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Chapter 3 Review of Literature Biopolymers Based Drug Delivery Systems 11 REVIEW OF LITERATURE 3.1 DOSAGE FORMS 17-22 It is common to differentiate various types of dosage forms by classifying them according to their physical state into gaseous (e.g. anaesthetics), liquid (e.g. solutions, emulsions, suspensions), semisolid (e.g. creams, ointments, gels and pastes) and solid dosage forms (e.g. powders, granules, tablets and capsules). Another way of differentiating dosage forms is according to their site or route of administration. They can be classified as oral, topical, rectal, parenterals, vaginal, ophthalmic, otic, etc. Another method that can be used to differentiate drug delivery systems is according to the way the drug is released. Broadly, one can differentiate as follows: Immediate release drug is released immediately after administration. Modified release drug release only occurs some time after the administration or for a prolonged period of time or to a specific target in the body. 3.1.1 Immediate release Many dosage forms are designed to release the drug immediately or at least as quickly as possible after administration. This is useful if a fast onset of action is required for therapeutic reasons. For example, a tablet containing a painkiller should disintegrate quickly in the gastrointestinal tract to allow a fast uptake into the body. In oral solutions, the drug is in the solution and will simply mix with the gastrointestinal fluids. However, powders and granules need to dissolve first before the drug is released by dissolution. For tablets, it is initially necessary that the tablet disintegrates (if it is formed from compressed granules this will initially happen to the level of the granules, from which further disintegration into powder particles and finally drug dissolution occurs). For capsules to release their drug content, it is

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REVIEW OF LITERATURE

3.1 DOSAGE FORMS17-22

It is common to differentiate various types of dosage forms by classifying them

according to their physical state into gaseous (e.g. anaesthetics), liquid (e.g. solutions,

emulsions, suspensions), semisolid (e.g. creams, ointments, gels and pastes) and solid

dosage forms (e.g. powders, granules, tablets and capsules). Another way of

differentiating dosage forms is according to their site or route of administration. They

can be classified as oral, topical, rectal, parenterals, vaginal, ophthalmic, otic, etc.

Another method that can be used to differentiate drug delivery systems is according to

the way the drug is released. Broadly, one can differentiate as follows:

Immediate release – drug is released immediately after administration.

Modified release – drug release only occurs some time after the administration

or for a prolonged period of time or to a specific target in the body.

3.1.1 Immediate release

Many dosage forms are designed to release the drug immediately or at least as quickly

as possible after administration. This is useful if a fast onset of action is required for

therapeutic reasons. For example, a tablet containing a painkiller should disintegrate

quickly in the gastrointestinal tract to allow a fast uptake into the body.

In oral solutions, the drug is in the solution and will simply mix with the

gastrointestinal fluids. However, powders and granules need to dissolve first before

the drug is released by dissolution. For tablets, it is initially necessary that the tablet

disintegrates (if it is formed from compressed granules this will initially happen to the

level of the granules, from which further disintegration into powder particles and

finally drug dissolution occurs). For capsules to release their drug content, it is

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necessary for the capsule shell material (for example, gelatin or

hydroxypropylmethylcellulose (HPMC)) first to disintegrate. Thereafter, the drug can

either dissolve from the usually solid powders or granules in the case of hard gelatin

or HPMC capsules or it can be dispersed from the usually liquid, lipophilic content of

a soft gelatin capsule. These types of immediate-release dosage forms have an onset

of action in the order of minutes to hours.

Immediate-release dosage forms usually release (dissolve or disperse) the drug

in a single action following a first-order kinetics profile. This means, the drug is

released quickly which then passes through the mucosal membrane of the body,

reaching the highest plasma level (termed Cmax) in a short time (tmax). Once taken up

by the body, the drug is distributed throughout the body and then it is eliminated by

metabolism and excretion. Figure 3.1 shows an idealised plasma concentration versus

time profile of an immediate-release oral dosage form.

Figure 3.1: Idealised plasma concentration versus time profile of an immediate-

release oral dosage form.

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The biological half-life of a drug is defined as the time required to reduce the

plasma concentration by 50% by metabolism or excretion. Many studies show that a

large proportion of patients do not take drugs as directed (for example three times a

day), especially if the disease is (at least initially) not accompanied by strong

symptoms, for example in the treatment of high blood pressure or glaucoma. To

reduce the frequency of drug administration, it is often not possible simply to increase

the dose of an immediate-release dosage form as the peak plasma concentrations may

be too high and lead to unacceptable side-effects. Therefore the drug concentration

within the plasma should be above the minimal effective concentration (MEC) and

below the minimal toxic concentration (MTC), i.e. within the therapeutic range

(Figure 3.2).

Figure 3.2: Idealised plasma concentration versus time profile showing the

concentration and time intervals between the minimal effective concentration

(MEC) and the minimal toxic concentration (MTC).

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3.1.2 Modified release

Dosage forms can be designed to modify the release of the drug over a given time or

after the dosage form reaches the required location.

3.1.2.1 Delayed release

Delayed-release dosage forms can be defined as systems which are formulated to

release the active ingredient at a time other than immediately after administration.

Delayed release oral dosage forms can control the release of the drug to a particular

location, e.g. when the dosage form reaches the small intestine (enteric-coated dosage

forms) or the colon (colon-specific dosage forms).

