablets or capsules.[60]

(a). Single Layer Floating Tablets: They are formulated by intimate mixing of drug with a

gel-forming hydrocolloid, which swells in contact with gastric fluid and maintains bulk

density of less than unity. They are formulated by intimate mixing of drug with low-density

enteric materials such as HPMC.

(b). Bi-layer Floating Tablets: A bi-layer tablet contain two layer one immediate release

layer which releases initial dose from system while the another sustained release layer

absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and

maintain a bulk density of less than unity and thereby it remains buoyant in the stomach.

Figure 6: Intragastric floating tablet.

(2). Micro porous compartment system

This technology is comprised of encapsulation of a drug reservoir inside a micro porous

compartment with pores along its top and bottom surfaces. The peripheral walls of the drug

reservoir compartment are completely sealed to prevent any direct contact of gastric mucosal

surface with undissolved drug. In stomach, the floatation chamber containing entrapped air

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causes the delivery system to float over the gastric contents. Gastric fluid enters through the

pores, dissolves the drug and carries the dissolved drug for continuous transport across the

Intestine for absorption.

Figure 7: Micro porous intra-gastric floating drug delivery device

(3). Alginate Beads

Multi-unit floating dosage forms were developed from freeze dried calcium alginate.

Spherical beads of approximately 2.5 mm diameter can be prepared by dropping sodium

alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium

alginate leading to formation of porous system, which can maintain a floating force for over

12 hours. When compared with solid beads, which gave a short residence time of 1 hour, and

these floating beads gave a prolonged residence time of more than 5.5 hours.

(4). Hollow Microspheres

Hollow microspheres (microballoons), loaded with drug in their outer polymer shells are

prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane

solution of the drug and an enteric acrylic polymer is poured into an agitated aqueous

solution of PVA that is thermally controlled at 40 °C. The gas phase generated in dispersed

polymer droplet by evaporation of dichloromethane forms an internal cavity in microsphere

of polymer with drug. The microballoons float continuously over the surface of acidic

dissolution media containing surfactant for more than 12 hours.

Figure 8: Mechanism of micro balloon formation by emulsion-solvent diffusion Method.

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(B). Effervescent FDDS

A drug delivery system can be made to float in the stomach by incorporating a floating

chamber, which may be filled with vacuum, air or inert gas. The gas in floating chamber can

be introduced either by volatilization of an organic solvent or by effervescent reaction

between organic acids and bicarbonate salts [61].

Figure10: Floating pills a) The penetration of water into effervescent layer leads to a

CO2 generation and makes the system to float.

(1).Volatile liquid containing system

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 Poly vinyl alcohol, 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[62].

(a). Inflatable gastrointestinal delivery systems

In these systems an inflatable chamber is incorporated, which contains liquid that gasifies at

body temperature to cause the chamber to inflate in the stomach. The inflatable chamber

automatically inflates and retains the drug reservoir compartment in floating position. The

drug continuously released from the reservoir into the gastric fluid.

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Figure12: Inflatable gastrointestinal delivery system

(b). Intragastric osmotically controlled drug delivery system

It is comprised of an osmotic pressure controlled drug delivery device and an inflatable

floating support in a biodegradable capsule. In the stomach capsule quickly disintegrates to

release the intragastric osmotically controlled drug delivery device. The inflatable support

inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body

temperature to inflate the bag. The osmotic pressure controlled drug delivery device consists

of two components; drug reservoir compartment and an osmotically active compartment. The

drug reservoir compartment is enclosed by a pressure responsive collapsible bag, which is

impermeable to vapour and liquid and has a drug delivery orifice. The osmotically active

compartment contains an osmotically active salt and is enclosed within a semi permeable

housing. In the stomach, the water in the GI fluid is continuously absorbed through the

semipermeable membrane into osmotically active compartment to dissolve the osmotically

active salt. An osmotic pressure is thus created which acts on the collapsible bag and turns in

forces the drug reservoir compartment to reduce its volume and activate the drug reservoir

compartment to reduce its volume and activate the drug release in solution form through the

delivery orifice. The floating support is also made to contain a bioerodible plug that erodes

after a predetermined time to deflate the support. The deflated drug delivery system is then

emptied from the stomach.

