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Chapter 2

Objectives of the

Study

OBJECTIVES OF THE STUDY

9 pH dependent drug delivery systems

OBJECTIVES OF THE STUDY

1. To formulate and evaluate pH dependent microspheres as gradient release

drug delivery system

2. To formulate and evaluate mucoadhesive pH dependent microspheres as

intestinal drug delivery system

3. To formulate and evaluate pH dependent superporous hydrogel as

gastroretentive drug delivery system

Chapter 3

Review of

Literature

REVIEW OF LITERATURE


3.0 OVERVIEW OF GASTROINTESTINAL TRACT22

The gastrointestinal tract (GIT) comprises of a number of components, their

primary function being secretion, digestion and absorption. The mean length of the

entire GIT is 450 cm. The major functional components of the GIT are stomach, small

intestine (duodenum, jejunum and ileum) and large intestine (colon) which grossly

differs from each other in terms of anatomy, function, secretions and pH (Figure 3.01

and Table 3.01).

Figure 3.01: Schematic representation of the GIT and different sites of drug

absorption



Table 3.01. Anatomical and functional differences between the important regions

of the GIT

Stomach Small

Intestine

Large

Intestine

Rectum

pH range 1-3 5-7.5 6.0-8.0 6.0-8.0

Length (cms) 20 300-500 110 20

Diameter (cms) 15 2.5 5 2.5

Surface area (m2) 0.1-0.2 200 0.15 0.02

Blood flow (L/min) 0.15 1.0 0.02 ---

Transit time (h) 1-5 3-6 6-12 6-12

Absorptive role Lipophilic,

acidic and

neutral drugs

All types of

drugs

Some drugs,

water and

electrolytes

All types of

drugs

Absorptive

mechanisms

Passive

diffusion,

convective

transport

All absorption

mechanisms

Passive

diffusion,

convective

transport

Passive

diffusion,

convective

transport,

endocytosis

The entire length of the GI mucosa from stomach to large intestine is lined by

a thin layer of mucopolysaccharides (mucus/mucin) which normally acts as an

impermeable barrier to the particulates such as bacteria, cells or food particles.



Stomach

The stomach is a bag like structure having smooth mucosa and thus small

surface area. Its acidic pH, due to secretion of HCl, favors absorption of acidic drugs

which are soluble in the gastric fluids since they are unionized to a large extent in

such a pH. The gastric pH aids dissolution of basic drugs due to salt formation and

subsequent ionization which are therefore absorbed to a lesser extent from stomach

because of the same reason.

The stomach is not the principle region for drug absorption because:

The total mucosal area is small.

The epithelium is dominated by mucus-secreting cells rather than absorptive

cells.

The gastric residence time is limited due to which there is limited opportunity

for gastric uptake of drug.

Small intestine

It is the major site for absorption of most drugs due to its special

characteristics as discussed below;

1. Large surface area: The folds in the intestinal mucosa, called as the folds of

kerckring, result in 3 fold increase in the surface area. The surface of these folds

possesses finger like projection called villi which increases the surface area 30

times. From the surface of villi protrude several microvilli (about 600 from each

absorptive cell that lines the villi) resulting in 600 times increase in the surface

area. The large surface area is represented in Figure 3.02.

2. Great length of small intestine: Results in more than 200 square meters of

surface which is several times that of stomach.

3. Great blood flow: The blood flow to the small intestine is 6 to 10 times that of



stomach.

4. Favourable pH range: The pH range of small intestine is 5 to 7.5 which is

favourable for most drugs to remain unionised.

5. Slow peristaltic movement: Prolongs the residence time of drug in the intestine.

6. High permeability: The intestinal epithelium is dominated by absorptive cells.

Figure 3.02: Representation of the components of the intestinal epithelium that

accounts for its large surface area

Large intestine

Its length and mucosal surface area is very small (villi and microvilli are

absent) in comparison to small intestine and thus absorption of drugs from this region

is insignificant. Its contents are neutral or alkaline. The main role of large intestine is

in the absorption of water and electrolytes. However, because of the long residence

time (6 to 12 hrs), colonic transit may be important in the absorption of some poorly

soluble drugs and sustained release dosage forms.



APPROACHES FOR pH SENSITIVE DRUG DELIVERY

3.1 pH-sensitive hydrogels

3.1.1 Polymer structures

All the pH-sensitive polymers contain pendant acidic (e.g. carboxylic and

sulfonic acids) or basic (e.g., ammonium salts) groups that either accept or release

protons in response to change in environmental pH. The polymers with a large

number of ionizable groups are known as polyelectrolytes. Figure 3.03 shows

structure of anionic and cationic polyelectrolytes and their pH-sensitive ionization.

Poly (acrylic acid) (PAA) becomes ionized at high pH, while poly (N, N -

diethylaminoethyl methaacrylate) (PDEAEM) becomes ionized at low pH. As shown

in Figure 3.03, cationic polyelectrolytes, such as PDEAEM, dissolve more, or swell

more if cross linked, at low pH due to ionization. On the other hand, polyanions, such

as PAA, dissolve more at high pH.

3.1.2 Properties of pH-sensitive hydrogels

Hydrogels made of crosslinked polyelectrolytes display big differences in

swelling properties depending on the pH of the environment. The pendant acidic or

basic groups on polyelectrolytes undergo ionization just like acidic or basic groups of

monoacids or monobases. Ionization on polyelectrolytes, however, is more difficult

due to electrostatic effects exerted by other adjacent ionized groups. This tends to

make the apparent dissociation constant (Ka) different from that of the corresponding

monoacid or monobase. The presence of ionizable groups on polymer chains results

in swelling of the hydrogels much beyond which can be achievable by nonelectrolyte

polymer hydrogels. Since the swelling of polyelectrolyte hydrogels is mainly due to

the electrostatic repulsion among charges present on the polymer chain, the extent of

swelling is influenced by any condition that reduce electrostatic repulsion, such as pH,



ionic strength and type of counter ions23

.

Figure 3.03: pH-sensitive ionization of polyelectrolytes [Poly (acrylic acid) (top)

and poly (N, N-diethylaminoethyl methacrylate) (bottom)]

The swelling and pH-responsiveness of polyelectrolyte hydrogels can be

adjusted by using neutral co-monomers, such as 2-hydroxyethyl methacrylate, methyl

methacrylate and maleic anhydride24-27

. Different co-monomers provide different

hydrophobicity to the polymer chain, leading to different pH-sensitive behavior.

Hydrogels made of poly (methacrylic acid) (PMA) grafted with poly (ethylene glycol)

(PEG) have unique pH-sensitive properties28

. At low pH, the acidic protons of the

carboxyl groups of PMA interact with the ether oxygen of PEG through hydrogen

bonding and such complexation results in shrinkage of the hydrogels. As the carboxyl

groups of PMA become ionized at high pH, the resulting decomplexation leads to

swelling of the hydrogels. The same principle can be applied to IPN systems where

two different types of polymer chain interact through pH-sensitive hydrogen bonding.

3.1.3 Applications of pH-sensitive hydrogels in controlled drug delivery

pH-sensitive hydrogels have been most frequently used to develop controlled

release formulations for oral administration. The pH in the stomach (<3) is quite

different from the neutral pH in the intestine and such a difference is large enough to



elicit pH sensitive behavior of polyelectrolyte hydrogels. For polycationic hydrogels,

the swelling is minimal at neutral pH, thus minimizing drug release from the

hydrogels. This property has been used to prevent release of bitter-tasting drugs into

the neutral pH environment of the mouth. When caffeine was loaded into hydrogels

made of copolymers of methyl methacrylate and N, N-dimethyl aminoethyl

methacrylate (DMAEM), it was not released at neutral pH, but released at zero-order

at pH 3-5 where DMAEM became ionized29

. Polycationic hydrogels in the form of

semi-IPN have also been used for drug delivery in the stomach. Semi-IPN of

crosslinked chitosan and PEO showed more swelling under acidic conditions (as in

the stomach). This type of hydrogels would be ideal for localized delivery of

antibiotics, such as amoxicillin and metronidazole, in the stomach for the treatment

of Helicobacter pylori30

.

Hydrogels made of PAA or PMA can be used to develop formulations that

release drugs in a neutral pH environment31, 32

. Hydrogels made of polyanions (e.g.,

PAA) crosslinked with azoaromatic crosslinkers were developed for colon-specific

drug delivery. Swelling of such hydrogels in the stomach is minimal and thus, the

drug release is also minimal.

http://scialert.net/asci/result.php?searchin=Keywords&cat=&ascicat=ALL&Submit=Search&keyword=Helicobacter+pylori



Figure 3.04: Schematic illustration of oral colon-specific drug delivery using

biodegradable and pH-sensitive hydrogels

The extent of swelling increases as the hydrogel passes down the intestinal

tract due to increase in pH leading to ionization of the carboxylic groups. But, only in

the colon, can the azoaromatic cross-links of the hydrogels be degraded by

azoreductase produced by the microbial flora of the colon, as shown in Figure 3.04.

