chapter -isradipine

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Chapter-1

1. INTRODUCTION

1.1 NOVEL DRUG DELIVERY SYSTEM

The design of oral controlled DDS should be primarily aimed to achieve more predictable

and increased bioavailability. Now a day’s most of the pharmaceutical scientist is

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. Controlled release implies the predictability

and reproducibility to control the drug release, drug conc in target tissue and optimization

of the therapeutic effect of a drug by controlling its release in the body with lower and

less fre uent dose .!"# $owever, this approach is be dilled with several physiologicaldifficulties such as in ability to restrain and locate the controlled drug delivery system

within the desired region of the %&T due to variable gastric emptying and motility.

'urthermore, the relatively brief %(T in humans which normally average )*+ hrs through

the ma or absorption zone, i.e., stomach and upper part of the intestine can result in

incomplete drug release from the drug delivery system leading to reduced efficacy of the

administered dose. Therefore, control of placement of a DDS in a specific region of the

%& tract offers advantages for a variety of important drugs characterized by a narrow

absorption window in the %&T or drugs with a stability problem. !)#

Anatomy and physiolo y o! stoma"h #$%

The stomach is the most dilated part of the %&T and is situated between the lower end of

the oesophagus and the small intestine .&ts opening to the duodenum is controlled by the

pyloric sphincter .The stomach can be divided into four anatomical regions, namely the

fundus, the body, the antrum and the pylorus.



Chapter-1

&i 1 Anatomy o! stoma"h

The two ma or functions of the stomach are

To act as a temporary reservoir for ingested food and to deliver it the duodenum

at a controlled rate.To reduce the ingested solids to uniform creamy consistency, -nown as chime, by

the action of acid and enzymatic digestion. This enables better contact of the

ingested material with the mucous membrane of the intestines and their by

facilitates absorption.nother perhaps less obvious, function of stomach is its role in reducing the ris-

of no/ious agents reaching intestine.

Gast'i" motility

%astric emptying occurs during fasting as well as fed states. During the fasting state an

inter digestive series of electrical events ta-e place, which cycles through stomach and

intestine every ) to + hrs. This is called the inter digestive mylo electric cycle or

migrating mylo electric cycle !00C#, which is further divided into 1 phases as described

by 2ilson and 2ashington. !1, 3#

4hase & !basal phase# lasts from 15 to 65 min with rare contractions.



Chapter-1

4hase && !preburst phase# lasts for 15 to 65 min with intermittent action and potential

contractions. s the phase progresses the intensity and fre uency also increases

gradually.

4hase &&& !burst phase# lasts for 1 to 6 min. &t includes intense and regular contractions for short period. &t is due to this wave that all the undigested material is swept out of the

stomach down to the small intestine. &t is also -nown as the house-eeper wave. 4hase &7

lasts for 5 to 3 min and occurs between phases &&& and & of ) consecutive cycles.

fter the ingestion of a mi/ed meal, the pattern of contractions, changes from fasted to

that of fed state. This is also -nown as digestive motility pattern and comprises

continuous contractions as in phase && of fasted state. These contractions result in

reducing the size of food particles !to less than " mm#, which are propelled toward the pylorus in a suspension form. During the fed state onset of 00C is delayed resulting in

slowdown of gastric emptying rate. Scintigraphic studies determining gastric emptying

rates revealed that orally administered controlled release dosage forms are sub ected to

basically two complication, that of short gastric residence time and unpredictable gastric

emptying rate !6, 8#

C'it('ia !o' s(l("tion o! d') "andidat( !o' GRDDS #*%

The %9DDS are suitable for following types of drug therapy

bsorption from upper %&T, drugs have a particular site for ma/imum absorption

eg. Ciproflo/acin, whose ma/imum absorption is in the stomach only. The

absorption of 0etformin hydrochloride is confirmed to small intestine only and

the conventional sustained release dosage forms may have poor bioavailability

since absorption appears to diminish when the dosage form pass in to large

intestine.Drugs having low 4:a, which remains unionized in stomach for better absorption.Drugs having reduced solubility at higher p$ eg. Captopril and Chlordiazepo/ide

and the bioavailability of drugs that get degraded in al-aline p$ can be increased

by formulating gastro*retentive dosage forms eg. Do/ifluridine, which degrades

in small intestine.



Chapter-1

;ocal action as it is seen in the treatment of $. 4ylori by mo/icillin and

0isoprostol for ulcers.To minimize gastric irritation that may be caused by sudden increase of drug

concentration in the stomach eg. NS &Ds.

&mprove effectiveness of particular drugs eg. ntibiotics in the colon tend todisturb the micro flora causing overgrowth of micro organisms li-e Clostridium

difficile causing colitis.