Figure13: Intragastric osmotically controlled drug delivery system

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(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[62, 63].

(3). Raft Forming systems

Here, a gel-forming solution (e.g. Sodium alginate solution containing carbonates or

bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO2 bubbles on

contact with gastric fluid. Formulations also typically contain antacids such as aluminium

hydroxide or calcium carbonate to reduce gastric acidity. Because raft forming systems

produce a layer on the top of gastric fluids, they are often used for gastro-oesophageal reflux

treatment as with Liquid Gaviscon (GlaxoSmithKline) [64].

Polymers And Other Ingredients Used In Preparations Of Floating Drugs [65-66]

The following types of the ingredients can be incorporated in to FDDS

1.Hydrocolloids/polymer

2.Inert fatty materials

3.Effervescent agents

4.Release rate accelerants

5.Release rate retardant

6.Buoyancy increasing agents

7.Low density material

8.Miscellaneous

Hydrocolloids: Suitable hydrocolloids are synthethics, anionic or non ionic like hydrophilic

gumes, modified cellulose derivatives. Example. Acacia, pectin, agar, alginates, gelatin,

casein, bentonite, veegum, HPMC K4 M, Calcium alginate, Eudragit S100, Eudragit RL,

Propylene foam, Eudragit RS, ethyl cellulose, poly methyl methacrylate, Methocel K4M,

Polyethylene oxide, β Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol,

polycarbonate, PVA, Polycarbo-nate, Sodium alginate, HPC-L, CP 934P, HPC, Eudragit S,

HPMC, Metolose S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic

polymer, E4 M and Carbopol.can be used.

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Inert fatty materials (5%-75%) : Edible, inert fatty materials having a specific gravity of

less than one can be used to decrease the hydrophilic property of formulation and hence

increase buoyancy. E.g. Beeswax, fatty acids,long chain fatty alcohols, Gelucires 39/01and

43/01.

Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium

Glycine Carbonate, CG (Citroglycine).

Release rate accelerants (5%-60%): eg. lactose, mannitol

Release rate retardants (5%-60%): eg Dicalcium phosphate, talc, magnesium stearate.

Buoyancy increasing agents (upto80%): eg. Ethyl cellulose.

Low density material : Polypropylene foam powder (Accurel MP 1000).

Miscellaneous: Pharmaceutically acceptable adjuvant like preservatives, stabilizers, and

lubricants can be incorporates in the dosage forms as per the requirements.

Selection of polymer [27,67, 68,69]

(A). Gas generating agent or alkalinizing agents and acidulent

Sodium bicarbonate, Calcium carbonates, Citric acid, Tartaric acid, Adipic acid.

Rational behind the selection

Effervescent compound generally use for this purpose. Sodium bicarbonate,calcium

carbonate with citric acid and tartaric acid. When these compounds come in contact with the

acidic gastric contents, carbon dioxide is liberated and gets entrapped in swelled

hydrocolloids, which provide buoyancy to the dosage forms. Sodium bicarbonate and

reduced CO2 generation in the presence of dissolution medium (0.1 N HCL).

Acidulent is used; since the pH of the stomach is elevated under fed condition (~3.5).

Acidulent (Citric acid, Tartaric acid, Adipic acid) was incorporate in the formulation to

provide an acidic medium for sodium bicarbonate.

(B). Viscolyzing agent

Sodium alginate, Carbopol 934

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They used to increase the viscosity in the system. Tablet formulations using Carbopol

polymers have demonstrated zero-order and near zero-order release kinetics.The Carbopol

polymers produce tablets of excellent hardness and low friability. Carbomers show larger

dissolution times at lower concentrations than other excipients.

(C). Swelling agent/Gel forming polymer

Hydroxypropylmethylcellulose (HPMC)


Hypermellose powder is stable material, although it is hygroscopic after drying. Solution is

stable at pH 3-11. Increasing temperature reduces the viscosity of solutions. Hypermellose

undergoes a reversible sol-gel transformation upon heating and cooling, respectively. The gel

point 50-90°C, depending upon grade and concentration of material. Grades which are

generally used in floating tablet are, which are highly viscous in nature like HPMC K 100,

HPMC K 4, HPMC K 15.