Delayed-release systems can be used to protect the drug from degradation in

the low pH environment of the stomach or to protect the stomach from irritation by

the drug. In these cases, drug release should be delayed until the dosage form has

reached the small intestine. Often polymers are used to achieve this mission. The

dosage form (for example, a tablet or the granules before tableting) can be coated with

a suitable polymer. The polymer dissolves as a function of pH, so when the dosage

forms travel from the low-pH environment of the stomach to the higher-pH

environment of the small intestine, the polymer coat dissolves and the drug is

released. Once this occurs, the drug release is immediate and the resulting plasma

concentration versus time curve is similar to the one for immediate-release dosage

forms.

The development of colon-specific drugs and dosage forms may be

advantageous for the treatment of local and systemic diseases, including colorectal

cancer and Crohn’s disease. Especially for peptide and protein drugs, this form of

release may also be advantageous for systemic administration as more favourable pH

conditions exist in the colon compared to stomach, and also lower enzymatic activity

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compared to the small intestine. Figure 3.3 shows an idealised plasma concentration

versus time profile of a delayed-release oral dosage form. tmax (but not Cmax) is

strongly dependent on the gastric emptying times which, as stated above, may be

quite variable.

3.1.2.2 Extended release

Extended-release systems allow the drug to be released over prolonged time periods.

By extending the release profile of a drug, the frequency of dosing can be reduced.

For immediate-release dosage forms, the time interval during which the plasma

concentration is in the therapeutic range for a drug can be quite short. Hence frequent

dosing, with its associated compliance problems, is required. This is especially an

issue in chronic diseases when patients need to take the medicine for prolonged

periods of time, often for the rest of their life. Extended release can be achieved using

sustained- or controlled-release dosage forms.

Figure 3.3: Idealised plasma concentration versus time profile of a delayed-

release oral dosage form compared to an immediate-release dosage form.

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3.1.2.3 Sustained release

These systems maintain the rate of drug release over a prolonged period (Figure 3.4).

For example, if the release of the drug from the dosage form is sustained such that the

release takes place throughout the entire gastrointestinal tract, one could reduce Cmax

and prolong the time interval of drug concentration in the therapeutic range. This in

turn may reduce the frequency of dosing, for example from three times a day to once

a day. Sustained-release dosage forms achieve this mainly by the use of suitable

polymers, which are used either to coat granules or tablets (reservoir systems) or to

form a matrix in which the drug is dissolved or dispersed (matrix systems). The

release kinetics of the drug from these systems may differ:

Reservoir systems often follow a zero-order kinetics (linear release as a

function of time).

Matrix systems often follow a linear release as a function of the square root of

time.

Figure 3.4: Idealised plasma concentration versus time profile of a sustained-

release oral dosage form compared to an immediate-release dosage form.

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3.1.2.4 Controlled release

Controlled-release systems also offer a sustained-release profile but, in contrast to

sustained-release forms, controlled-release systems are designed to lead to predictably

constant plasma concentrations, independently of the biological environment of the

application site. This means that they are actually controlling the drug concentration

in the body, not just the release of the drug from the dosage form, as is the case in a

sustained-release system. Another difference between sustained- and controlled-

release dosage forms is that the former are basically restricted to oral dosage forms

whilst controlled-release systems are used in a variety of route of administration,

including transdermal, oral and vaginal administration.

Controlled release of drugs from a dosage form may be achieved by the use of

so-called therapeutic systems. These are drug delivery systems in which the drug is

released in a predetermined pattern over a fixed period of time. The release kinetics is

usually zero-order. In contrast to sustained-release systems, the dose in the therapeutic

systems is of less importance than the release rate from the therapeutic system.

Ideally, the release rate from the dosage form should be the rate-determining step for

the absorption of the drug and in fact for the drug concentration in the plasma and

target site. However, controlled-release systems are not necessarily target-specific,

which means that they do not ‘exclusively’ deliver the drug to the target organ. This

may be achieved by so-called targeted delivery systems which aim to exploit the

characteristics of the drug carrier and the drug target to control the biodistribution of

the drug. Figure 3.5 shows an idealised plasma concentration versus time profile of a

controlled-release dosage form.

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Figure 3.5: Idealised plasma concentration versus time profile of a controlled-

release dosage form.

3.1.2.5 Targeted-release dosage forms

Whilst controlling the rate of release of a drug from its delivery system can control

plasma drug concentration levels, once released there is often little control over the

distribution of the drug in the body. Very few drugs bind exclusively to the desired

therapeutic target and this can give rise to reduced efficacy and increased toxicity.

Drug targeting aims to control the distribution of a drug within the body such

that the majority of the dose selectively interacts with the target tissue at a cellular or

subcellular level. By doing so, it is possible to enhance the activity and specificity of

the drug and to reduce its toxicity and side-effects. Drug targeting can be achieved by

designing systems that passively target sites by exploiting the natural conditions of the

target organ or tissue to direct the drug to the target site. Alternatively drugs and

certain delivery systems can be actively targeted using targeting groups such as

antibodies to bind to specific receptors on cells.

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3.2 ORAL DRUG DELIVERY23-27

The oral route is often the most convenient route for drug delivery; however, drugs

delivered via this route can be metabolised by the hepatic first-pass effect. The

suitability and convenience of this route of delivery make oral dosage forms the most

common of all drug delivery systems. However, some factors should be considered

when looking to administer drugs via this route. In particular, the transit time in the

gastrointestinal tract may vary considerably:

between patients and within the same patient, with the gastric residence time

being the most variable

with the state of the dosage form (liquid dosage forms are emptied out of the

stomach faster than solid dosage forms)

with the fasted or fed state of the patient.