&a"to's a!!("tin ast'o '(t(nti+( syst(m

The %9T of dosage forms is controlled by several factors such as density and size of the

dosage form, food inta-e, nature of the food, posture, age, gender, sleep and disease state

of the individual !eg. Crohn s disease and diabetes# and administration of drugs such as‟

pro-inetic agents !0osapiride and 0etoclopramide#. !<#

D(nsity o! dosa ( !o'm

Dosage forms having a density lower than that of gastric fluid e/perience floating

behavior and hence gastric retention. density of =".5 gm>cm+ is re uired to e/hibit

floating property. $owever, the floating tendency of the dosage form usually decreases as

a function of time, as the dosage form gets immersed into the fluid, as a result of the

development of hydrodynamic e uilibrium !"5#

Si,( and shap(

Dosage form unit with a diameter of more than 8.3 mm are reported to have an increased

%9T competed to with those with a diameter of <.< mm. The dosage form with a shape

tetrahedron and ring shape devises with a fle/ural modulus of 1? and )).3 :S& are

reported to have better %&T at <5 to "55 @ retention for )1 hrs compared with other

shapes.!""#

&(d o' )n!(d stat(



Chapter-1

Ander fasting conditions, the %& motility is characterized by periods of strong motor

activity or the 00C that occurs every ".3 to ) hrs. The 00C sweeps undigested

material from the stomach and if the timing of administration of the formulation

coincides with that of the 00C, the %9T of the unit can be e/pected to be very short.

$owever, in the fed state, 00C is delayed and %9T is considerably longer. !")#

Nat)'( o! th( m(al

'eeding of indigestible polymers of fatty acid salts can change the motility pattern of the

stomach to a fed state, thus decreasing the %(9 and prolonging the drug release !"+#

Calo'i" "ont(nt

%9T can be increased between 1 to "5 hrs with a meal that is high in proteins and fats.

&'(-)(n"y o! !((d

The %9T can increase by over 155 min when successive meals are given compared with

a single meal due to the low fre uency of 00C !"1#

E!!("t o! (nd(' post)'( and a (

'emales showed comparatively shorter mean ambulatory %9T than males, and the gastric

emptying in women was slower than in men. !"3#

The floating and non*floating systems behaved differently. &n the upright position,

the floating systems floated to the top of the gastric contents and remained for a longer

time, showing prolonged %9T. But the non*floating units settled to the lower part of the

stomach and underwent faster emptying as a result of peristaltic contractions, and the

floating units remained away from the pylorus. !"6# $owever, in supine position, the

floating units are emptied faster than non*floating units of similar size. !"8#

1./ A00ROAC ES TO GASTRIC RETENTION



Chapter-1

number of approaches have been used to increase the %9T of a dosage form in stomach

by employing a variety of concepts. These include

&loatin syst(ms #1*%

'DDS have a bul- density lower than gastric fluids and thus remain buoyant in the

stomach for a prolonged period of time, without affecting the %(9. 2hile the system is

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

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

These results in an increase in the %9T and a better control of fluctuations in the plasma

drug concentration. 'loating systems can be classified into two distinct categories,

effervescent and non*effervescent systems.

2io3M)"o4adh(si+( syst(ms #15%

Bio adhesive 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 bio adhesive polymers that can be adhering to

the epithelial surface of the %&T. The proposed mechanism of bio adhesive is the

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

S6(llin and (7pandin syst(ms #/8 /1%

These are the dosage forms, which after swallowing swell to an e/tent that prevents their

e/it from the pylorus. s a result, the dosage form is retained in the stomach for a longer.

These systems may be named as plug type systemE since they e/hibit the tendency to

remain logged at the pyloric sphincter if that e/ceed a diameter of appro/imately

")*"? mm in their e/panded state. Such polymeric matrices remain in the gastric

cavity for several hrs even in the fed state.

balance between the e/tent and duration of swelling is maintained by the degree of

cross*lin-ing between the polymeric chains. high degree of cross*lin-ing retards the

swelling ability and maintains its physical integrity for prolonged period.

i h d(nsity syst(ms #//%



Chapter-1

These systems with a density of about + g>cm+ are retained in the rugae of the stomach

and are capable of withstanding its peristaltic movements. density of ).6* ).? g>cm+

acts as a threshold value after which systems can be retained in the lower part of the

stomach. $igh*density formulations include coated pellets. Coating is done by heavy

inert materials such as barium sulphate, zinc o/ide, titanium dio/ide, and iron powder.

In"o'po'ation o! passa ( d(layin !ood a (nts #/$%

'ood e/cipients li-e fatty acids eg. Salts of myristic acid change and modify the pattern

of the stomach to a fed state, thereby decreasing %(9 and permitting considerable

prolongation of release. The delay in the gastric emptying after meals rich in fats is

largely caused by saturated fatty acids with chain length of C "5 *C"1 .

Ion (7"han ( '(sins #/9%

coated ion e/change resin bead formulation has been shown to have gastric retentive

properties, which was loaded with bicarbonates. &on e/change resins are loaded with

bicarbonate and a negatively charged drug is bound to the resin. The resultant beads were

then encapsulated in a semi*permeable membrane to overcome the rapid loss of carbon

dio/ide. Apon arrival in the acidic environment of the stomach, an e/change of

chloride and bicarbonate ions ta-e place, as a result of this reaction carbon dio/ide was

released and trapped in the membrane thereby carrying beads towards the top of gastric

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

which will sin- uic-ly.