(D). Disintegrating agent

Povidone, Polyplasdone XL and XL-10


PVP belongs to a class of compounds known as superdisintegrantes. They used as highly

active explosive agent and as an accelerating agent for disintegration of solid medications. In

tabletting, povidone solutions are used as binder in the wet granulation processes.

Table 2: List of Drugs Formulated as Single and Multiple Unit Forms of Floating Drug

Delivery Systems 70-109

S.

No.

DOSAGE

FORM

DRUGS

1. Microspheres Aspirin, Grisiofulvin, pnitroanilline,Ibuprofen,

Terfinadine, Tranilast.

2. Granules Diclofenac sodium[88]Diltiazem [89]Indomethacin [90]

Fluorouracil [91]Prednisolone [92]Isosorbide mononitrate [86]Isosorbide dinitrate [84]

3. Films p-Aminobenzoic acid [77,78]Cinnarizine [8]Piretanide

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[94]Prednisolone[95]Quinidine gluconate [95]

4. Powders Several basic drugs like Riboflavin-59-phosphate [96,97]

Sotalol [85] Theophylline [82]

5. Capsules Ursodeoxycholic acidVerapamil HCl [98,99,100]

Chlordiazepoxide HCl [101] Diazepam [101,102]

Furosemide [103] L-Dopa and benserazide [104]

Misoprostol [105,106] Propranolol HCl [107]

Ursodeoxycholic acid [108] Nicardipine[109]

6. MicrospheresTable

ts/pills

Chlorpheniramine maleate [72]

Aspirin [72] griseofulvin[72]Acetaminophen [73, 75]

p-nitroaniline [74] Acetylsalicylic acid [74] Ibuprofen[75]

Amoxycillin trihydrate [76] Terfenadine [77] Ampicillin [78]

Tranilast[74, 79] Atenolol [79, 80]

Theophylline [81] Captopril [82] Isosorbide di nitrate [83] Sotalol [85] Isosorbidemononitrate acid[86]

Amoxicillin trihydrate, Ampicillin, Atenolol,

Chlorpheniramine, Cinnarizine, Diltiazem, Fluorouracil,

Isosorbide mononitrate, Isosorbide dinitrate, p-aminobenzoic

acid, Piretanide, Prednisolone, Quinidine gluconate.

Marketed Products of FDDS [110-118]

Table 4: Generally Manufactured Marketed Product

S.No BRAND

NAME

DRUG (DOSE) COMPANY,

COUNTRY

REMARKS

Valrelease Diazepam

(15 mg)

Hoffmann-

La Roche,USA

Floating capsule

Valrelease Diazepam

(15 mg)

Hoffmann-

La Roche,USA

Floating capsule

Liquid

Gavison®

Al hydroxide

(95 mg),

Mg carbonate (358 mg)

Glaxo Smith

Kline, India

Effervescent

floating liquid

Alginatepreparation

Topalkan® Al-Mg

Antacid

Pierre Fabre

Drug,

Floating liquid

alginate

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France preparation

Conviron Ferrous

Sulphate

Ranbaxy,

India

Colloidal gel

forming FDDS

Cifran

OD®

Ciprofloxaci

n (1 gm)

Ranbaxy,

India

Gasgenerating

Floating tablet

Cytotec®

Misoprostal

(100 mcg/200 mcg)

Pharmacia,

USA

Bilayer floating

Capsule

Oflin OD® Ofloxacin (400mg) Ranbaxy, India Gas generating

Floating tablet

Evaluation Techniques

In-vitro evaluation of floating tablets For Single Unit Dosage Forms (ex: tablets).

I. Pre-compression parameters

a) Angle of Repose [119]

The frictional forces in a loose powder or granules can be measured by angle of repose. This

is the maximum angle possible between the surface of a pile of powder or granules and the

horizontal plane.

The granules were allowed to flow through the funnel fixed to a stand at definite height (h).

The angle of repose was then calculated by measuring the height and radius of the heap of

granules formed.

tan Ə = h/r

Ə = tan-1 (h/r)

Ə = angle of repose

h = height of the heap

r = radius of the heap

b) Compressibility Index

The flow ability of powder can be evaluated by comparing the bulk density (ρo) and tapped

density (ρt) of powder and the rate at which it packed down. Compressibility

index was calculated by –

Compressibility index (%) = ρ t _ ρo x 100 ρt

Where ρo = Bulk density g/ml

ρt = Tapped density g/ml.