3.2.1 Oral sustained release dosage forms

Oral sustained drug delivery can be achieved by one of the following ways;

Dissolution-sustained release

o Encapsulation dissolution control

o Matrix dissolution control

Diffusion-sustained release

o Reservoir devices

o Matrix devices

Methods using osmotic pressure

pH independent formulations

Altered density formulations

Gastro retentive systems

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3.2.1.1 Advantages of sustained release dosage forms:

Reduction in dosing frequency.

Reduced fluctuations in circulating drug levels.

Avoidance of night time dosing.

Increased patient compliance.

More uniform effect.

3.2.1.2 Disadvantages of sustained release dosage forms:

Unpredictable or poor in vitro - in vivo correlation.

Dose dumping.

Reduced potential for dosage adjustment.

Poor systemic availability in general.

3.2.1.3 Factors governing the design of sustained release dosage forms:

Molecular size and diffusivity

Solubility

pKa- ionization constant

Partition coefficient

Release rate and dose

Absorption

Distribution

Elimination half life

Drug-protein binding

Duration of action

Therapeutic index

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3.3 STOMACH SPECIFIC DRUG DELIVERY SYSTEMS28-33

Gastroretensive systems can remain in the gastric region (stomach) of the

gastrointestinal tract (Figure 3.6) for several hours and hence significantly prolong the

gastric residence time of drugs. Prolonged gastric retention improves bioavailability,

reduces drug wastage and improves solubility for drugs that are less soluble in a high

pH environment. It has applications also for local drug delivery to the stomach and

proximal small intestines. Gastro retention helps to provide better availability of new

products with new therapeutic possibilities and substantial benefits for patients.

Various attempts have been made to retain the dosage form in the stomach as a way of

increasing retention time.

Figure 3.6: Figure depicting human GIT

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3.3.1 Approaches to gastric retention

Over the last three decades, various approaches have been pursued to increase the

retention of an oral dosage form in the stomach (Figure 3.7).

Figure 3.7: Picturisation of various approaches to gastroretentive formulations

3.3.1.1 High-density systems: These systems, which have a density of ~3 g/cm3, are

retained in the rugae of the stomach and are capable of withstanding its peristaltic

movements. Above a threshold density of 2.4–2.8 g/cm3, such systems can be retained

in the lower part of the stomach. The only major drawbacks with such systems is that

it is technically difficult to manufacture them with a large amount of drug (>50%) and

to achieve the required density of 2.4–2.8 g/cm3. Diluents such as barium sulphate,

zinc oxide, titanium dioxide, and iron powder must be used to manufacture such high-

density formulations.

3.3.1.2 Swelling systems: After being swallowed, these dosage forms swell to a size

that prevents their passage through the pylorus. As a result, the dosage form is

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retained in the stomach for a long period of time. These systems are sometimes

referred to as plug type systems because they tend to remain lodged at the pyloric

sphincter. These polymeric matrices remain in the gastric cavity for several hours

even in the fed state. Upon coming in contact with gastric fluid, the polymer imbibes

water and swells. The extensive swelling of these polymers is a result of the presence

of physical–chemical cross-links in the hydrophilic polymer network. These cross-

links prevent the dissolution of the polymer and thus maintain the physical integrity of

the dosage form. However, a balance between the rate and extent of swelling and the

rate of erosion of the polymers is crucial to achieve optimum benefits and to avoid

unwanted side effects.

3.3.1.3 Bio/mucoadhesive systems: Bio/mucoadhesive systems bind to the gastric

epithelial cell surface, or mucin, and extend the gastric residence time(GRT) by

increasing the intimacy and duration of contact between the dosage form and the

biological membrane. Mucus secreted continuously by the specialized goblet cells

located throughout the GIT plays a cytoprotective role. The epithelial adhesive

properties of mucin have been applied to the development of GRDDS through the

binding of polymers to the mucin epithelial surface can be subdivided into three broad

categories: hydration-mediated adhesion, bonding-mediated adhesion, and receptor-

mediated adhesion. In hydration-mediated adhesion, the hydrophilic polymer imbibes

water and become sticky and acquires bioadhesive property. Bonding mediated

adhesion may involve mechanical or chemical bonding. Chemical bonds may involve

covalent or ionic or Vander Waal’s forces between polymer molecules and the mucus

membrane. Receptor mediated adhesion takes place between certain polymers and

specific receptors expressed on gastric cells. The polymers could be anionic, cationic

or neutral.

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3.3.1.4 Floating systems: Floating systems, first described by Davis in 1968, are low-

density systems that have sufficient buoyancy to float over the gastric contents and

remain in the stomach for a prolonged period. While the system floats over the gastric

contents, the drug is released slowly at the desired rate, which results in increased

GRT and reduces fluctuation in plasma drug concentration. However, besides a

minimal gastric content needed to allow proper achievement of the buoyancy

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

dosage form reliably buoyant on the surface of the meal.

3.3.2 Criteria for choosing drugs for gastroretentive drug delivery system

The concept of gastroretention holds validity for the drugs having atleast one or all of

the enlisted properties i.e. drug with a narrow window of absorption, which act locally

in the stomach (stomach being the primary site for absorption), are rapidly absorbed

from the gastrointestinal tract or the drugs which are poorly soluble at an alkaline pH.

3.3.3 Types of formulation used for floating drug delivery systems

Based on the mechanism of buoyancy two distinctly different technologies or types

have been utilized in the development of FDDS.