Osmoti" '( )lat(d syst(ms #/:%

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

floating support in a bio erodible capsule. &n the stomach the capsule uic-ly

disintegrates to release the &ntragastric osmotically controlled drug delivery device. The

inflatable support inside forms a deformable hollow polymeric bag that contains a li uid

that gasifies at body temperature to inflate the bag. The osmotic controlled drug delivery

device consists of two components, drug reservoir compartment and osmotically active

compartment.



Chapter-1

&i / Classi!i"ation o! ast'o '(t(nti+( d') d(li+('y

1.$ &LOATING DRUG DELIVERY SYSTEMS #&DDS%

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

utilized in the development of 'DDS, which are effervescent system and non*

effervescent system.

E!!('+(s"(nt syst(m #/; /< /*%

(ffervescent systems include use of gas generating agents, carbonates !Sodium

bicarbonate# and other organic acid !Citric acid and Tartaric acid# to produce carbon

dio/ide !CF)# gas, thus reducing the density of the system and ma-ing it to float on the

gastric fluid. These effervescent systems further classified into two types

%as generating systems

&ntra gastric single layer floating tablet or $ydro dynamically balanced system !$BS#



Chapter-1

&i $ yd'o dynami"ally =alan"(d syst(m

These are formulated by mi/ing the CF) generating agents and the drug within the

matri/ tablet !'ig + #. These have a bul- density lower than gastric fluids and therefore

remain floating in the stomach unflattering the %(9 for a prolonged period. The drug is

slowly released at a desired rate from the floating system and after the complete release

the residual system is e/pelled from the stomach. This leads to an increase in the %9T

and a better control over fluctuations in plasma drug concentration.

Int'a ast'i" =ilay('(d !loatin ta=l(ts

These are also compressed tablet and contain two layers forG

&mmediate release layer andSustained release layer !'ig.1#



Chapter-1

&i ; Sta (s o! !loatin m("hanism

. 4enetration of water

B. %eneration of CF) and floating

C. Dissolution of drug

Int'a ast'i" !loatin ast'oint(stinal d') d(li+('y syst(m

This system can be made to float in the stomach because of floatation chamber,

which may be a vacuum or filled with air or a harmless gas, while drug reservoir is

encapsulated inside a microporus compartment !'ig 8#.

&i < Int'a ast'i" !loatin ast'oint(stinal d') d(li+('y d(+i"( In!lata=l(ast'oint(stinal d(li+('y syst(ms



Chapter-1

&n these systems an inflatable chamber is incorporated, which contains li uid that gasifies

at body temperature to cause the chamber to inflate in the stomach. These systems are

fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug,

impregnated polymeric matri/, then encapsulated in a gelatin capsule. fter oral

administration the capsule dissolves to release the drug reservoir together with the

inflatable chamber. 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 !'ig ? #.

&i * In!lata=l( ast'oint(stinal d(li+('y syst(m

Int'a ast'i" osmoti"ally "ont'oll(d d') d(li+('y syst(m

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

floating support in a biodegradable capsule. &n the stomach capsule uic-ly disintegrates

to release the intragastric osmotically controlled drug delivery device.

The inflatable support inside forms a deformable hollow polymeric bag that contains a

li uid 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.



Chapter-1

They are formulated by intimate mi/ing of drug with a gel*forming hydrocolloid, which

swells in contact with gastric fluid and maintain bul- density of less than unity. The air

trapped by the swollen polymer confers buoyancy to these dosage forms.

Al inat( =(ads

0ulti unit floating dosage forms were developed from freeze*dried calcium alginate.

Spherical beads of appro/imately ).3 mm diameter can be prepared by dropping a

sodium alginate solution into a ueous solution of calcium chloride, causing

precipitation of calcium alginate leading to formation of porous system, which can

maintain a floating force for over ") hrs. These floating beads gave a prolonged residence

time of more than 3.3 hrs.

1.9 &LOATING MICROS0 ERES

0ultiple*unit floating !hollow# microspheres by emulsion solvent diffusion techni ue

were prepared with Drug and acrylic polymer. These were dissolved in an ethanol*

dichloromethane mi/ture, and poured into an a ueous solution of 47 with stirring to

form emulsion droplets. The rate of drug release in micro balloons was controlled by

changing the polymer to drug ratio. 0icrobaloons were floatable in vitro for ") hrs when

immersed in a ueous media. 9adio graphical studies proved that microbaloons orally

administered to humans were dispersed in the upper part of stomach and retained there

for + hrs against peristaltic movements.