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II. Post-compression parameters

a) Shape of Tablets

Compressed tablets were examined under the magnifying lens for the shape of the tablet.

b) Tablet Dimensions

Thickness and diameter were measured using a calibrated varniear caliper. Three tablets of

each formulation were picked randomly and thickness was measured individually.

c) Hardness [120]

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The

hardness of the tablets was determined using Monsanto hardness tester. It was expressed in

kg/cm2. Three tablets were randomly picked and hardness of the tablets was determined.

d) Friability test [119]

The friability of tablets was determined by using Roche Friabilator. It was expressed in

percentage (%).Ten tablets were initially weighed (W in initial) and transferred into

friabilator. The friabilator was operated at 25rpm for 4 minutes or run up to 100 revolutions.

The tablets were weighed again (Wt final). The % friability was then calculated by –

% of Friability = 100 (1-W0/W)

% Friability of tablets less than 1% was considered acceptable.

e) Tablet Density [121]

Tablet density was an important parameter for floating tablets. The tablet would floats only

when its density was less than that of gastric fluid (1.004). The density was determined using

following relationship.

V = r2h d = m/v

v = volume of tablet (cc)

r = radius of tablet (cm)

h = crown thickness of tablet (g/cc)

m = mass of tablet

f) Weight Variation Test [119]

Ten tablets were selected randomly from each batch and weighed individually to check for

weight variation. A little variation was allowed in the weight of a tablet by U.S.

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Pharmacopoeia.The following percentage deviation in weight variation was allowed show in

table.

g) Buoyancy / Floating Test

The time between introduction of dosage form and its buoyancy on the simulated gastric fluid

and the time during which the dosage form remain buoyant were measured. The time taken

for dosage form to emerge on surface of medium called Floating Lag Time (FLT) or

Buoyancy Lag Time (BLT) and total duration of time by which dosage form remain buoyant

is called Total Floating Time (TFT).

h) Swelling Study

The swelling behavior of a dosage form was measured by studying its weight gain or water

untake, the dimensional changes could be measured in terms of the increase in tablet diameter

and/or thickness over time. Water uptake was measured in terms of percent weight gain, as

given by the equation.

WU = (W1 – W0)

--------------× 100

W0

Wt = Weight of dosage form at time t.

W0 = Initial weight of dosage form

. i) In-vitro drug release studies

The test for buoyancy and in vitro drug release studies are usually carried out in simulated

gastric and intestinal fluids maintained at 37 o C. In practice, floating time is determined by

using the USP dissolution apparatus containing 900ml of 0.1 HCl as a testing medium

maintained at 37 o C. The time required to float the HBS dosage form is noted as floating (or

floatation) time.

Charecterization parameter

1. 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 was determined using

Sieve analysis, Air elutriation analysis, Photo analysis, Optical microscope ,Electro résistance

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counting methods (Coulter counter), Sedimentation techniques, Laser diffraction methods,

ultrasound attenuation spectroscopy, Air Pollution Emissions Measurements etc [120].

2. Floating properties

Effect of formulation variables on the floating properties of gastric floating drug delivery

system was determined by using continuous floating monitoring system and statistical

experimental design[121].

3. Surface topography

The surface topography and structures were determined using scanning electron microscope

(SEM, JEOL JSM – 6701 F, Japan) operated with an acceleration voltage of 10k.v, Contact

angle meter, Atomic force microscopy (AFM), Contact profiliometer [122].

4. Determination of moisture content

The water content per se is seldom of interest. Rather, it shows whether a product intended

for trade and production has standard properties such as-

1. Storability

2. Agglomeration in the case of powders

3. Microbiological stability

4. Flow properties, viscosity

5. Dry substance content

6. Concentration or purity

7. Commercial grade (compliance with quality agreements)

Thus moisture content of the prepared formulations was determined by Karl fisher titration,

vacuum drying, Thermo gravimetric methods, Air oven method, Moisture Meters, Freeze

drying as well as by physical methods [123].

5. Swelling studies

Swelling studies were performed to calculate molecular parameters of swollen polymers.