1. Gas generating/Effervescent systems

2. Non-Effervescent systems.

3.3.3.1 Effervescent systems

The buoyant delivery systems are prepared with swellable polymers such as methocel

or polysaccharides e.g. chitosan and effervescent components, e.g. sodium

bicarbonate and citric or tartaric acid or matrices containing chambers of liquids that

gasify at body temperature.

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The matrices are fabricated so that upon contact with gastric fluid, carbon

dioxide is liberated by the acidity of gastric contents and is entrapped in the gellyfied

hydrocolloid; this produces an upward motion of the dosage form and maintains its

buoyancy. The carbon dioxide generating components may be intimately mixed

within the tablet matrix to produce a single layered tablet or a bi-layered tablet may be

compressed which contains the gas generating mechanism and the drug in the other

layer formulated for the sustained release effect.

3.3.3.2 Non-Effervescent systems

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type

hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate,

polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a

simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid.

After oral administration this dosage form swells in contact with gastric fluids and

attains a bulk density of < 1. The air entrapped within the swollen matrix imparts

buoyancy to the dosage form. The so formed swollen gel-like structure acts as a

reservoir and allows sustained release of drug through the gelatinous mass.

3.3.4 Advantages of floating drug delivery systems

1. The gastroretensive systems are advantageous for drugs absorbed through the

stomach. E.g. Ferrous salts, antacids.

2. Acidic substances like aspirin cause irritation on the stomach wall when it comes in

contact with it. Hence such formulations may be useful for the administration of

aspirin and other similar drugs.

3. Administration of prolonged release floating dosage forms viz., tablet or capsules,

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

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

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

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

intestine.

4. The gastroretentive systems are advantageous for drugs meant for local action in

the stomach. e.g. antacids.

5. When there is a vigorous intestinal movement and a short transit time as might

occur in certain type of diarrhea, poor absorption is expected. Under such

circumstances it may be advantageous to keep the drug in floating condition in

stomach to get a relatively better response.

3.3.5 Disadvantages of floating drug delivery system:

1. Floating system is not feasible for those drugs that have solubility or stability

problem in G.I. tract.

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

and work efficiently.

3. The drugs that are significantly absorbed through out gastrointestinal tract, which

undergo significant first pass metabolism, are only desirable candidate.

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

3.3.6 First-pass metabolism

Importantly, drugs that are taken up into the body through the gastrointestinal mucosa

will be transported to the liver via the portal vein before going into general

circulation. As the liver is the main metabolic organ of the body, if the drug is

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susceptible to metabolic degradation in the liver, this may considerably reduce the

activity of the drug. This phenomenon is known as the hepatic first-pass effect.

3.3.7 Types of gastroretentive drug delivery systems

Varied formulations for gastroretentive drug delivery are available as shown in Table

3.1.

Table 3.1: List of drugs formulated as floating drug delivery systems

Tablets Chlorpheniramine maleate, theophylline, furosemide, ciprofloxacin,

captopril, acetylsalicylic acid, nimodipine, amoxycillin trihydrate,

verapamil HCI, isosorbide di nitrate, sotalol, isosorbide mononitrate,

aceraminophen, ampicillin, cinnarazine, dilitiazem, florouracil,

piretanide, prednisolone, riboflavin- 5`phosphate, etc.

Capsules Nicardipine, L-dopa and benserazide, chlordizepoxide HCI,

furosemide, misoprostal, diazepam, propranlol, urodeoxycholic acid,

etc.

Microspheres Verapamil, aspirin, griseofulvin, and p-nitroanilline, ketoprofen,

tranilast, ibuprufen, terfenadine etc.

Granules Indomethacin, diclofenac sodium, prednisolone, etc.

Films Cinnarizine etc.

Powders Several basic drugs.

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3.4 POLYMERS

Polymers or macromolecules are composed of very large molecules with molecular

weights ranging from a few thousand to as high as millions of grams/mole. The

pharmaceutical applications of polymers range from their use as binders in tablets to

viscosity and flow controlling agents in liquids, suspensions and emulsions. Polymers

can be used as film coating material to mask the unpleasant taste of a drug, to enhance

drug stability and to modify drug release characteristics. Pharmaceutical polymers are

widely used to achieve taste masking; thickening (rheology modifier), gelling

(controlled release), adhesion (binding), pH-dependent solubility (controlled release),

controlled release (e.g., extended, pulsatile, and targeted), barrier properties

(protection and packaging), enhanced stability, and improved bioavailability 34

.

3.4.1 Polymers in pharmaceutical and biomedical applications35, 36

3.4.1.1 Water-soluble synthetic polymers

Poly (acrylic acid)-Cosmetic, pharmaceuticals, immobilization of cationic

drugs, base for Carbopol polymers

Poly (ethylene oxide)-Coagulant, flocculent, very high molecular-weight up to

a few millions, swelling agent

Poly (ethylene glycol) Mw <10,000; liquid (Mw <1000) and wax (Mw

>1000)-Plasticizer, base for suppositories

Poly (vinyl pyrrolidone)-Used to make betadine (iodine complex of PVP) with

less toxicity than iodine, plasma replacement, tablet granulation

Poly (vinyl alcohol)-Water-soluble packaging, tablet binder, tablet coating

Polyacrylamide-Gel electrophoresis to separate proteins based on their

molecular weights, coagulant, absorbent

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Poly (isopropyl acrylamide) and poly (cyclopropyl methacrylamide)