Lo6 d(nsity syst(m 3 !loatin d') d(li+('y syst(m #&DDS%

;ow density system have a bul- density less than gastric fluids and so remain buoyant in

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

2hile the system is floating on the gastric contents, the drug is released slowly at the

desired rate. !+"#



Chapter-1

&i 18 Int'a ast'i" !loatin mi"'o=aloons d') d(li+('y syst(m

These are made of the low density materials because of low density core these are called

microbaloons. The low density materials used in this method of preparation are

4olycarbonate, (udragit S, cellulose acetate, calcium alginate agar and lowmetho/ylated pectin are commonly used as polymers. !+)#

Ad+anta (s o! &DDS #$$%

The gatroretentive systems are advantageous for drugs absorbed through the

stomach eg. 'errous salts, antacids.cidic substances li-e aspirin cause irritation on the stomach wall when come in

contact with it. $ence $BS formulation may be useful for the administration of

aspirin and other similar drugs.dministration of prolongs release floating dosage forms, tablet 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. &t is therefore e/pected that a drug will be fully absorbed from

floating dosage forms if it remains in the solution form even at the al-aline p$ of

the intestine.The gatroretentive systems are advantageous for drugs meant for local action in

the stomach eg. ntacids.2hen there is a vigorous intestinal movement and a short transit time as might

occur in certain type of diarrhea, poor absorption is e/pected. Ander such

circumstances it may be advantageous to -eep the drug in floating condition in

stomach to get a relatively better response.



Chapter-1

Disad+anta (s o! &DDS

'loating system is not feasible for those drugs that have solubility or stability

problem in %&T.These systems re uire a high level of fluid in the stomach for drug delivery to

float and wor- efficiently.The drugs that are significantly absorbed through out gastrointestinal tract, which

undergo significant first pass metabolism, are only desirable candidate.

A00LICATIONS #$9 $: $;%

S)stain(d d') d(li+('y

$ydrodynamically balanced system 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 controlled release formulation,

hence, can be overcome with these systems. These systems have bul- density of =", as a

result of which they can float on the gastric contents. 9ecently sustained release floating

capsules of nicardipine were developed and evaluated in vivo. The formulation

compared with commercially available 0&C 9D capsules using rabbits. 4lasma conc

time curves showed a longer duration for administration !"6 hrs# in the sustained release

floating capsules as compared with conventional 0&C 9D cap !? hrs#.

Sit( sp("i!i" d') d(li+('y

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

stomach or the pro/imal part of the small intestine eg. 9iboflavin, 'urosemide and

0isoprostal. bilayer floating capsule was developed for local delivery of 0isoprostol,

which is a synthetic analog of 4rostaglandin (, used as protectant of gastric ulcer caused

by administration of NS &Ds. By targeting slow delivery of misoprostol to the stomach,desired therapeutic level could be achieved and drug waste could be reduced.

A=so'ption (nhan"(m(nt

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

part of the %&T are potential candidates to be formulated as 'DDS, thereby ma/imizing



Chapter-1

their absorption. significant increase in the bioavailability of floating dosage forms

!1).<@# could be achieved as compared with commercially available ; S&I tablet

!++.1@# and enteric coated ; S&I*long product !)<.3@#.

Maint(nan"( o! "onstant =lood l(+(l

These systems provide an easy way of maintaining constant blood level with an ease of

administration and better patient compliance.

Limitations #$<%

The floating system re uires a sufficiently high level of fluid in the stomach for

the system to float. This problem can be overcome by coating the dosage form

with bio adhesive polymer which adhere to gastric mucosa or administeringdosage form with a glass full of water !)55*)35 ml#.'loating system is not suitable for drugs that have stability or solubility problem

in gastrointestinal fluid or that irritate gastric mucosa. Drugs which have multiple

absorption site or which undergo first pass metabolism were not desirable

candidate for 'DDS.The single unit floating dosage form is associated with all or none conceptE.This problem can be overcome by formulating multiple unit system li-e floating

microsphere or microballons.'loating dosage form should not be given to the patients ust before going to the

bed as gastric emptying occurs rapidly when the sub ect remains in supine

posture.

CALCIUM C ANNEL 2LOC>ER?

Calcium channel bloc-ers !CCB#, calcium channel antagonists or calcium antagonists are

a number of medications that disrupts the movement of calcium !Ca)J# through calcium

channels. Calcium channel bloc-ers are used as antihypertensive drugs, i.e. as

medications to decrease blood pressure in patients with hypertension. CCBs are

particularly effective against large vessel stiffness, one of the common causes of elevated

systolic blood pressure in elderly patients. Calcium channel bloc-ers are also fre uently



Chapter-1

used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by

angina pectoris.

Despite their effectiveness, CCBKs often have a high mortality rate over

e/tended periods of use, and have been -nown to have multiple side effects. 4otentialma or ris-s however were mainly found to be associated with short*acting CCBs.

CLASESS?

"." Dihydropyridine

".) Non*dihydropyridine

".)." 4henylal-ylamine

".).) Benzothiazepine

".).+ Nonselective

".).1 LiconotideDihydropyridine

Dihydropyridine calcium channel bloc-ers are derived from the

molecule dihydropyridine and often used to reduce systemic vascular resistance and

arterial pressure. Sometimes when they are used to treat angina, the vasodilation andhypotension can lead to refle/ tachycardia, which can be detrimental for patients with

ischemic symptoms because of the resulting increase in myocardial o/ygen demand.

Dihydropyridine calcium channel bloc-ers can worsen proteinuria in patients with

nephropathy.

This CCB class is easily identified by the suffi/ M*dipineM.for e/amples mlodipine,

ranidipine, zelnidipine, Barnidipine,Cilnidipine &sradipine (fonidipine

'elodipine;acidipine Nicardipine Nifedipine .