Swelling studies was determined by using Dissolution apparatus, optical microscopy and

other sophisticated techniques which include H1NMRimaging, Confocal laser scanning

microscopy (CLSM), Cryogenic scanning electron microscopy (Cryo-SEM), Light scattering

imaging (LSI) etc. The swelling studies by using Dissolution apparatus (USP

dissolution apparatus (usp-24) labindia disso 2000) was calculated as per the following

formula [124].

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Swelling ratio = Weight of wet formulation / Weight of formulations

6. Determination of the drug content

Percentage drug content provides how much amount of the drug that was present in the

formulation. It should not exceed the limits acquired by the standard monographs. Drug

content was determined by using HPLC, HPTLC methods, Near infrared spectroscopy

(NIRS), Microtitrimetric methods, Inductively Coupled Plasma Atomic Emission

Spectrometer (ICPAES) and also by using spectroscopy techniques [125].

7. Percentage entrapment efficiency

Percentage entrapment efficiency was reliable for quantifying the phase distribution of drug

in the prepared formulations. Entrapment efficiency was determined by using three methods

such as Micro dialysis method, Ultra centrifugation, and pressure Ultra filtration [126].

8. In-vitro release studies

In vitro release studies (USP dissolution apparatus) were performed to provide the amount of

the drug that is released at a definite time period. Release studies were performed by using

Franz diffusion cell system and synthetic membrane as well as different types of dissolution

apparatus. [127].

9. Powder X-ray diffraction

X-ray powder diffraction (Philips analytical, model-pw1710) is the predominant tool for the

study of polycrystalline materials and is eminently suited for the routine characterization of

pharmaceutical solids. Samples were irradiated with α radiation and analyzed between 2 ºC

and 60 ºC .The voltage and current used were 30KV and 30mA respectively[128].

10. Fourier transform infrared analysis

Fourier transform infrared spectroscopy (FTIR, Shi-madzu, Model-RT-IR-8300) is a

technique mostly used to identify organic, polymeric, and some inorganic materials as well as

for functional group determination. Fourier Transform Infrared Analysis (FT-IR)

measurements of pure drug, polymer and drug loaded polymer formulations were obtained on

FTIR. The pellets were prepared on KBr-press under hydraulic pressure of 150kg/cm2; the

spectra were scanned over the wave number range of 3600 to 400 cm-1 at the ambient

temperature [128].

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11. Differential Scanning Calorimetry (DSC)

DSC (Shimadzu, Model-DSC-60/DSC-50) are used to characterize water of hydration of

pharmaceuticals .Thermo grams of formulated preparations were obtained using DSC

instrument equipped with an intercooler. Indium/Zinc standards were used to calibrate the

DSC temperature and enthalpy scale. The sample preparations were hermitically sealed in an

aluminum pan and heated at a constant rate of 10°C/min; over a temperature range of 25° C –

65°C. Inert atmosphere was maintained by purging nitrogen gas at the flow rate of 50ml/min [128].

Application of Floating Drug Delivery Systems

1. Sustained Drug Delivery

HBS systems can remain in the stomach for long periods and hence can release the drug over

a prolonged period of time. The problem of short gastric residence time encountered with an

oral CR formulation hence can be overcome with these systems. These systems have a bulk

density of <1 as a result of which they can float on the gastric contents. These systems are

relatively large in size and passing from the pyloric opening is prohibited [130].

2. Site-Specific Drug Delivery

These systems are particularly advantageous for drugs that are specifically absorbed from

stomach or the proximal part of the small intestine, eg. riboflavin and furosemide.Eg.

Furosemide is primarily absorbed from the stomach followed by the duodenum [131].

3. Absorption Enhancement:

Drugs that have poor bioavailability because of site-specific absorption from the upper part of

the gastrointestinal tract are potential candidates to be formulated as floating drug delivery

systems, thereby maximizing their absorption [130].

CONCLUSION

Gastro-retentive floating drug delivery systems have emerged as an efficient means of

enhancing the bioavailability and controlled delivery of many drugs .The increasing

sophistication pf delivery technology will ensure the development of increase number of

gastric retentive drug delivery to optimize the delivery of molecules that exhibits absorption

window, low bioavailability of extensive first pass metabolism.

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