Thermogelling acrylamide derivatives-Its balance of hydrogen bonding, and

hydrophobic association changes with temperature

3.4.1.2 Cellulose-based polymers

Ethyl cellulose-Insoluble but dispersible in water, used as aqueous coating

material for sustained release applications

Carboxymethyl cellulose-Super disintegrant, emulsion stabilizer

Hydroxyethyl and hydroxypropyl celluloses-Soluble in water and in alcohol,

tablet coating

Hydroxypropyl methyl cellulose-Binder for tablet matrix and tablet coating,

gelatin alternative as capsule material

Cellulose acetate phthalate-Enteric coating

3.4.1.3 Hydrocolloids

Alginic acid-Oral and topical pharmaceutical products; thickening and

suspending agent in a variety of pastes, creams, and gels, as well as a

stabilizing agent for oil-in- water emulsions; binder and disintegrant

Carrageenan-Modified release, viscosifier

Chitosan-Cosmetics and controlled drug delivery applications, mucoadhesive

dosage forms, rapid release dosage forms

Hyaluronic acid-Reduction of scar tissue, cosmetics

Pectin-Drug delivery

3.4.1.4 Water-insoluble biodegradable polymers

(Lactide-co-glycolide) polymers Microparticle–nanoparticle-Used for protein

delivery

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3.4.1.5 Starch-based polymers

Starch-Glidant, a diluent in tablets and capsules, a disintegrant in tablets and

capsules, a tablet binder

Sodium starch glycolate-Super disintegrant for tablets and capsules in oral

delivery

3.4.1.6 Plastics and Rubbers

Polyurethane-Transdermal patch backing (soft, comfortable, moderate

moisture transmission), blood pump, artificial heart, and vascular grafts, foam

in biomedical and industrial products

Silicones-Pacifier, therapeutic devices, implants, medical grade adhesive for

transdermal delivery

Polycarbonate-Case for biomedical and pharmaceutical products

Polychloroprene-Septum for injection, plungers for syringes, and valve

components

Polyisobutylene-Pressure sensitive adhesives for transdermal delivery

Polycyanoacrylate-Biodegradable tissue adhesives in surgery, a drug carrier in

nano and microparticles

Poly (vinyl acetate)-Binder for chewing gum

Polystyrene-Petri dishes and containers for cell culture

Polypropylene-Tight packaging, heat shrinkable films, containers

Poly (vinyl chloride)-Blood bag, hoses, and tubing

Polyethylene-Transdermal patch backing for drug in adhesive design, wrap,

packaging, containers

Poly (methyl methacrylate)-Hard contact lenses

Poly (hydroxyethyl methacrylate)-Soft contact lenses

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Acrylic acid and butyl acrylate copolymer-High Tg pressure–sensitive

adhesive for transdermal patches

2-Ethylhexyl acrylate and butyl acrylate copolymer-Low Tg pressure–

sensitive adhesive for transdermal patches

Vinyl acetate and methyl acrylate copolymer-High cohesive strength pressure–

sensitive adhesive for transdermal patches

Ethylene vinyl acetate and polyethylene terephthalate-Transdermal patch

backing (occlusive, heat sealable, translucent)

Ethylene vinyl acetate and polyethylene-Transdermal patch backing (heat

sealable, occlusive, translucent)

Polyethylene and polyethylene terephthalate-Transdermal patch backing

(when ethylene vinyl acetate copolymer is incompatible with the drug)

3.4.2 Natural polymers (biopolymers)37-39

Biopolymers like natural gums and polysaccharides are now extensively used for the

development of dosage forms for controlled/ sustained drug delivery. Although

natural polymers and their derivatives are used widely in pharmaceutical dosage

forms to deliver drugs, however, their use has been hampered by the synthetic

materials. These natural polysaccharides hold advantages over synthetic polymers,

generally because they are non toxic, less expensive and easily available from

renewable resources. Biopolymers can be modified to have tailor-made materials for

drug delivery systems and thus can compete with synthetic biodegradable materials

available commercially.

Natural polysaccharides and their derivatives represent a group of polymers

widely used in pharmaceutical sectors for controlled drug delivery systems. Various

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kinds of natural polymers such as acacia, agar, alginate, carrageenan, chitosan,

dextrin, gellan gum, guar gum, inulin, karaya gum, locust bean gum, pectin, starch,

xanthan gum etc., are used in the food industry and are regarded as safe for human

consumption. These polysaccharides are obtained usually as plant exudates containing

various sugars other than glucose and having siginificant quantities of oxidized

groups in addition to their normal polyhydroxy format. In many cases, water-soluble

polysaccharides are generally similar to the exudates of components of land and

marine plants and their seeds. These components result from normal metabolic

processes, and many times, they represent the reserve carbohydrates in that system.

Natural gums are often preferred over synthetic polymers due to their

nontoxicity, low cost and easy availability. It should be noted that many “old”

materials compete successfully today after almost a century of efforts to replace them.

It is the usual balance of economics and performance that determines the commercial

realities. Natural gums have been modified to overcome certain drawbacks like

uncontrolled rate of hydration, thickening, drop in viscosity on storage, microbial

contamination etc.

3.4.2.1 Advantages of natural polymers

Biodegradable – Naturally occurring polymers produced by all living

organisms. They show no adverse effects on the environment or human being.

Biocompatible and non-toxic – Almost all of these plant materials are

carbohydrates in nature and composed of repeating monosaccharide units.