The degradation kinetics and degradation pattern (e.g., surface erosion or bulk

erosion) can be controlled by the crosslinking density. The kinetics of hydrogel

swelling can be controlled by changing the polymer composition. The polymer

composition can be changed as the pH of the environment changes. Some pendant

groups, such as N-alkanoyl (e.g., propionyl, hexanoyl and lauroyl) and O-

acylhydroxylamine moieties, can be hydrolyzed as the pH changes from acidic to

neutral values and the rate of side-chain hydrolysis is sensitive to the length of the

alkyl moiety33, 34

.

pH-sensitive hydrogels were placed inside capsules or silicone matrices to

modulate the drug release. In the squeezing hydrogel system, drug release was



controlled by a mechanism shown in Figure 3.05. The only difference is that the

swelling-shrinking of hydrogels is controlled by changing pH, instead of temperature.

In the silicone matrix system, medicated pH-sensitive hydrogel particles made of

semi-IPN of PAA and PEO were used. The release patterns of several model drugs

having different aqueous solubilities and partitioning properties (including

salicylamide, nicotinamide, clonidine HCl and prednisolone) were correlated with the

pH-sensitive swelling pattern of the semi-IPN. At pH 1.2, the network swelling was

low and the release was limited to an initial burst. At pH 6.8, the network became

ionized and higher swelling resulted in increased release35-37

.

Figure 3.05: Schematic illustration of on-off release from a squeezing hydrogel

device for drug delivery

Poly (vinyl acetal diethyl amino acetate) (PVD) has pH-sensitive aqueous

solubility. Both the turbidity and SEM results showed that PVD formed a hydro-gel

upon increase in pH from 4 to 7.4. The release of a model drug, chlorpheniramine

maleate, was fast right after the PVD solution was introduced into a pH 7.4 buffer

solution, but release slowed down after the PVD hydrogel was formed. The pH-

sensitive sol-to-gel transformation of AEA (acetal diethyl amino acetate) was used to

develop nasal spray dosage forms for treating allergic rhinitis and sinusitis. The in



vivo rat study showed that the apparent disappearance rate constant of

chlorpheniramine maleate decreased with increase in the PVD concentration. The

hydrogel formation on the mucous membranes in the rat nasal cavity was visually

confirmed. If the time for sol-to-gel transition is shortened and the mucoadhesive

property is added, the PVD system could be an ideal system for nasal delivery38, 39

.

Hydrogels that are responsive to both temperature and pH can be made by

simply incorporating ioniz-able and hydrophobic (inverse thermosensitive) functional

groups to the same hydrogels. When a small amount of anionic monomer, such as

acrylic acid, is incorporated in a thermoreversible polymer, the Lower critical solution

temperature (LCST) of the hydrogel depends on the ionization of the pendant

carboxyl groups, i.e., the pH of the medium. As the pH of the medium increases

above the pKa of the carboxyl groups of polyanions, LCST shifts to higher

temperatures due to the increased hydrophilicity and charge repulsion. Terpolymer

hydrogels made of NIPAAm, vinyl terminated poly-dimethylsiloxane macromer and

acrylic acid was used for the delivery of indomethacin and amylase40, 41

. Other

terpolymer hydrogels containing NIPAAm, acrylic acid and 2-hydroxyethyl

methacrylate were prepared for the pulsatile delivery of streptokinase and heparin as a

function of stepwise pH and temperature changes42, 43

.

3.1.4 Other applications

pH-sensitive hydrogels have also been used in making biosensors and

permeation switches. The pH-sensitive hydrogels for these applications are usually

loaded with enzymes that change the pH of the local microenvironment inside the

hydrogels. One of the common enzymes used in pH-sensitive hydrogels is glucose

oxidase which transforms glucose to gluconic acid. The formation of gluconic acid

lowers the local pH, thus affecting the swelling of pH-sensitive hydrogels44

.



3.1.5 Limitations and improvements

One of the inherent limitations of synthetic pH sensitive polymers is their non-

biodegradability. For this reason, hydrogels made of non-biodegradable polymers

have to be removed from the body after use. The non-biodegradability is not a

problem in certain applications, such as in oral drug delivery, but it becomes a serious

limitation in other applications, such as the development of implantable drug delivery.

Attention has been focused on the development of biodegradable, pH-sensitive

hydrogels based on polypeptides, proteins and polysaccharides. Dextran was activated

with 4-aminobutyric acid for crosslinking 1,10-diaminodecane and also grafted with

carboxylic groups. The modified dextran hydrogels showed a faster and higher degree

of swelling at high pH conditions and changing the pH between 7.4 and 2.0 resulted

in cyclic swelling-deswelling. It was noted that dextran hydrogels may not be exactly

biodegradable, since the body or certain sites in the body may not have the enzyme to

degrade dextran molecules. Natural polysaccharides are not necessarily biodegradable

in the human body.

Synthetic polypeptides were also used in synthesis of biodegradable hydrogels

because of their more regular arrangement and less versatile amino acid residues than

those derived from natural proteins. Examples of such synthetic polypeptide

hydrogels include poly(hydroxyl-L-glutamate), poly(L-or-oxinithine), poly(aspartic

acid), poly(L-lysine) and poly-(L-glutamic acid). In addition to normal electro-static

effects associated with most pH-sensitive synthetic polymer hydrogels, secondary

structures of the polypeptide backbone may also contribute to the pH-sensitive

swelling behavior. The overall extent of pH-responsive swelling could be engineered

by modification of the polypeptide by changing its hydrophobicity and degree of



ionization45, 46

.

3.2 Superporous Hydrogels47-50

While the slow swelling property is the one that made hydrogels useful in

controlled drug delivery, many applications required fast swelling (i.e., swelling in a

matter of minutes rather than hours) of dried hydrogels. One way of overcoming the

slow absorption of water into glassy hydrogels by diffusion was to create pores that

are interconnected to each other throughout the hydrogel matrix. The interconnected

pores allow for fast absorption of water by capillary force. A superporous hydrogel

(SPH) is a 3-dimensional network of a hydrophilic polymer that absorbs a large

amount of water in a very short period of time due to the presence of interconnected

microscopic pores.

Because of the porous structure, SPHs possess more surface area and shorter

diffusion distance than conventional hydrogels. These features allow dried SPHs to

swell very fast to a very large size on contact with water. Because of these unique

properties, SPHs were initially proposed to develop gastric retention devices for

extending the gastric residence time of drugs for achieving long-term, oral controlled

drug delivery. Gastric retention devices would be most beneficial for drugs that need

to act locally in the stomach, e.g., antacids and antibiotics for bacteria-based ulcers or

drugs that may be absorbed primarily in the stomach. For many drugs that have a

narrow absorption window, i.e., mainly absorbed from the proximal small intestine,

such as riboflavin, levodopa, and p-aminobenzoic acid, the bioavailability would be

increased by gastric retention. For drugs that are absorbed rapidly from the

gastrointestinal (GI) tract, e.g., amoxicillin, slow release in the stomach is also

expected to improve the bioavailability. Gastric retention devices could also be used

for drugs that are poorly soluble at an alkaline pH or drugs that degrade in the colon



(e.g., metoprolol). Several important properties of SPHs, such as fast swelling, large

swelling ratio, and surface slipperiness, make them an excellent candidate to develop

gastric retention devices.

3.2.1 Applications of SPH

3.2.1.1 Development of gastric retention devices

Superporous hydrogels were initially developed to make gastric retention

devices. The idea was to make an oral formulation to swell fast to a size large enough

to prevent them from passing through the pylorus. To avoid emptying into the

intestine by the housekeeper waves of the stomach that occur about every 2 hours, the

oral formulation has to swell as fast as possible. This is because, it is difficult to know

when the next housekeeper wave will come following administration of a superporous

hydrogel formulation. The initial goal of fast swelling was to reach maximum

swelling in about 20 minutes because water is known to remain in the stomach for

about 30 minutes.

3.2.1.2 Gastroretentive tablets

Common processes of dry blending and direct compression have been used to

make gastroretentive tablets. The SPH particles of acrylic acid/sulfopropyl acrylate

copolymers were mixed with gelatin and tannic acid, and then tableted by direct

compression. Hydrogen bonding between gelatin and tannic acid, as well as the

carboxyl groups on the polymeric carrier, create an integrated matrix, which was

shown to be stable after swelling. In a 40-min period, the gastroretentive tablet could

swell up to 30 times its own volume while maintaining its original shape.

Furthermore, the swollen tablet could withstand up to 16 KPa compression force

before breaking apart. Depending on the pH of the swelling medium, the gelatin can

be replaced by carboxymethylcellulose or other polysaccharides.



3.2.1.3 Development of peroral peptide delivery systems

Superporous hydrogels are also used in the development of peptide delivery

systems via oral administration. Peptide drugs have been administered mostly by the

parenteral route, and no peroral formulation has been developed to date. Superporous

hydrogels and their composites increase their volume by about 200-fold. Such volume

increase allowed the gels to mechanically stick to the intestinal gut wall and deliver

the incorporated drug directly to the gut wall. The proper selection of functional

groups of the superporous hydrogels, e.g., carboxyl groups, induced the extraction of

calcium ions to initiate opening of the tight junctions of the gut wall and deactivate

the deleterious gut enzymes. After the peptide drugs have been delivered and

absorbed across the gut wall, the superporous hydrogels become over hydrated, their

structure is broken down by the peristaltic forces of the gut, and the remnants of the

delivery systems are easily excreted together with the feces as mini particulate

systems.