Non4dihyd'opy'idin(

0h(nylal@ylamin(



Chapter-1

4henylal-ylamine calcium channel bloc-ers are relatively selective for myocardium,

reduce myocardial o/ygen demand and reverse coronary vasospasm, and are often used

to treat angina. They have minimal vasodilatory effects compared with dihydropyridines

and therefore cause less refle/ tachycardia, ma-ing it appealing for treatment of angina,

where tachycardia can be the most significant contributor to the heartKs need for o/ygen.

Therefore, as vasodilation is minimal with the phenylal-ylamines, the ma or mechanism

of action is causing negative inotropy. 4henylal-ylamines are thought to access calcium

channels from the intracellular side, although the evidence is somewhat mi/ed.

7erapamil !Calan, &soptin#

%allopamil

'endiline

2(n,othia,(pin(?

Benzothiazepine calcium channel bloc-ers belong to the

benzothiazepine class of compounds and are an intermediate class between

phenylal-ylamine and dihydropyridines in their selectivity for vascular calcium channels.

By having both cardiac depressant and vasodilator actions, benzothiazepines are able to

reduce arterial pressure without producing the same degree of refle/ cardiac stimulation

caused by dihydropyridines.

Nons(l("ti+(

2hile most of the agents listed above are relatively selective, there are

additional agents that are considered nonselective. These include mibefradil,bepridil,

flunarizine !BBB crossing#, fluspirilene !BBB crossing#,O?P and fendiline.O<P

i"onotid(

Liconotide, a peptide compound derived from the omega*conoto/in, is a selective N*type

calcium channel bloc-er that has potent analgesic properties that are e uivalent to

appro/imate ",555 times that of morphine. &t must be delivered via the intrathecal

!directly into the cerebrospinal fluid# route via an intrathecal infusion pump.



Chapter-1

M("hanisam o! a"tion?

&n the bodyKs tissues, the concentration of calcium ions !Ca)J# outside of cells is

normally about ten*thousand*fold higher than the concentration inside of cells. (mbedded

in the membrane of some cells are calcium channels. 2hen these cells receive a certainsignal, the channels open, letting calcium rush into the cell. The resulting increase in

intracellular calcium has different effects in different types of cells. Calcium channel

bloc-ers prevent or reduce the opening of these channels and thereby reduce these

effects.

There are several types of calcium channels, and a number of classes of calcium channel

bloc-ers, but almost all of them preferentially or e/clusively bloc- the ;*type voltage*

gated calcium channel.

;*type calcium channels are responsible for e/citation*contraction coupling of s-eletal,

smooth and cardiac muscle and for hormone secretion in endocrine cells. &n the heart they

are also involved in the conduction of the pacema-er signals. CCBs used as medications

primarily have three effectsG

By acting on vascular smooth muscle they reduce contraction of the arteries and cause an

increase in arterial diameter, a phenomenon called vasodilation !CCBs do not wor- on

venous smooth muscle#

By acting on cardiac muscles !myocardium#, they reduce the force of contraction of the

heart

By slowing down the conduction of electrical activity within the heart, they slow down

the heart beat.Since blood pressure is determined by cardiac output and peripheral

resistance, CCBs reduce blood pressure. 2ith relatively low blood pressure, the afterload

on the heart decreases this decreases how hard the heart must wor- to e ect blood into

the aorta, and so the amount of o/ygen re uired by the heart decreases accordingly. This

can help ameliorate symptoms ofischaemic heart disease such as angina pectoris.

9educing the force of contraction of the myocardium is -nown as the

negative inotropic effect of calcium channel bloc-ers. Slowing down the conduction of



Chapter-1

electrical activity within the heart, by bloc-ing the calcium channel during the plateau

phase of the action potential of the heart !seeG cardiac action potential#, results in a

negative chronotropic effect, or a lowering of heart rate.

This can increase the potential for heart bloc-. The negative chronotropic effects of calcium channel bloc-ers ma-e them a commonly used class of agents in individuals with

atrial fibrillation or flutter in whom control of the heart rate is generally a goal. Negative

chronotropy can be beneficial when treating a variety of disease processes because lower

heart rates represent lower cardiac o/ygen re uirements.

(levated heart rate can result in significantly higher Mcardiac wor-,M which can result in

symptoms of angina.

&i 11 "al"i)m "hann(l (m=(dd(d in a "(ll m(m='an(

The class of CCBs -nown as dihydropyridines mainly affect arterial

vascular smooth muscle and lower blood pressure by causing vasodilation. The

phenylal-ylamine class of CCBs mainly affect the cells of the heart and have negative

inotropic and negative chronotropic effects. The benzothiazepine class of CCBs combine

effects of the other two classes.

&t is because of the negative inotropic effects that the nondihydropyridine calcium

channel bloc-ers should be avoided !or used with caution# in individuals with

cardiomyopathy.



Chapter-1

this, calcium channel bloc-ers arenKt usually the first medication youKd be prescribed to

lower your blood pressure.