Hence they are non-toxic.

Economic - They are cheaper and their production cost is less than synthetic

material.

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Safe and devoid of side effects – As they are from natural source, they are safe

and without side effects.

Easy availability – In many countries, they are produced due to their

application in many industries.

3.4.2.2 Disadvantages of natural polymers:

Microbial contamination – During production, they are exposed to external

environment and hence, there are chances of microbial contamination.

Batch to batch variation – Synthetic manufacturing is controlled procedure

with fixed quantities of ingredients while production of natural polymers is

dependent on environment and various physical factors.

The uncontrolled rate of hydration—Due to differences in the collection of

natural materials at different times, as well as differences in region, species,

and climate conditions the percentage of chemical constituents present in a

given material may vary.

Slow Process – As the production rate is depends upon the environment and

many other factors, it can’t be changed. So natural polymers have a slow rate

of production.

Heavy metal contamination – There are chances of Heavy metal

contamination often associated with natural polymers.

3.4.3 Use of natural polymers in pharmacy

Natural gums are promising biodegradable polymeric materials. It is clear that natural

polymers have many advantages over synthetic ones and has been established in the

field of pharmaceuticals. However, there is a need to identify, isolate and modify

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other polymers amongst the nature as well as its evaluation in relation to not only the

quality and efficacy but with the compatibility of existing natural polymeric material

for its safe use in pharmaceutical formulations. Therefore in the years to come there

will be continued interest in natural polymers and their modifications.

Recent trend towards the use of vegetable and nontoxic products demands the

replacement of synthetic additives with natural one. Many natural polymeric materials

have been successfully used in sustained-release tablets. These materials include: guar

gum, isapghula husk, pectin, galactomannon from Mimosa scabrella, Gleditsia

triacanthos Linn (honey locust gum) , Sesbania gum , mucilage from the pods of

Hibiscus esculenta , tamarind seed gum , gum copal and gum dammar, agar, konjac,

chitosan etc.

3.4.3.1 Carrageenan

Carrageenans are marine hydrocolloids obtained by extraction from some

members of the class Rhodophyceae. The most important members of this class are

Kappaphycus cottonii, Eucheuma spinosum and Gigartina stellata. There are three

different types of carrageenans viz., kappa [κ], iota [ι] and lambda [λ]-carrageenan.

All consists chiefly of the sulfated esters of D-galactose and 3, 6-anhydro-D-galactose

coplymers, linked α-1,3 and β-1,4 in the polymer. It appears as yellowish to

colourless, coarse to fine powder which is practically odourless. The λ-carrageenan

does not contain 3,6-anhydro galactose and is highly sulfated. It does not gel and is

used as a thickeninig agent. The κ -ι -carrageenans are very similar in structure,

except that, ι -carrageenan is sulfated at carbon-2. Both the forms swells and gels. The

κ-carrageenan form strong, rigid and brittle gels. A very small amount of potassium

ion is essential for this. The ι -carrageenan forms elastic gels that show thixotropy,

mainly in the presence of calcium ions40

.

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Figure 3.8: Chemical structures of different types of carrageenans

Carrageenans were mainly used as gelling and thickening agents. Only few

studies have dealt with carrageenans for controlled-release tablets. In a study of four

natural hydrophilic gums formulated as mini-matrices in hard gelatin capsules, it was

concluded that carrageenan used in the study did not produce sufficient sustained

release41

. Single unit, floating controlled drug delivery system was prepared using

matrix-forming polymers like hydroxypropyl methylcellulose [HPMC], polyacrylates,

sodium alginate, corn starch, carrageenan, gum guar and gum arabic and it was

concluded that carrageenan can be used as a matrix material in formulating floating

tablets 42

.

Lambda-carrageenan, an anionic polymer ionically interacted with alkaline

drug, timolol maleate, resulting in a complex that releases the drug slowly43

.

Carrageenan and gelatin in different ratios were combined for modulating the drug

release profiles. Sponge-like, in situ gelling inserts based on carrageenan using

oxymetazoline HCl was prepared by Ulrike Bertram et al.44

. They stated that, the drug

release decreased with increase in polymer content of the insert and concluded that

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bioadhesive nasal inserts have a high potential as new nasal dosage form for extended

drug delivery. Pourjavadi et al. prepared novel, highly swelling hydrogels by grafting

crosslinked polyacrylic acid-co-poly-2-acrylamido-2-methylpropanesulfonic acid

[PAA-co-PAMPS] chains onto κ-carrageenan through free radical polymerization

method. The swelling of superabsorbent hydrogels was measured in various solutions

with pH values ranging from 1 to 13. The hydrogels swelled to a range of 135–

800 g/g indicating it to be a suitable candidate for drug delivery45

.

A novel approach of nanosizing a drug/polymeric complex to increase both

solubility and dissolution rate of poorly water-soluble compounds was studied by

Wei-Guo etal.46

. κ-carrageenan was complexed with a poorly water-soluble

compound to increase the compound's aqueous solubility. The compound/carrageenan

complex was further nanosized by wet-milling to enhance the dissolution rate, which

increased the aqueous solubility of the compound from less than 1 μg/mL to 39

μg/mL. Ana et al. prepared crosslinked κ-carrageenan hydrogel nanoparticles

(nanogels) with an average size smaller than 100 nm using reverse microemulsions

combined with thermally induced gelation technique47

. The nanogels were found to be

thermo-sensitive in a temperature range acceptable for living cells (37–45 °C)

undergoing reversible volume transitions in response to thermal stimuli making them

possibile to explore the application in smart therapeutics such as thermo-sensitive

drug carriers.