3.2.1.4 Development of fast-dissolving tablets

For more than a decade, fast-dissolving (also called fast-melting) tablet

technologies have been used to develop a large number of successful commercial

products. The main advantage of the fast-dissolving tablet technologies is that the

dosage forms can be administered easily in the absence of water and without the need

of swallowing. This feature is especially beneficial to paediatric and geriatric patients.

The initial success of the first fast-dissolving tablet technology led to the development

of many different technologies. There are basically three different technologies:

freeze-drying, sublimation or heat molding, and direct compression. Freeze-drying

technology produces tablets that can dissolve in less than 5 seconds, while the



sublimation and molding technology allow tablets to dissolve in less than 15 seconds.

The two technologies, however, are expensive, and the prepared tablets are not

mechanically strong. For this reason, direct compression technologies, which afford

low cost of production and good physical resistance, are preferred.

One way of making fast-dissolving tablets by the direct compression method

is to add fine particles of superporous hydrogels to the drug and other excipients. The

size and shape of superporous hydrogel particles can be varied (the shape can be

varied from sphere to membrane). Superporous hydrogels can be ground in the dry

state to make porous super disintegrant microparticles. The superporous hydrogels

have numerous pores smaller than 1 mm, and thus the ground superporous hydrogel

microparticles possess open pore structures. This unique porous structure allows for

transport of water through capillary forces, resulting in an extremely fast wicking

effect into the tablet core. Tablets prepared by direct compression in the presence of

superporous hydrogel microparticles disintegrate in less than 10 seconds due to the

fast uptake of water into the core of the tablet.

3.2.1.5 Chemoembolization and occlusion devices

Chemoembolization is a combined method of embolization and chemotherapy.

Embolization has been used for cancer treatment by restricting the oxygen supply to

the growing tumours. This method could be combined with chemotherapeutic agents

to achieve local delivery and low systemic toxicity. A chemotherapeutic agent and an

anti-angiogenic agent could be loaded into SPHs for chemoembolization therapy. The

strong SPHs would likely be better candidates for this application as they fit better in

the blood vessels and provide better blocking. SPHs can also be used to develop

biomedical devices for treating aneurysms. After determining the size and shape of an

aneurysm site, an equivalent SPH is prepared in smaller size. Because of the rapid and



extensive swelling properties, the hydrogel will swell at the aneurysm site and clot the

blood. Studies have shown that the SPH results in a 95% aneurysm occlusion without

parent artery compromise and without inflammatory response.

3.2.1.6 Development of diet aid

Controlling body weight is an important aspect in maintaining a healthy body.

Diet soft drinks, meal replacement shakes, diet drugs, and even surgical methods have

been used for lowering the body weight. As the main goal of these approaches is

simply to reduce the amount of food intake, one alternative approach would be

administering superporous hydrogel tablets so that the swollen superporous hydrogels

can occupy a significant portion of the stomach space, leaving less space for food.

Taking superporous hydrogel tablets can be compared to taking Jello before a meal.

The presence of a bulky gel or gels in the stomach is expected to suppress the

appetite.

For oral drug delivery as well as for diet control, superporous hydrogels can be

modified to delay the swelling. Superporous hydrogels can be loaded inside hard

gelatin capsules. In addition, the superporous hydrogels can be made to swell after a

predetermined delay time. This will eliminate any concern on the premature swelling

of superporous hydrogels for clinical applications.

3.2.1.7 Other applications

SPHs can also be used in industries other than pharmaceutical and biomedical,

where rapid and extensive swelling in an aqueous medium are major requirements.

Hygiene, agriculture, horticulture, pet, toy and many other industries may benefit

from the use of SPHs in their products. As shown with the superabsorbent polymers,

children can enjoy the immediate swelling of SPHs and learn the associated science

and knowledge. The SPHs can be coloured and may find decorative applications.



SPHs quickly absorb moisture from the surrounding environment and may be a

suitable substitute for silica gel. The high swelling pressure of SPHs can potentially

be used to trigger an alarm system upon the invasion of water. Applications of SPHs

will be further realized as scientists in different disciplines become aware of the

unique properties of these new materials.

Figure 3.06: Illustration of the transit of the superporous hydrogel

Figure 3.07: A superporous hydrogel in its dry (right) and water-swollen (left)

state



Figure 3.06 illustrates the expected transit of the nonswollen/fully swollen

superporous hydrogel as it is initially retained for the desired period of time and then

passes into the intestine. In addition to its passage through the pylorus being hindered

by its large dimensions, swollen superporous hydrogels can float on gastric fluid. The

swollen and dry superporous hydrogel can be seen in Figure 3.07.

3.3 Enteric-coated systems

Enteric-coated formulations are suitable vehicles to modify the release of

active substances such that release at specific target areas within the gastrointestinal

(GI) tract can be affected, although the effectiveness of this methodology has long

been a point of discussion. Kramer et al. has investigated the use of enteric coatings

of 261 pharmaceutical products (Figure 3.08). The intended use included taste (9.6%)

and odor (1%) masking, drug stabilization (31%), protection against local irritation

(38%) and release directed to defined segments in the digestive tract (51%). Enteric

coatings have traditionally been used to prevent the release of a drug in the stomach

(Figure 3.09). A major aim of enteric coating is protection of drugs that are sensitive

or unstable at acidic pH. This is particularly important for drugs such as enzymes and

proteins, because these macromolecules are rapidly hydrolyzed and inactivated in

acidic medium. Antibiotics, especially macrolide antibiotics like erythromycin, are

also rapidly degraded by gastric juices. Others, such as acidic drugs like NSAID‟s

(e.g., diclofenac, valproic acid, or acetylsalicylic acid) need to be enteric coated to

prevent local irritation of the stomach mucosa51

.



Figure 3.08: Functions of enteric coatings according to the statements of the

pharmaceutical manufacturers. 1, Taste masking; 2, stability; 3, protection

against local irritation; 4, drug release in specific parts; 5, odor masking

Figure 3.09: Schematic representation of enteric coated system

Another purpose of enteric coating is drug targeting, as in the case of 5- amino

salicylic acid or the prodrugs, mesalazine and sulfasalizine. In these cases, enteric

coating is applied such that the drug concentration is increased in the lower parts of

the GI tract. Although the use of enteric coating to achieve modified release has been

known for a long time, it has always been criticized as to its true value of providing

protection and targeted release of the coated active agents.

A survey of the German market showed that more than 50% of enteric

formulations were coated with methacrylate copolymers, about 40% with cellulose

derivatives, 5% with shellac and 3% with other materials. Enteric coating materials

(Table 3.02) are described in various publications52, 53

. In addition to polymers



mentioned in Table 3.02, others are being studied (e.g., to obtain release at lower

pH)54

. Polymers with dissolution at lower pH are intended for the protection of drugs

in acidic medium and not for the protection of the gastric mucosa.

The conclusion of this review is that, from a technical point of view, progress

in film-forming polymers, together with advances in excipient technology and modern

coating equipment design, has greatly facilitated the design of enteric-coated

formulations that fulfill the requirements for controlled and targeted release.

3.3.1 Dosage forms

In general, film-coated dosage forms can be divided into multiple-unit and

single unit dosage forms. Single units comprise tablets and film-coated capsules or

other forms, usually monolithic structures. Multiple-unit dosage forms can be

packages containing granules, capsules containing pellets, or compressed film-coated

particles. In the latter situation, total dosage is divided into multiple units that are

dispersed in the GI tract, which often results in safer and usually faster action of the

drug. Recently, it has also been reported that aqueous dispersions or suspensions can

be produced, in which the drug is present in enteric-coated form. The enteric-coated

Time Clock System consists of a tablet core coated with a mixture of hydrophobic

material and surfactant, which is applied as an aqueous dispersion55

. The drug release

from the core of the Time Clock system occurs after a predetermined lag time. This

lag time mainly depends on the thickness of the hydrophobic layer and thus is

insensitive of GI pH. Investigations that used scintigraphic studies demonstrated that

the method for in vitro testing was a good predictor of in vivo release. A greater

targeting specificity can be achieved when an enteric coat is additionally applied to

this system to avoid problems caused by longer gastric resistance time.



Table 3.02: Properties and applications of enteric coating materials

Chemical name abbreviation Functional

groups

Soluble

above pH

Trade name

(company)

Application form Remarks

Cellulose acetate phthalate

CAP

USP23/NF18

Acetyl ,phthalyl 6 CAP (Eastman comp.)