$owever, for blac-s, calcium channel bloc-ers may be more effective than other blood

pressure medications, such as beta bloc-ers, C( inhibitors or angiotensin && receptor bloc-ers.

Cal"i)m "hann(l =lo"@('s 6o'@s?

Calcium channel bloc-ers are drugs that bloc- the entry of calcium into the muscle cells

of the heart and arteries.

The entry of calcium is critical for the conduction of the electrical signal that

passes from muscle cell to muscle cell of the heart, and signals the cells to contract.

&t also is necessary in order for the muscle cells to contract and thereby pump

blood.

&n the arteries, the entry of calcium into muscle cells causes contraction of the

cells and thereby dilates !widens# the arteries.

Thus, by bloc-ing the entry of calcium, calcium channel bloc-ers reduce

electrical conduction within the heart, decrease the force of contraction !wor-# of themuscle cells, and dilate arteries.

Dilation of the arteries reduces blood pressure and thereby the effort the heart

must e/ert to pump blood.

Combined with decreases in the force of contraction, this leads to a reduced

re uirement for o/ygen by the heart.

Dilation of the arteries provides more o/ygen*carrying blood to the heart.

The combination of reduced demand for o/ygen and increased delivery of o/ygen

prevents angina or heart pain. ! ngina occurs when the heart is not getting enough

o/ygen relative to the amount of wor- it is doing.#



Chapter-1

&n addition, calcium channel bloc-ers slow electrical conduction through the heart

and thereby correct abnormal rapid heartbeats.

/. REVIEB O& LITERATURE



Chapter-1

Y)+('a Sin h et al., studied the floating microspheres of 7erapamil

$ydrochloride for improving the drug bioavailability by prolongation of gastric

residence time by using polymers such as cellulose acetate, acrycoat S"55

and eudragit S"55. The prepared microspheres e/hibited prolong buoyant for

more than ") hrs.

Gattani YS et al., formulated and evaluated the controlled release system

for ceclofenac to increase its residence time in the stomach without contact with

the mucosa, achieved through the preparation of floating microparticles by the

emulsification solvent*evaporation techni ue consisting of eudragit 9S "55 as a

polymer. The prepared microspheres e/hibited prolonged drug release !Q ")hrs#

and remained buoyant for Q ") hrs.

S'i+asta+a A> et al. , "3 studied the floating microsphere of Cimetidine by

solvent evaporation method using polymers of hydro/ylpropylmethyl cellulose

and ethyl cellulose. The prepared microspheres e/hibited prolonged drug release

!R? hrs# and remained buoyant for Q "5 hrs. The mean particle size increased and

the drug release is decreased at higher polymer concentration.

&)'s)l( RA et al., "8 formulated and evaluated oil entrapped floating gel

beads ofmo/icillin Trihydrate prepared by using sodium alginate as gelling

agent, the entrapped gel beads can be used as floating drug delivery system for

local as well as systemic drug delivery.

>)ma'(sh SS et al., "? studied the effect of co e/cipients on drug release and

floating property of Nifedipine hollow microspheres and they developed by

incorporating the drug in cellulose acetate hollow microspheres by solvent

diffusion*evaporation techni ue in presence of coe/cipient. The percentage

buoyancy followed the ran- order of blan- !no coe/cipient# Q dibutyl phthalate Q

polyethylene glycol Q poly ! * caprolactone# after "3 hrs of floating. 9elease of

Nifedipine was enhanced by the addition of coe/cipients.



Chapter-1

ain A> et al., )" formulated 'amotidine floating microspheres by

solvent evaporation method using polymer acrycoat S"55 and cellulose acetate.

The microspheres e/hibit prolonged drug release !"? hrs# and remain buoyant

for more than ") hrs.

2asa+a'a 2.V et al., )) studied micro balloons loaded with drug Diclofenac

Sodium in their outer polymer shells by novel emulsion solvent diffusion. The

ethanolG dichloromethane solution of drug and eudragit*S were poured into

an a ueous solution of 47 that was thermally controlled at 1 5 C. The gas phase

generated in the dispersed polymer droplet by the evaporation of solvent formed

an internal cavity in the microsphere of the polymer with the drug. The

microspheres continuously float for more than ") hrs in the acidic medium.

>la)sn(' A et al., )6 were prepared microbaloons by the emulsion*solvent

diffusion method using drug Tranilast and acrylic polymer. The drug release

profiles from microbaloons e/hibited enteric behavior. The release rate was

controlled by changing the ratio of polymer to drug in the microbaloons. 0ost of

the microbaloons were floatable in vitro even testing for ") hrs when immersed in

a ueous media, owing to their low particle density !less than unity#.

S)nil > et al., +1 studied on porous carrier*based floating

Frlistat microspheres for gastric delivery. Calcium silicate is used as porous

carrier and eudragit S as polymer. 'loating microspheres of Frlistat prepared by

the solvent evaporation method, the microspheres found to be regular in shape and

highly porous.The microspheres containing )55 mg calcium silicate showed the

best floating ability !??@ buoyancy# in simulated gastric fluid.