Kok Hoong et al.48

discussed the carboxymethylation of kappa-carrageenan, a

natural linear polysaccharide, to obtain a pH-dependent swelling property allowing

for intestinal-targeted delivery of bioactive macromolecules. They stated that

carboxymethylated kappa-carrageenan beads may provide an efficient alternative

approach for the oral delivery from hydrophilic macromolecules to the intestinal tract.

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3.4.3.2 Gellan gum

Gellan gum is a polysaccharide produced by Sphingomonas elodea, a bacterium. It

appears as off-white powder, soluble in water and used primarily as an alternative to

agar as a gelling agent in microbiological culture. It can withstand to 120 °C heat,

making it especially useful in culturing thermophilic organisms. As a food additive,

gellan gum is used as a thickener, emulcifier, and stabilizer. The high molecular

weight polysaccharide is principally composed of a tetrasaccharide repeating units of

one rhamnose, one glucuronic acid, and two glucose units, and is substituted with acyl

[glyceryl and acetyl] groups as the O-glycosidically-linked esters. The glucuronic acid

is neutralized to a mixed potassium, sodium, calcium, and magnesium salt. It usually

contains a small amount of nitrogen containing compounds resulting from the

fermentation procedures49

.

Figure 3.9: Chemical structure of gellan gum

Gellan gum beads of propranolol hydrochloride, a hydrophilic model drug,

were prepared by solubilising the drug in a dispersion of gellan gum and then

dropping the dispersion into calcium chloride solution50

. The droplets formed gelled

beads instantaneously by ionotropic gelation. Very high entrapment efficiencies were

obtained (92%) after modifying the pH of both the gellan gum dispersion and the

calcium chloride solution. Gellan gum could be a useful carrier for the encapsulation

of fragile drugs and provides new opportunities in the field of bioencapsulation.

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Gels formed in situ following oral administration of 1% (w/v) aqueous

solutions of gellan to rats and rabbits were evaluated as sustained-release vehicles51

.

The formulation contained calcium ions in complexed form, the release of which in

the acidic environment of the stomach caused gelation of the gellan gum.

Bioavailability of theophylline from gellan gels formed by in situ gelation in the

animal stomach was increased by four–five fold in rats and three fold in rabbits as

compared with that from the commercial oral formulation.

The effect of different ions in tear fluid (Na+, K

+, Ca

2+) on the gel strength and

the consequences of dilution due to the ocular protective mechanisms were

examined52

and it was found that Na+ was found to be the most important gel-

promoting ion in vivo. In situ gels of gellan for the oral delivery of cimetidine53

,

paracetamol54

and amoxicillin55

were also investigated. Literature data revealed that

gellan can be used for targeting the drugs to colon56

.

Ritu Goyal et al.57

blended branched polyethylenimine, 25 kDa (PEI) with

gellan gum, an anionic heteropolysaccharide, for partial neutralization of its excess

positive charge to form gellan gum-polyethylenimine (GP) nanocomposites. The

prepared nanocomposites showed the best transfection efficiency in tested cell lines in

comparison with the rest of the series, PEI, Lipofectamine and other commercial

transfection agents and they also exhibited minimum cytotoxicity. Their study

suggested that NPs may act as an efficient non-viral gene carrier with diverse

biomedical applications.

Shi-lei Cao et al.58

prepared a novel in situ gel system for nasal delivery of

mometasone furoate (MF) and study its efficacy on allergic rhinitis model. An ion-

activated in situ gel was developed and characterized with gellan gum as a carrier.

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A novel glipizide-loaded bead system was developed through ionotropic

gelation of gellan with trivalent Al+3

ions and covalent cross-linking with

glutaraldehyde (GA) by Sabyasachi et al. They stated that, the drug was relatively

stable and amorphous in the beads, and both GA-treated and -untreated Al+3

/gellan

beads could be useful carriers for the controlled oral delivery of glipizide59

.

3.4.3.3 Guar gum

Guar gum is a gum obtained from the ground endosperms of Cyamposis

tetragonolobus (Leguminosae family). It consists of high molecular weight

hydrocolloidal polysaccharide, composed of galactan and mannan units combined

through glycosidic linkages. The structure of guar gum is a linear chain of β-D-

mannopyranosyl units linked (1→ 4) with single-member α-D-galactopyranosyl units

occurring as side branches49

.

Guar gum is an interesting polymer for the preparation of hydrophilic matrix

tablets because of its high water swellability, nontoxicity, and low cost. Many

researchers have used guar gum as a controlled-release carrier. Baveja et al.60

examined 12 natural gums and mucilages as sustaining materials in tablet dosage

forms. Tablets prepared using guar gum as the sustaining material dissolved within 2

h due to the high erosion rate of the matrix. Bhalla and Gulati61

evaluated sustained

release theophylline tablets with eudragits and guar gum. Formulations based on 5%

guar gum gave an appropriate release pattern over a period of 12 h.

Alataf and co workers62

examined the use of guar gum for sustaining the

release of diltiazem. Their results indicated that, varying the lots or batches of guar

gum as well as using guar gum from different suppliers had little effect on diltiazem

dissultion behavior. The stabilities of guar gum based formulations under stressed

condition were established. All four formulations gave similar plasma concentration

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over time in pharmacokinetic studies of healthy volunteers. It was concluded that

matrix tablets based on guar gum represent a simple and economic alternative to

existing diltiazem sustained release dosage forms.