Aquateric (Lehmann

and Voss)

Organic solution

aqueous

Dispersion

(pseudolactices)

Sensitive to hydrolysis,

5-30% plasticizer

required. Micronized

powder (0.05-3µm)

Hydroxy

propyl

methyl cellulose phthalate

HPMC USP23/NF18

Type200731

Methoxy,hydroxy

propoxy

Pthalyl

type220824

Methoxy ,

hydroxypropoxy,

pthalate

5 HP 50,HP 55

(Syntapharm)

Organic solution

aqueous dispersion

(pseudolactices)

Less sensitive to

hydrolysis, plasticizer

not essential

powder<20µm,redisper

sible in water

Hydroxypropyl methyl

cellulose acetate succinate

HPMCAS

Methoxy,hydroxy

propoxy, acetyl,

succinyl

5 HPMCAS-L

HPMCAS-M

HMPCAS-H

(Syntapharm)

Aqueous dispersion Powder ,5µm

Elastic properties,

plasticizer not essential

slightly hygroscopic

not micronized

Carboxymethyl ethyl,cellulose

CMFC(standard of

pharmaceutical

ingredients,japan)

Carboxymethyl,

ethoxy

5 Duodcell OQ

Duodcell OQ

(Lehmann and voss)

Organic solution

Aqueous dispersion

Micronized stable, not

sensitive to moisture



3.3.2 Tablets

Tablets can easily be enteric coated and a variety of products are available on

the market, including drugs like acetylsalicylic acid, diclofenac, naproxen56

,

omeprazole, lansoprazole, sodium valproate and many others. Generally,

increased bioavailability, improved patient acceptance and formulation stability result

from the coating process.

Lehmann investigated the increased stability of acetylsalicylic acid tablets

when using enteric film coatings57

. Reduction of side effects and increase in patient

compliance of enteric-coated acetylsalicylic acid tablets has also been shown in

various clinical studies. In another study different enteric film coatings on pancreatic

enzymes were compared. It was found that products containing HPMCP adhered to

the gastric mucosa, causing unwanted side effects, including irritation and

inflammation of the gastric wall, whereas methacrylic acid copolymers and CAP

encountered no such problems. The residence time of the tablets in fed dogs was

found to be 6-8 h, which is undesirably long and requires a revised dosage regimen of

the tablet (fasted or preprandial) 58-60

.

3.3.3 Capsules

Capsule coating often requires extra precautions (e.g., increased plasticizer

content or sometimes an insulating layer), otherwise film coatings or capsule shells

may become brittle during storage. Usually the thickness of the film coating layer has

to be increased to ensure proper coating of the capsule closure. Vilivalam et al.61

demonstrated enteric film coatings with methacrylic copolymers on starch capsules

filled with 5-ASA resulted in good storage stability. Good stability was also reported

for the enteric coating of hard gelatin capsules containing acetaminophen 62

. Cellulose

acetate phthalate was used for an enteric coating on hard gelatin capsules filled with



aspirin crystals 63

. Water uptake into the capsule was found to be unacceptably high,

which was attributed to high water vapor permeability of cellulose film coatings

compared with the more dense methacrylate copolymers. Soft gelatin capsules were

also coated with transparent film coatings and were found to be stable on storage64

.

3.3.4 Multiple units

A widely used method to produce multiple-unit dosage forms has been the

production of sachets that contain film-coated granules. More common is the use of

capsules in which enteric-coated particles are filled. A study that used radioactive

tracers revealed that enteric-coated erythromycin pellets in capsules were superior to

enteric-coated tablets with respect to faster action of the drug caused by a shorter

passage time of the coated granules in the stomach65-67

. In 1998, the first tablet

containing enteric-coated particles was marketed (Losec Mups, Omeprazole-

Magnesium by ASTRA, Sweden). This was a novel principle and might serve as a

model of how enteric dosage forms may be designed in the future. However, flexible

polymers are required for this purpose and a variety of other factors have to be

considered68, 69

. In addition to flexibility of the film coating, suitable larger sized

filler-binders and stable and strong pellet cores also have to be taken into account.

Only the methacrylic acid copolymers seem to have suitable properties necessary to

produce these dosage forms. As another example, small microcapsules of ibuprofen

were film coated with cellulose acetate phthalate and dispersed in water before

administration70

. Plasma levels were as expected and did not differ from those of a

conventional enteric-coated tablet.

3.4 pH-sensitive gels



Many polyanionic materials, such as poly (acrylic acid), are pH sensitive and

the degree of swelling of such polymers can be modulated by changing the pH. An

application of such technology has been in the development of biomimetic secretory

granules for drug delivery applications.

Secretory granules within certain cells consist of a polyanionic polymer

network encapsulated within a lipid membrane. The polymer network, which contains

biological mediators such as histamine, exists in a collapsed state as a consequence of

the internal pH and ionic content which is maintained by the lipid surrounding the

granule. Release of histamine from such granules is initiated through the fusion of the

granule with the cell membrane exposing the polyanionic internal matrix to the

extracellular environment. The change in pH and ionic strength results in ion

exchange and swelling of the polyanionic network which in turn causes release of the

endogenous mediators.

An environmentally responsive, hydrogel microsphere coated with a lipid

bilayer has recently been shown to act as a biomimetic secretory granule (Figure

3.10). Methylene-bis-acrylamide/methacrylic acid anionic microgels were prepared

by precipitation polymerization and loaded with doxorubicin and condensed by

incubating in buffer at pH 5. The condensed particles were then coated with a lipid

bilayer. Disruption of the lipid bilayer by electroporation was shown to cause the

microgel particles to swell and release the drug.

The use of these systems in conjunction with temperature-sensitive lipids

offers potential to target drugs to areas of inflammation or to achieve site-specific,

pulsatile drug delivery through the localized external application of ultrasound or

heating to disrupt the lipid bilayers71

.



Figure 3.10: A schematic diagram showing the release of drug from a biomimetic

secretory granule on disruption of the external lipid bilayer

Figure 3.11: Schematic illustration of a pH-activated drug delivery system and

the pH-dependent formation of microporous membrane in the intestinal tract



3.5 pH-activated drug delivery systems

For a drug labile to gastric fluid or irritating to gastric mucosa, this type of

CrDDS has been developed to target the delivery of the drug only in the intestinal

tract, not in the stomach. It is fabricated by coating a core tablet of the gastric fluid-

sensitive drug with a combination of intestinal fluid-insoluble polymer, like ethyl

cellulose and intestinal fluid-soluble polymer, like hydroxylmethyl cellulose phthalate

(Figure 3.11).

In the stomach, the coating membrane resists the drug molecules from

degradation by gastric fluid (pH<3) and are thus protected from the acidic

degradation. After gastric emptying, the CrDDS travels to the small intestine and the

intestinal fluid-soluble component in the coating membrane is dissolved away by the

intestinal fluid (pH>7.5). This produces a microporous membrane of intestinal fluid-

insoluble polymer to control the release of drug from the core tablet. The drug is thus

delivered in a controlled manner in the intestine by a combination of drug dissolution

in the core and diffusion through the pore channels (Figure 3.11). By adjusting the

ratio of the intestinal fluid-soluble polymer to the intestinal fluid-insoluble polymer in

the membrane, the rate of drug delivery can be regulated. Representative application

of this type of CrDDS is the oral controlled delivery of potassium chloride, which is

highly irritating to gastric epithelium72

.

3.6 pH-sensitive liposomes

The concept of pH-sensitive liposomes emerged from the observation that

certain enveloped viruses infect cells following acidification of the endosomal lumen

to infect cells and from the knowledge that some pathological tissues (tumors,

inflamed and infected tissue) have a more acidic environment compared to normal

tissues. Although, pH-sensitive liposomes are stable at physiological pH, they



destabilize under acidic conditions, leading to the release of their aqueous

contents73-75

. In addition, they appear to destabilize or fuse with the membranes of

endosomes in which they are internalized, enabling even macromolecular liposome

contents to enter the cytoplasm76, 77

.

The response to acidic pH can be facilitated by a variety of molecules78-81

,

including fusogenic peptides incorporated in the lipid bilayer82-86

, pH-sensitive

lipids87-89

and pH-sensitive polymers on the surface of liposomes90-92

. The

combination of phosphatidyl ethanolamine (PE) or its derivatives with molecules

having protonatable group (e.g., carboxylic group) that acts as a stabilizer of PE

membranes at neutral pH, is the most commonly used composition. PE has a small

head group which is hydrated that occupies a lower volume compared to the

hydrocarbon chains and can be imagined to have a cone shape, in contrast to the

cylinder shape exhibited by phospholipids such a phosphatidylcholine (PC). Strong

intermolecular interactions between the amino and phosphate groups of neighboring

polar headgroups, along with the cone shape, facilitate the formation of an inverted

hexagonal phase at temperatures above a critical temperature (TH) characteristic of

the species of PE93-94

. These properties preclude the preparation of liposomes

composed solely of PE or its derivatives under physiological conditions of pH, ionic

strength and temperature. Several conditions tend to facilitate the formation of

liposomes composed mostly of PE95

:

(1) PE can be mixed with other phospholipids, including the zwitter ionic PC

and the negatively charged phosphatidylglycerol or phosphatidylserine (PS) etc.

These lipids decrease the intermolecular interactions between the polar head groups of

PE and increase the hydration layer of the membrane.

(2) High pH (>9.0) confers a net negative charge on PE molecules, due to



deprotonation of the amino groups, decreases the intermolecular interactions between

the polar headgroups and increases the hydration layer.