Cha+anpatil M et al., 15 developed Fflo/acin sustained release floating oral

delivery system in order to prolong the gastric retention time. Different polymers

such as psyllium hus-, $40C :"550, crospovidone were used. &t was

found that dimensional stability of the formulation increases with the increasing

psyllium hus- concentration and also in vitro drug release rate increased with

increasing amount of crospovidone.



Chapter-1

D((pa M> et al., 35 formulated the Cefedo/ime 4ro/etil floating

microspheres by non*a ueous solvent evaporation method using polymers such as

hydro/yl propyl methyl cellulose !$40C : "3 0#, ethyl cellulose in different

ratios of Cefpodo/ime 4ro/etil formulation. The best drug release profiles wereseen with formulation at the ratio of drug to polymer was "G).

Sahoo S> et al., 3" studied floating microspheres of Ciproflo/acin

$ydrochloride. The microspheres were prepared by simple dripping method by

using sodium alginate and hydro/y propyl methyl cellulose !$40C# as a carrier,

Sodium bicarbonate was used as the gas forming agent and "@ calcium

chloride solution containing "5@ acetic acid for carbon dio/ide release and gel

formation. The enhanced buoyancy and controlled release properties of sodium

bicarbonate containing microspheres made them an e/cellent candidate for floating

drug dosage form.

Madha+i 22 et al., 3) developed a new class of antidepressants its higher

solubility in water results in burst effect with sudden pea- levels of drug in blood.

The half lives of 7enlafa/ine $ydrochloride !7(N#. The microbeads were

prepared by the ionotropic gelation of sodium alginate in calcium chloride

solution. The method had resulted in good encapsulation efficiency and micron

sized alginate spheres. The drug release was found to be sustained for "6 hrs and

was found to follow the :orsemeyer 4eppas -inetics.

Na'(nd'a C et al., 3+ developed bilayer floating tablet of 0etoprolol Tartarate

using different ratio of $40C :10 and $40C :"50 cp, SC0C and 474

:+5. Tablets were studied for in vitro dissolution studies, buoyancy

determination, floating time. &t showed that increase in conc of both $40C

:10 and $40C :"550 increase floating time and SC0C is re uired in

formulation to maintain the integrity of tablet.

os(ph N et al., 55 developed floating type dosage form !'D'# of 4iro/icam

in hollow polycarbonate !4C# microspheres capable of floating on simulated



Chapter-1

gastric and intestinal fluids was prepared by a solvent evaporation techni ue.

&ncorporation efficiencies of over <3@ were achieved for the encapsulation. In

vitro release of 4iro/icam from 4C microspheres into simulated gastric fluid at

+8o

C showed no significant burst effect. The amount released increased with timefor about ? hrs after which very little was found to be released up to )1 hrs.

G)(''('o S et al., 56 prepared :etotifen !:T#*loaded chitosan microspheres !0S#

for controlled release delivery systems. 0icrospheres were prepared by a spray*

drying technology followed by treating with glutaraldehyde solutions in methanol

as cross* lin-er. 9esults showed that very small spherical microspheres with a high

load of :T were obtained. :T loading decreased with cross*lin-ing .&nteractions

between :T and chitosan avoided total :T release from cross*lin-ed 0S. fter intraperitoneal !i.p.# administration, microsphere aggregations were adhered to

muscle sub acent to the tegument and to adipose tissue, and there were no evident

sings of re ection :T was detected in blood stream !5.+8 5.)3 l g>ml# at )1 hrs,

which was longer than the i.p. administration of the drug in solution !+<.1 l g>ml

at )1 hrs#.

M),,a'(llia C et al., 38 prepared chitosan*polyuronan microspheres, in

which chitosan were used as cationic polymer and alginic acid, polygalacturonicacid, carbo/ymethyl cellulose, carbo/ymethyl guaran, acacia gum, 6*o/ychitin,

/anthan, hyaluronic acid, pectin, -*carrageenan, and guaran as an ionic polymer.

Those made of chitosan /anthan or chitosan guaran was une/pectedly found to

be soluble in water similarly, the chitosan pectin microspheres were almost

soluble. The microspheres containing hyaluronic acid or -*carrageenan underwent

swelling when contacted with water the other ones were insoluble. The

microspheres were characterized by 'T&9, I*ray diffraction spectrometry and

scanning electron microscopy. The structural alterations detected were mainly due

to interactions between the amino groups and the carbo/yl groups.

St'()=(l A et al., 3? evaluated single unit 'DDS consisting of propylene foam

powder ! ccurel 04 "55), 04 "555#, matri/ forming materials, drug and filler. &t



Chapter-1

is observed that all foam powder containing tablets remained floating for at least ?

hrs in 5." N $C; at +8 oC.

Li S et al., 3< studied the effect of $40C !different viscosity grades# and

carbopol <+14 on the release and floating properties of gastric drug delivery

system carried out using factorial design. The study concluded that polymer with

lower viscosity was found to be beneficial than the higher viscosity grades of

$40C type in improving the floating properties and incorporation of carbopol

however was found to compromised the floating capabilities and release rate of

active drug, which might be due to difference in the basic properties of three

polymers due to their water upta-e potential and functional group substitution.