(3) Amphiphilic molecules containing a protonatable acidic group that is

negatively charged at physiological pH can be incorporated alongwith PE in the

liposome membrane. These molecules not only cause electrostatic repulsion between

bilayers, but also disrupt the strong interactions between PE head groups, thereby

allowing the formation of bilayer structures and liposomes at physiological pH and

temperature96-98

. With this approach, stable liposomes are formed at physiological pH,

while at mildly acidic pH the carboxyl groups of the amphiphiles are protonated and

their stabilizing effect on PE bilayers is diminished.

Following binding to cells, the liposomes are internalized through the

endocytotic pathway. Liposomes are retained in early endosomes that mature into late

endosomes. The potential of pH-sensitive liposomes lies in their ability to undergo

destabilization at this stage, thus preventing their degradation at the lysosomal level

and consequently increasing access to the cytosolic or nuclear targets99

. Although,

non-pH-sensitive liposomes [e.g., containing PC instead of dioleoyl phosphatidyl

ethanolamine (DOPE)] are internalized as extensively as pH-sensitive

immunoliposomes, their capacity to mediate cytoplasmic delivery of the encapsulated

molecules is significantly lower100

. This observation suggests that fusion or

destabilization of liposomes induced by acidification of the endosomal lumen

represents the most important stage in the process of intracellular delivery (Figure

3.12).



Figure 3.12: Intracellular delivery of oligonucleotides by pH-sensitive liposomes

The liposomes are internalized by endocytosis after binding to cell surface

receptors. The lumen of resulting endosomes is acidified by the action of an

HP-ATPase. The liposomes destabilize at acidic pH, the threshold pH being

determined by the composition of the liposomes. The liposomes in the figure have

been designed (“programmed”) to destabilize at the lower pH achieved in late

endosomes. In case A, the encapsulated oligonucleotides are released into the

endosome lumen, but the endosome is not destabilized and thus the contents are

trapped in the endosome. In case B, the endosome membrane is also destabilized due

to the structural transformation of the pH-sensitive liposomes, enabling the

cytoplasmic entry of the oligonucleotides. Alternatively (case C), the liposomes may

undergo fusion with the endosome membrane and release their contents directly into

the cytoplasm. Some of the oligonucleotides can diffuse into the nucleus.



Studies involving the incubation of cells with lysosomotropic agents (e.g.,

ammonium chloride or chloroquine) that prevents endosome acidification demonstrate

that the efficacy of pH-sensitive liposomes depends on the pH, decrease upon

endosome maturation. Different molecular mechanisms by which the liposomes

release their contents into the cytoplasm have been proposed: (1) destabilization of

pH-sensitive liposomes triggers the destabilization of the endosomal membrane, most

likely through pore formation, leading to cytoplasmic delivery of their contents; (2)

upon liposome destabilization, the encapsulated molecules diffuse to the cytoplasm

through the endosomal membrane; and (3) fusion between the liposome and the

endosomal membranes, leading to cytoplasmic delivery of their contents101

. The

fusogenic properties of PE associated with its tendency to form an inverted hexagonal

phase under certain conditions favor hypotheses (1) and (3). The fusogenic properties

of the liposomes do not always correlate with their efficacy in mediating intracellular

delivery. Although aggregated, release of contents and lipid intermixing are observed

at low pH with DOPE:cholesteryl hemisuccinate (CHEMS) liposomes, no intermixing

of aqueous contents takes place102

, but these liposomes are efficient in delivering their

encapsulated contents into cultured cells. Divalent cations may also play a role in

delivery by pH-sensitive liposomes. PE:oleic acid (OA) liposomes undergo fusion in

the presence of millimolar concentrations of Ca2þ or Mg2þ and the rate of fusion

under acidic conditions is enhanced significantly in the presence of 2 mM Ca2þ.

Cytoplasmic delivery of calcein by DOPE:CHEMS liposomes is inhibited in the

presence of ethylenediamine tetraacetic acid (EDTA)103

, indicating that divalent

cations participate in the destabilization of pH-sensitive liposomes and endosomal

membranes, or their fusion with each other.

The efficiency of interaction of pH-sensitive liposomes with cells is sensitive



upon inclusion of DOPE in their composition and are not sensitive on the type of the

amphiphilic stabilizer used. In fact, some DOPE-containing liposomes shown to be

non-pH-sensitive by biophysical assays, mediated cytoplasmic delivery of their

contents as efficiently as well known pH-sensitive formulations. Nevertheless, among

the different formulations studied, DOPE:CHEMS liposomes had the highest extent

of cell association. Results with cells pretreated with metabolic inhibitors or

lysosomotropic agents indicate clearly that DOPE-containing liposomes are

internalized essentially by endocytosis and that acidification of the endosomes is not

the only mechanism involved in the destabilization of the liposomes inside the cell104

.

Although, some of the liposomes tested had similar abilities to deliver calcein, the

delivery of higher molecular weight molecules was highest when encapsulated in pH-

sensitive DOPE:CHEMS liposomes compared to other DOPE-containing

liposomes105

.

Bertrand et al. characterized the pharmacokinetics (PK) and biodistribution of

pH-responsive N-isopropylacrylamide (NIPAAm) copolymers and determined the

impact of some physicochemical parameters on their biological profiles. Radiolabeled

copolymers of NIPAAm and methacrylic acid (MAA) of different molecular weight,

amphiphilicity and LCST were synthesized and injected intravenously to rats. The PK

and excretion profiles were monitored over 48 h. It was found that elimination

occurred mainly through urinary excretion, which was mainly governed by molecular

weight. The polymers with an LCST situated below the physiological temperature did

not circulate for prolonged period in the bloodstream and were highly captured by the

organs of the mononuclear phagocyte system. Finally, the complexation of an

alkylated pH-sensitive polymer with a molecular weight of 10,000 to the bilayer of

PEGylated liposomes produced a drastic change in the PK parameters, indicating that

http://scialert.net/fulltext/?doi=ajdd.2011.24.48#574040_ja



the polymer remained anchored in the phospholipid bilayer in the bloodstream. These

data indicate that stable pH-sensitive liposomes can be produced using excretable

NIPAAm copolymers106

.

Yuba et al. demonstrated that these linear polymer-modified liposomes

exhibited a pH-dependent membrane fusion behavior in cellular acidic compartments.

They investigated the backbone structure for obtaining pH-sensitive polymers with

much higher fusogenic activity and to reveal the effect of the polymer backbone

structure on the interaction with the membrane. Hyper branched poly(glycidol) (HPG)

derivatives were prepared as a new type of pH-sensitive polymer and used for the

modification of liposomes. HPG derivatives showed a stronger interaction with the

membrane than the linear polymers. Liposomes modified with HPG derivatives of

high DP delivered contents into the cytosol of DC 2.4 cells, a dendritic cell line, more

effectively than the linear polymer-modified liposomes do. Results show that the

backbone structure of pH-sensitive polymers affected their pH-sensitivity and

interaction with liposomal and cellular membranes107

.

3.7 pH sensitive microspheres

The pH of the human gastrointestinal tract was shown to increase

progressively from the stomach (pH 2-3), small intestine (pH 6.5- 7) to the colon (7.0-

7.8)108

. Recent studies using sensitive equipment have given exact data showing that

the pH values in the stomach range from 1.2 to 5.0, while the pH values in the

duodenum, jejunum, ileum and colon are 6.6±0.5, 7.4±0.4, 7.5±0.4 and 7.0±0.7,

respectively109-111

. It has also been reported in many articles that the average gastric

emptying time of multiple units was in the range 1-3 h in a fasted state and 2-4 h in a

fed state. The small intestinal transit is surprisingly constant at 3-4 h and appears to be

insensitive of the type of dosage form and whether the subject is in the fasted or fed

http://scialert.net/fulltext/?doi=ajdd.2011.24.48#1446_op



state112, 113

. Therefore, a dosage form could take from 4 to 8 h to arrive at the colon

following oral administration. It was found that the changes in the pH of the

gastrointestinal tract had a certain gradient and the transit time of materials through

the gut was comparatively long. Moreover, many pH-sensitive polymers (Table 3.03)

such as Eudragit E, Eudragit L, Eudragit S, HP-55 and CAP, etc., which could

dissolve at different pH values, have been synthesized and exploited widely in

designing dosage forms. These findings formed the basis for designing pH-sensitive

drug delivery system. Since the drug release persists throughout the gastrointestinal

tract, resulting in sustained transport of the drug, its pharmacological action is

prolonged. Only part of the formulated drug was released from the system at different

locations in the gastrointestinal tract, the peak and valley phenomenon of

conventional formulations could be avoided and the side effects of the drug could also

be reduced.

Based on the above consideration Yang et al.114

developed pH-dependent

delivery system of nitrendipine in which they have mixed three kinds of pH

dependent microspheres made up of acrylic resins Eudragit E-100,

Hydroxypropylmethylcellulose phthalate and Hydroxypropylmethylcellulose acetate

succinate as pH sensitive polymers. In one of the study carried out

by Mastiholimath et al.115

attempt was made to deliver theophylline into colon by

taking the advantage of the fact that colon has a lower pH value (6.8) than that of the

small intestine (7.0-7.8). So, by using the mixture of the polymers, i.e., Eudragit L and

Eudragit S in proper proportion, pH sensitive release in the colon was obtained.