Sa6i"@i B et al., 65 prepared 7erapamil $ydrochloride !7$# floating pellets

using -ollicoat S9 +5 D as a coating agent and "5@ plasticizers li-e propylene

glycol, triethyl citrate and dibuthyl sebecate. Two -inds of cellulose,

microcrystalline and sodium hydrocarbonate were the main components of pellet

core. Tablets were evaluated as regards to effect of upper punch compression force

on mechanical strength, friability and floatation starting time. &t was proved that

increasing compression force contributed to greater hardness, lower friability,

lower release and delayed start of floatation time.

S'iamo'nsa@ 0 et al., 6" prepared 0etronidazole emulsion gel beads using

calcium pectinate by emulsion*gelation method. &t was found that increasing

drug to pectin ratio in the beads slowed the drug release from the conventional

and (0% beads. The result suggests the release behaviour of (0% beads could be

modified by hardening with )@ glutaraldehye or by coating with eudragit 9;.

Rao MR et al., 6) developed 9osiglitazone maleate microspheres by

solvent diffusion evaporation. full factorial design was applied to optimize the

formulation. The results of +) full factorial design revealed that the conc of ethyl

cellulose 8 cps !I " # and stirring speed !I ) # significantly affected drug entrapment

efficiency, percentage release after ? hrs and particle size of microspheres.

>amila M et al., 6+ developed multiunit floating drug delivery



Chapter-1

system of 9osiglitazone maleate !9L0# by encapsulating the drug into eudragit

9S"55 through non a ueous emulsification>solvent evaporation method. In

vitro release was optimized by a U+, +V simple/ lattice mi/ture design to

achieve predetermined target release. The in vivo performance of the optimized

formulation was evaluated in streptozotocin*induced diabetic rats. In vivo

evaluation in albino rats suggested that floating microspheres of 9L0 could be a

promising approach for better glycemic control.

S(nthil@)ma' S> et al., 64 developed floating microsphere using

9abeprazole Sodium !9S# as a model drug for prolongation of the gastric retention

time. The microspheres were prepared by the solvent evaporation method using

different polymers li-e hydro/y propyl methyl cellulose and methyl cellulose. The

average diameter and surface morphology of the prepared microsphere were

characterized by optical microscope and scanning electron microscopic methods

respectively. In vitro drug release studies were performed and the drug release

-inetics was evaluated using linear regression method. The effect of various

formulation variables on the size and drug release was investigated.

2a'hat( SD et al., 65 developed multiparticulate gastro retentive drug delivery

system of :etorlac Trometamol. The gastro retentive drug delivery system can be

prepared to improve the absorption and bioavailability of -etorlac Trometamol by

retaining the system in to the stomach for prolonged period of time. The floating

drug delivery system of :etorlac Trometamol was prepared by emulsion solvent

diffusion method by using ethyl cellulose, $40C :10, (udragit 9 "55, (udragit

S "55 polymers in varying concentration. The optimized formulation shows good

buoyancy and In vitro controlled release of :etorlac Trometamol.

$. AIM AND O2 ECTIVES

$.1 AIM? 'ormulation and evaluation of floating microspheres of &sradipine



Chapter-1

$./ O2 ECTIVES?

To formulate &sradipine floating microspheres using polymers li-e $40C :"30 and (C for controlled delivery of calcium channel bloc-ers !CCBs#, of

&sradipine.To evaluate the polymer characteristics and &D4 floating microsphere

characteristics.To study polymers concentration on &D4 floating microsphere characteristics.To evaluate physico*chemical characteristics li-e drug interaction study !'T&9#,

mean particle size, and size distribution etc.To evaluate the drug entrapment efficiency of the formulations.To perform in vitro dissolution studies.To evaluate the release -inetics.

$.$ NEED O& STUDY?

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

significantly prolong the %9T of drugs. 4rolonged gastric retention improves

bioavailability, reduces drug waste and improves solubility for drugs that are less soluble

in a high p$ environment. &t has applications also for local drug delivery to the stomach

and pro/imal small intestine. %astro retention helps to provide better availability of new

products with new therapeutic possibilities and substantial benefits for patients. !+5#

&sradipine has a half life of !? hrs# and it reaches a pea- plasma concentration after "hr. &t

is highly soluble in 5."0 $C; !"".?5+ mg>ml# and solubility decreases with increasing

p$ over the physiological range which ma-es &D4 as a suitable candidate for 'DDS in

order to prolong the %9T. !+?, +<#

9. 0LAN O& BOR>

1. 0'(!o'm)lation st)di(s



Chapter-1

Solubility0elting pointA7 spectroscopyD9(C studies4reparation studies

/. 0'(pa'ation o! Is'adipin(!loatin mi"'osph('(s )sin polym('s li@( 0MC >1:

M and EC !o' Cont'oll(d d') d(li+('y.

$. E+al)ation st)di(s

Drug interaction study !'T&9#4article size distribution of prepared &sradipine floating microspheresDrug entrapment efficiency&n vitro dissolution studies:inetics of dug release

chapter -isradipine

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