Table 3.03: pH sensitive polymer with their threshold pH





Polymer Threshold pH

Eudragit*L 100 6.0

Eudragit*L-30D 5.6

Eudragit*S 100 7.0

Eudragit*FS 30D 6.8

Eudragit*L 100-55 5.5

Polyvinyl acetate phthalate 5.0

Hydroxy propyl methyl cellulose phthalate 4.5-4.8

Hydroxy propyl methyl cellulose phthalate-50 5.2

HPMC 55 5.4

Cellulose acetate trimelliate 4.8

Cellulose acetate phthalate 5.0

3.8 pH sensitive nanoparticles

Indeed, it was recently reported that particles in the size range 40-120 nm

were translocated both by transcellular and paracellular route116

. In addition to the

potential for enhancing drug bioavailability via particle uptake mechanisms,

particulate oral delivery systems can protect labile macromolecules from stomach acid

and from the first-pass metabolism in the gastrointestinal tract. Likewise, particulate

formulations also can increase transit times than larger dosage forms and can increase

the local concentration gradient across absorptive cells. Thereby enhancing local and

systemic delivery or both free and bound drugs across the gut117

. Previous studies

have described the use of pH sensitive polymers such as

hydroxypropylmethylcellulose phthalate118

, Eudragit® L100 and Eudragit

® S100

119,120

or cellulose acetate phthalate121

to encapsulate antigens or proteins for oral



administration. These pH-sensitive particles are matrix-type dispersed systems.

Release of the highly dispersed drug at a specific pH within the gastrointestinal tract,

as close as possible to the absorption window of the drug, is expected to increase the

probability of drug absorption and to minimize the first-pass metabolism of drug.

On the basis of the above mentioned considerations, Dai et al.122

were thought

plausible to combine the advantages of nanoparticles as oral delivery systems with the

benefits of the pH-sensitive property.

Lu et al.123

prepared pH-sensitive nanoparticle drug delivery system derived

from natural polysaccharide pullulan for doxorubicin (DOX) release. Pullulan was

functionalized by successive carboxymethylization and amidation to introduce

hydrazide groups. DOX was then grafted onto pullulan backbone through the pH-

sensitive hydrazone bond to form a pullulan/DOX conjugate. This conjugate self-

assembled to form nano-sized particles in aqueous solution as a result of the

hydrophobic interaction of the DOX. Transmission Electron Microscope (TEM) and

Dynamic Light Scattering (DLS) characterization showed that the nanoparticles were

spherical and their size was less than 100 nm. The DOX released from the

nanoparticles in a pH-sensitive manner.

Methods of preparing of polymeric nanoparticles124, 125

include ionic gelation,

coacervation, solvent evaporation, spontaneous emulsification/solvent diffusion,

salting out/emulsification-diffusion, supercritical fluid technology and

polymerization.





3.9 DRUG PROFILE

3.9.1 LERCANIDIPINE HYDROCHLORIDE126

Chemical Name

:

3, 5-pyridinedicarboxylic acid, 1, 4- dihydro-2, 6-dimethyl-4-

(3-nitrophenyl)-2-[(3, 3-diphenylpropyl) methylamino]-1, 1-

dimethylethyl methyl ester hydrochloride.

Molecular Structure

:

.HCl

Molecular Formula : C36H41N3O6.HCl

Molecular weight : 648.24

Description : Lercanidipine Hydrochloride is a light yellow amorphous

powder

Solubility : Lercanidipine and its salts insoluble in water, with a

solubility of about 5µg/ml. Lercanidipine solubility is

marginally greater in acidic media. At pH higher than 5,

solubility is less than 5µg/ml.

Lercanidipine is insoluble in GI pH range of 1 to 8.

Soluble in chloroform and methanol

pKa : 6.83

Dose : 10-20 mg daily in divided doses

Melting Point : 119o -123

oC



Pharmacokinetic profile

Absorption

: Lercanidipine is completely absorbed after oral

administration. The absolute bioavailability of lercanidipine

is about 10%, because of high first pass metabolism.

With oral administration, lercanidipine exhibits non-linear

kinetics.

Distribution : Distribution of lercanidipine from plasma to tissues and

organs is rapid and extensive.

Metabolism

: As for other dihydropyridine derivatives, lercanidipine is

extensively metabolised by CYP3A4. It is predominantly

converted to inactive metabolites; no parent drug is found in

the urine or faeces. About 50% of the dose is excreted in the

urine.

Elimination

: The mean terminal elimination half-life of S- and R-

lercanidipine enantiomers is 5.8 ± 2.5 and 7.7 ± 3.8 hours,

respectively. No accumulation was seen upon repeated

administration. The therapeutic activity of lercanidipine lasts

for 24 hours, due to its high binding to lipid membranes.

Therapeutic uses : For the treatment of Hypertension, management of angina

pectoris and Raynaud's syndrome



3.9.2 ESOMEPRAZOLE MAGNESIUM127

Chemical Name : bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)

methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium

Molecular Structure

:

Molecular Formula : (C17H18N3O3S)2 Mg


Description : Pale cream colored powder in amorphous form

Solubility : Slightly soluble in methanol, soluble in N, N-dimethyl

formamide, Very slightly soluble in water

pKa : 8.8



oC


Absorption

: Rapidly absorbed from the Gastrointestinal track. Single oral

doses generally give rise to peak plasma concentrations

within 1–4 hours, but after several days of once-daily

administration these levels may increase by about 50%.

Distribution : Esomeprazole exhibits about 97% protein binding



Metabolism

: Extensively hepatic; converted to hydroxy and desmethyl

metabolites.

Elimination

: The drug is rapidly cleared from the body, largely by urinary

excretion of pharmacologically-inactive metabolites such as

5-hydroxymethylesomeprazole and 5-carboxyesomeprazole

Therapeutic Uses : Esophagus problems (e.g., acid reflux or GERD, erosive

esophagitis). Decreasing excess stomach acid can help relieve

symptoms such as heartburn, difficulty swallowing, persistent

cough, and trouble sleeping. It can also prevent serious acid

damage to your digestive system (e.g., ulcers, cancer of the

esophagus).



3.9.3 LOSARTAN POTASSIUM128

Chemical Name : 2-butyl-4-chloro-1-[p-(o-1Htetrazol-5ylphenyl) benzyl]

imidazole- 5-methanol mono potassium salt

Molecular Structure

:

Molecular Formula : C22H22ClKN6O


Description : white to off-white free-flowing crystalline powder

Solubility : It is freely soluble in water, soluble in alcohols, and slightly

soluble in common organic solvents, such as acetonitrile and

methyl ethyl ketone

pKa : 4



oC


Absorption

: Losartan Potassium is absorbed from the gastro intestinal

tract. Bioavailability: 25-35 %

Distribution : Both Losartan and its active metabolite are highly bound to

plasma proteins, primarily albumin, with plasma free

fractions of 1.3 % and 0.2 % respectively



Metabolism

: Undergoes substantial first-pass metabolism by cytochrome

P450 enzymes

Elimination : Plasma half life of Losartan Potassium is about 1.5 to 2 h.

Therapeutic Uses : Losartan Potassium is used in treatment of hypertension



3.10 Excipient profile

3.10.1 EUDRAGIT E100129

Structure :

Chemical/ IUPAC name : Poly(butyl methacrylate-co-(2- dimethylaminoethyl)

methacrylate-co-methyl methacrylate) 1:2:1

Functional Category : cationic copolymer based on dimethylaminoethyl

methacrylate, butyl methacrylate, and methyl

methacrylate

Molecular formula : C21H37NO6


Physical Description : It consists of colourless to yellow tinged granules

with a characteristic amine-like odor

Targeted Drug Release Area : Stomach

Solubility : Soluble in gastric fluid up to pH 5.0, Methanol,

Ethanol, Acetone

Toxicological Information : Based on relevant chronic oral toxicity studies in rats

and conventionally calculated with a safety factor of

100 a daily intake in the range of 2 - 20 mg/kg body

weight



3.10.2 HYDROXYPROPYL METHYLCELLULOSE PHTHALATE130

Structure :

Chemical/ IUPAC name : Cellulose, 2-Hydroxypropylmethyl Ether;

Functional Category : Used as a emulsifier, film former, protective

colloid, stabilizer, suspending agent, or thickener in

food or coating agent

Molecular formula : C56H108O30

Molecular weight : approximately 22 kDa

Physical Description : A white or yellowish white, fibrous or granular

Powder.

Targeted Drug Release Area : Colon, intestine

Solubility : Readily soluble in a mixture of acetone and methyl

or I n a mixture of dechloramethane and ethanol

(1:1), Practically insoluble in water

Toxicological Information : LD50 in rats:

>1gm/ kg body wt when given by oral route

5gm/ kg body wt when given by intraperitoneal

route



3.10.3 EUDRAGIT S-100131

Structure :

CH2C

C O

OH

CH2 C

C O

Chemical/ IUPAC name : 2-methylprop-2-enoic acid

Functional Category : Film former, enteric coating


Molecular weight : 135 kDa

Physical Description : White powder with a faint characteristic odour

Targeted Drug Release Area : Intestine

Solubility : Soluble in methanol, ethanol, in aqueous isopropyl

alcohol, acetone and 1 N sodium hydroxide. It is

practically insoluble in ethyl acetate, methylene

chloride, petroleum ether and water.

Toxicological Information : Based on relevant chronic oral toxicity studies in rats

and conventionally calculated with a safety factor of

100 a daily intake in the range of 2 - 20 mg/kg body

weight



3.10.4 HYDROXYPROPYL METHYLCELLULOSE ACETATE SUCCINATE

(HPMC-AS) 132

Structure :

O

O

H

H

CH2OR

H

ORH

OR H

*

O

OH

H

H

ORH

OR

CH2OR

H

*

n

R = -H

-CH3

-COCH3

-COCH2CH2COOH

-CH2CH(OH)CH3

-CH2CH(OCOCH3)

-CH2CH(OCOCH2CH2COOH)CH3

Chemical/ IUPAC name : 2-hydroxypropylmethyl ether, acetate hydrogen

butanedioate

Functional Category : component of controlled release and sustained

release dosage forms; enteric coating; film forming

agent; solid dispersion vehicle


Molecular weight : 55-93 KDa

Physical Description : white to off-white powder or granules

Targeted Drug Release Area : Intestine

Solubility : Soluble in acetone, methanol, ethanol:water (8:2),

methylene chloride:ethanol (1:1)

Toxicological Information : Acute toxicity studies in rats and rabbits showed a

LD50 greater than 2.5gm/kg body.wt



3.10.5 GLYOXAL133

Structure :

Chemical/ IUPAC name : Ethane-1,2-dione

Functional Category : It is used as a solubilizer and cross-linking agent in

polymer chemistry



Physical Description : Colorless liquid

Materials to avoid: : Strong bases, Strong oxidizing agents

Solubility : Soluble in water

Toxicological Information : LD50: Oral Rat 1100 mg/kg; LD50: Dermal Guinea

pig 6600 mg/kg

CH

OHC

O

http://en.wikipedia.org/wiki/Solubility



3.10.6 CHITOSAN134

Structure :

Chemical/ IUPAC name : β-(1-4) linked N-acetyl-D-glucosamine

Functional Category : Flocculant, protein precipitation, encapsulating agent

and aqueous thickener. Forms gels with multivalent

anions. It is biocompatible, antibacterial and

environmentally friendly polyelectrolyte with a

variety of applications including water treatment,

chromatography, additives for cosmetics, textile

treatment for antimicrobial activity, novel fibers for

textiles, photographic papers, biodegradable films,

biomedical devices, films and microcapsule implants

for controlled release in drug delivery.

Molecular formula : (C6H11NO4)n

Molecular weight : 50,000 - 190,000 daltons

Physical Description : Solid light yellow powder

Materials to avoid: : Strong oxidizing agents

Solubility : Soluble in acetic acid solution, insoluble in water or

organic solvents

Toxicological Information : LD50: Oral rat > 10,000 mg/kg

O

O

HO

HO

NH2

O

NH2

OH

HO

*

OH

n



3.10.7 XANTHAM GUM135

Structure :

Functional Category : Xanthum gum is used as suspending agent in food

industry, Thickening agent, stabilizing agent, foaming

agent


Molecular weight : Lies between 4 and 12 X 106 g mol

-1

Physical Description : white or cream color and free flowing powder

Materials to avoid: : Diabetes medications

Solubility : Soluble in water, insoluble in methanol

Toxicological

Information

: A daily intake of 1-10mg/kg body weight is acceptable.

The LD50 was found to be >1kg/kg body weight in rats

and 20kg/ kg body weight in dogs when given by oral

route



3.10.8 KARAYA GUM136

Synonyms : Karaya, gum karaya, Sterculia, gum sterculia, Kadaya, Katilo,

Kullo, kuterra

Definition : A dried exudation from the stems and branches of

Sterculia urens Roxburgh and other species of Sterculia

(Fam. Sterculiaceae) or from Cochlospermum gossypium

A.P. De Candolle or other species of Cochlospermum

(Fam. Bixaceae); consists mainly of high molecular-

weight acetylated polysaccharides, which on hydrolysis

yield galactose, rhamnose, and galacturonic acid, together

with minor amounts of glucuronic acid.

Description : Unground product: occurs in tears of variable size and in

broken irregular pieces having a characteristic semi-

crystalline appearance; pale yellow to pinkish brown;

translucent. Powdered product: pale grey to pinkish

brown; a distinctive odour of acetic acid. Items of

commerce may contain extraneous materials such as

pieces of bark which must be removed.

Functional uses : Emulsifier, stabilizer, thickening agent

Solubility : 2 g added to 50 ml of water swells to form a granular,

stiff, slightly opalescent gel which is acid to litmus;

insoluble in ethanol

Microbiological criteria : Salmonella spp.:Negative in 1 g ; E. coli:Negative in 1 g



N O

CH

CH2 n

3.10.9 POLYVINYL PYRROLIDONE (PVP)137

Structure :

Chemical/ IUPAC name

:

Poly-[1-(2-oxo-1-pyrrolidinyl)- ethylene]

Functional Category : Clarifying agent, stabilizer, dispersing agent,

dissolution enhancer, viscosity-increasing agent,

suspending agent and tablet binder

Molecular formula : (C6H9NO)n

Molecular weight : 40000

Physical Description : White to creamy- white colored powder

Materials to avoid: : Strong oxidizing agents

Solubility : Soluble in water, in ethanol, in chloroform, insoluble

in ether

Toxicological Information : LD50: Oral - rat – 10,000 mg/kg



Review of research papers

Yang et al.138

prepared a novel pH dependent gradient release system for

nitrendipine using pH dependent polymers such as Eudragit E, hydroxy propyl methyl

cellulose phthalate (HPMCP) and hydroxy propyl methyl cellulose acetate succinate

(HPMCAS). The release behavior of the system under simulated gastrointestinal

environment proved that microspheres comprising of pH dependent polymers released

the drug in a particular region of GIT.

Yang et al.139

in an another research work conducted in vivo studies of above

formulations and proved that the bioavailability of poorly water soluble drug such as

nitrendipine could be improved by formulating it as microspheres.

Tang et al.140

have prepared and evaluated pH dependent gradient release

pellets for traditional Chinese medicinal compound recipe using HPMC, HPMCP and

Eudragit L100/S 100. In vitro and in vivo evaluation showed that the prepared

formulation exhibited gradient release in stomach, duodenum and jejunum.

Shah et al.141

have prepared gellan gum microspheres of Sildenafil citrate, for

intranasal delivery to bypass the first pass metabolism. The microspheres were

prepared using spray drying method. The microspheres were evaluated for

characteristics like particle size, incorporation efficiency, degree of swelling, zeta

potential, in-vitro mucoadhesion, ex-vivo mucoadhesion, thermal analysis, XRD study

and in-vitro drug release. Drug release confirmed diffusion controlled drug delivery

from gellan gum microspheres. The results of DSC and XRD studies revealed the

molecular amorphous dispersion of Sildenafil citrate in the gellan gum microspheres.

Microspheres so prepared were discrete, bulky, free flowing and showed an average

encapsulation efficiency ranging from 95-98%. The formulation exhibited a good



mucoadhesive strength which was determined in in vitro conditions through falling

film technique and was compared with ex vivo studies.

Arya et al.142

have prepared mucoadhesive microspheres with Famotidine as

model drug for prolongation of gastric residence time by using w/o emulsification

solvent evaporation method using mucoadhesive polymers like sodium CMC and a

release controlling polymer as sodium alginate. The shape and surface morphology of

prepared microspheres were characterized by optical and scanning electron

microscopy, respectively. In vitro drug release studies were performed and evaluated.

Effects of the stirring rate and polymer concentration on size of microspheres and

drug release were observed. The prepared microspheres exhibited prolonged drug

release (8h) the mean particle size and mucoadhesion increased as the concentration

of sodium alginate increased, and the rate of drug release decreased at higher

concentration of sodium alginate. Significant effect of the stirring rate on the size of

microspheres was observed. In vitro studies demonstrated diffusion-controlled drug

release from the microspheres.

Singh et al.143

have prepared amoxicillin trihydrate mucoadhesive

microspheres using Eudragit RS100 as matrix and HPMC K4M as mucoadhesive

polymer for the potential use of treating gastric and duodenal ulcers, which were

associated with H.pylori. The morphological characteristics of the mucoadhesive

microspheres were studied under scanning electron microscope. The percentage yield

of microspheres of all formulations was in the range of 78.90% to 90.95%. The drug

content determination showed that even if the polymer composition was changed, the

solvent evaporation process was highly efficient to give maximum drug loading in

microspheres. They concluded that the prolonged gastrointestinal residence time and

enhanced stability of amoxicillin trihydrate resulting from the mucoadhesive



microspheres might have contributed to H. pylori clearance.

Zhu et al.144

have developed a novel duodenum-specific microsphere (DSM)

consisting of three-layer structure to enhance the drug concentration and retention

time in duodenal mucus layer. First, a core-shell mucoadhesive microsphere was

prepared with a novel emulsification/coagulation coating method by introducing drug

loaded eudragit cores into a thiolated chitosan mucoadhesive layer. Then the obtained

core-shell mucoadhesive microspheres were further coated with hydroxypropyl

methylcellulose acetate maleate as the pH-sensitive layer to trigger mucoadhesion and

drug release in duodenum. Fluorescence microscopic and scanning electron

microscopic images confirmed the three-layer structure. The microspheres exhibited a

duodenum-specific trigger performance, good mucoadhesive property and pH-

dependent drug release. In vivo study performed in rats demonstrated that DSM

exhibited about 3-fold augmentation of AUC and about 5-fold augmentation of Cmax

for duodenal mucus drug concentration compared to free drug suspension. These

results suggest that the three-layer structure microspheres may provide a promising

approach for duodenum-targeting drug delivery system.

Hyojin P et al.145

have prepared chitosan and glycol chitosan superporous

hydrogels, and investigated their swelling behaviors in acidic solution for the

application as gastric retention device. The optimum preparation condition of

superporous hydrogels was obtained from the gelation and blowing kinetics measured

at varying acidic conditions. Both the swelling rate and swelling ratio of glycol

chitosan hydrogels were higher than those of chitosan hydrogels. They revealed

swelling behaviors which were significantly affected by not only foaming/drying

methods but also with crosslinking density, as the sizes and structures of pores

generated were highly dependent on those preparation conditions. The prepared



superporous hydrogels were highly sensitive to pH of swelling media, and showed

reversible swelling and de-swelling behaviors maintaining their mechanical stability.

The degradation kinetics in simulated gastric fluid was also studied.

Vishal GN and Shivakumar HG146

have prepared superporous hydrogels of

rosiglitazone using chitosan as a polymer & glyoxal as a crosslinking agent by gas

blowing method. The effect of pH and ionic strength on the swelling ratio was

determined. Swelling reversibility studies were also carried out. FTIR analysis was

undertaken to characterize the superporous hydrogels, while dissolution studies were

carried out to assess release characteristics. The higher the amount of crosslinking

agent, the lower the swelling ratio. Higher ionic strength in pH 1.2 solution led to a

decrease in swelling ratio. The superporous hydrogels were highly sensitive to pH of

swelling medium, and showed reversible swelling and de-swelling behavior while still

maintaining their mechanical stability. Apparent density was dependent on the

volume of the superporous hydrogels and decreased with increasing crosslink density.

Degradation kinetics showed that chitosan superporous hydrogels had good water

retention capability. Drug release was inversely proportional to the amount of

crosslinking agent and fitted best to the Korsmeyer-Peppas model. The studies

showed that chitosan-based superporous hydrogels can be used as a gastroretentive

drug delivery system in view of their swelling characteristics in acidic pH.

Joohyang P and Dukjoon K147

have examined the effect of the concentration of

polymer solution on the swelling and mechanical properties of glycol chitosan (GCS)

superporous hydrogels (SPHs). GCS SPHs were synthesized using a gas blowing

method using glyoxal as a crosslinking agent at different concentration of polymer

solution. A small change in the GCS solution concentration resulted in a remarkable

change in compression strength and swelling kinetics without any significant loss in



equilibrium water imbibing capacity. The increase in mechanical strength

accompanied by the decrease in swelling kinetics was caused by the generation of

smaller pores during the gelation process of the reactant systems associated with a

higher polymer solution viscosity. The apparent diffusion coefficients for a variety of

GCS/simulated gastric fluid solution systems were determined from the theoretical

fitting of experimental dynamic swelling data, explaining the effects of the solution

concentration and crosslinking density on the swelling kinetics. The diffusion

coefficients determined in this study are expected to be used as the basic information

in estimating the swelling kinetics of samples in different dimension.

Jin WL et al.148

have synthesized and characterized the interpenetrating

polymer networks (IPNs) hydrogel composed of chitosan and poly (acrylic acid).

Chitosan/poly (acrylic acid) IPNs exhibited relatively high equilibrium water content

and also showed reasonable sensitivity to pH.

Zhou D et al.149

have developed a duodenum-specific drug delivery system on

the basis of a pH-sensitive coating and a mucoadhesive inner core for eradication of

Helicobacter pylori (H. pylori) in the ulcer duodenum. Hydroxypropyl

methylcellulose acetate maleate (HPMCAM) was used as the pH-sensitive material,

which dissolves around pH 3.0. The mucoadhesive microspheres loaded with

furazolidone (FZD-ad-MS) were prepared by the emulsification-solvent evaporation

method using Carbopol 971NP as the mucoadhesive polymer. The prepared pH-

sensitive coated mucoadhesive microspheres (AM-coated-MS) were characterized

with regards to particle size, drug loading efficiency, morphological change, drug

stability, drug release and in vitro anti-H. pylori activity. The particle size was 160.97

± 47.24 μm and 336.44 ± 129.34 μm, and the drug content was 42.33 ± 3.43% and

10.96 ± 1.29% for FZD-ad-MS and AM-coated-MS, respectively. The morphological

http://www.ncbi.nlm.nih.gov/pubmed?term=Zhou%20D%5BAuthor%5D&cauthor=true&cauthor_uid=22644851



changes in different pH media were characterized by scanning electron microscopy

(SEM). HPMCAM coating improved the stability of the FZD-ad-MS and these

particles were expected to remain intact until their arrival in the duodenum.

The drug release was extremely suppressed at pH 1.2 for AM-coated-MS, but

increased at pH 4.0 after regeneration of FZD-ad-MS. In addition, FZD-ad-MS

exhibited excellent anti-H. pylori activity in vitro. Thus, the HPMCAM-coated

microspheres developed in this study hold great promise for use as a duodenum-

specific drug delivery system for H. pylori clearance.

Rasool F et al.150

formulated metoprolol tartrate loaded Eudragit FS

microparticles using solvent evaporation technique by varying polymer contents and

then compressing into tablets. The dissolution test was performed in simulated

gastrointestinal fluid. All tabletted microparticles were tested for stability after storage

in accelerated conditions. As a result of various analytical tests like FTIR, XRD and

DSC analyses, drug was found stable in the microparticles. Metoprolol tartrate loaded

Eudragit FS tabletted microparticles were stable in accelerated storage conditions.

The release behavior of pH-dependent formulations was affected by the dissolution

medium pH and the concentration of polymer used. There was a decrease in drug

release rate with the increase in polymer concentration. In vitro drug release data

(except test formulation F3) were best fitted to zero order model, which indicated the

controlled release nature of formulation, while the Korsmeyer-Peppas model explored

that drug release followed case II relaxation transport mechanism (n > 0.89). Based on

the results, it can be concluded that Eudragit FS is a suitable polymer to

design pH dependent microparticles using solvent evaporation technique for the

release of drug in colon and T2 can be considered as an optimum formulation on the

basis of model independent (f2 test) kinetic interpretation of dissolution results (f2 <

http://www.ncbi.nlm.nih.gov/pubmed?term=Rasool%20F%5BAuthor%5D&cauthor=true&cauthor_uid=22568051



50 for T2 versus reference).

Wang XQ et al.151

have prepared pH-sensitive polymeric nanoparticles with

polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of

drug release are the result of carriers' dissolution, swelling or both of them at

specific pH. The possible reasons for improvement of oral bioavailability include the

following: improve drug stability, enhance mucoadhesion, prolong resident time in GI

tract, ameliorate intestinal permeability and increase saturation solubility and

dissolution rate for poorly water-soluble drugs. As for the advantages of pH-

sensitive nanoparticles over conventional nanoparticles, it was concluded that (1)

most carriers used were enteric-coating materials and their safety is established.

(2) The rapid dissolution or swelling of carriers at specific pH results in quick drug

release and high drug concentration gradient, which might be helpful for absorption.

(3) At the specific pH, carriers dissolve or swell, and the bioadhesion of carriers to

mucosa becomes high because nanoparticles turn from solid to gel, which can

facilitate drug absorption.

Sogias IA et al.152

have prepared chitosan-based mucoadhesive tablets for oral

delivery of ibuprofen. Initially, the powder formulations containing the polymers and

the drug were prepared by either co-spray drying or physical co-grinding. Polymer-

drug interactions and the degree of drug crystallinity in these formulations were

assessed by infrared spectroscopy and differential scanning calorimetry. Tablets were

prepared and their swelling and dissolution properties were studied in media of

various pHs. Mucoadhesive properties of ibuprofen-loaded and drug-free tablets were

evaluated by analysing their detachment from pig gastric mucosa over a range of pHs.

Greater polymer-drug interactions were seen for spray-dried particles compared to co-

ground samples and drug loading into chitosan-based microparticles (41%) was

http://www.ncbi.nlm.nih.gov/pubmed?term=Wang%20XQ%5BAuthor%5D&cauthor=true&cauthor_uid=22885229

http://www.ncbi.nlm.nih.gov/pubmed?term=Sogias%20IA%5BAuthor%5D&cauthor=true&cauthor_uid=22842627



greater than the corresponding half-acetylated chitosan samples (32%). Swelling and

drug release was greater with the half-acetylated chitosan tablets than tablets

containing the parent polymer and both tablets were mucoadhesive, the extent of

which was dependent on substrate pH. The results illustrate the potential sustained

drug delivery benefits of both chitosan and its half-acetylated derivative as

mucoadhesive tablet excipients.

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