Figure 3.10: Chemical structure of guar gum

Gebert and Friend63

purified guar galactomannan and assessed certain

pharmaceutical attributes. The viscosity of 1% purifed galactomannan aqueous

solution is typically 40-50% higher than its unpurified precursor. The hydration rate

of 1% aqueous solution increases by 100% after purification. This data demonstrated

the need for less guar gum to sustain the release of water-soluble drug.

In spite of the wide pharmaceutical application of guar gum, its use is limited

by its uncontrolled rate of hydration, decreased viscosity on storage, and microbial

contamination. Paranjothy and Thampi64, 65

synthesized derivatives of guar, such as

guar succinate, guar benzoate, polygalactomannan (borate reaction), oxidized guar

gum, hydroxyl propyl guar and sodium carboxy methyl guar. The solubility studies

showed that sodium carboxy methyl guar gave a transparent gel. A 2% sodium

carboxy methyl guar solution in water was poured over a mercury pool produced a

very good flexible, clear, transparent film. Later, a transdermal patch of verapamil

hydrochloride was prepared using sodium carboxy methyl guar as a polymer matrix66

.

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In vitro release studies through mouse skin showed that sodium carboxy methyl guar

was a suitable polymer.

The functioning of guar gum crosslinked products (GGP) as possible colon-

specific drug carriers was analyzed by studying the release kinetics of pre-loaded

hydrocortisone from GGP hydrogels in buffer solutions with, or without GG

degrading enzymes (α-galactosidase and β-mannanase)67

. It was concluded that

crosslinked guar gum can be biodegraded enzymatically and is able to retard the

release of a low water-soluble drug, which could potentially be used as a vehicle for

colon-specific drug delivery.

Furthermore, guar gum and methylated guar gum were used to prepare

hydrophilic matrix controlled release tablets using chlorpheniramine maleate as model

drug68

. Drug release profile from guar gum matrix tablets showed a high percentage

of drug release (31.06±2.56%) in the first half hour and then the rate of drug release

decreased with time. In the case of methylated guar gum, significant reduction in the

amount of drug released in the first half hour (18.77± 0.68%) was observed. The rate

of hydration increased hence, the onset of the obstructive gel layer formation was

faster as compared to guar gum. The results also showed that the drug release rate

increased with degree of methylation. Carboxymethyl guar (CMGS), an anionic

semisynthetic guar gum derivative was evaluated for its suitability of use in

transdermal drug-delivery systems using terbutaline sulfate (TS) as a model drug69

. It

was found that, diffusion of terbutaline sulfate from CMGS solution was relatively

slower at pH 5 than at pH 10.

Cross-linked hydrogels of polyacrylamide-grafted guar gum were prepared by

emulsification method by saponification of the –CONH2 group to the –COOH

group70

. It was noted that the increased swelling of microgels when the pH of the

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medium changed from acidic to alkaline. The pH-sensitive microgels were loaded

with diltiazem hydrochloride and nifedipine and their release studies indicated quicker

release in pH 7.4 buffer than in 0.1 N HCl solution. George et al. prepared a pH

sensitive alginate-guar gum hydrogel crosslinked with glutaraldehyde. The beads with

alginate to guar gum ratio of 3:1 showed better encapsulation efficiency, bead

forming property and drug release.

Novel polyelectrolyte hydrogels (GA) based on cationic guar gum (CGG) and

acrylic acid monomer were synthesized by photoinitiated free-radical

polymerization71

. Swelling experiments indicated that the ketoprofen loaded GA

hydrogels were highly sensitive to pH environments. The results implied that the GA

hydrogels can be exploited as potential carriers for colon-specific drug delivery.

Shiwali Thakur et al.72

synthesized acryloyl guar gum (AGG) and its hydrogel

materials for use as carriers and slow release devices of two pro-drugs, l-tyrosine and

3,4-dihydroxy phenylalanine (l-DOPA). The hydrogel materials were loaded with two

pro-drugs, and their cumulative release behavior was studied at pH 2.2 and pH 7.4.

Xiuyu Li et al.73

synthesized thermo-responsive guar gum (GG)/poly(N-

isopropylacrylamide) (PNIPAAm) hydrogels with interpenetrating polymer network

(IPN). The thermo-responsive GG/PNIPAAm IPN hydrgels with different response

rates were prepared by changing the proportion of GG to NIPAAm. The introduction

of GG component with IPN technology improved the temperature sensitivity and

permeability of GG/PNIPAAm IPN hydrogels which served as good candidates for

the controlled drug delivery system with both thermo-responsive and specific-colonic

drug release behaviors.

Gautam Sen et al.74

studied the applicability of microwave initiated

synthesized polyacrylamide grafted guar gum (GG-g-PAAm) as matrix for controlled

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release of 5-amino salicylic acid. They have drawn a correlation between net time of

irradiation and rate of drug release from the matrix. Debasis Das et al.75

intrinsically

modified guar gum, a polymeric galactomannan to guar gum benzamide.

Benzoylation reaction was carried out by benzoyl chloride reaction in water medium

and a propyl amine spacer was used to impart a high degree of hydrophobicity.

3.4.3.4 Inulin

Inulins are a group of naturally occurring polysaccharides belonging to a class of

carbohydrates known as fructans. Inulin is used by some plants as a means of storing

energy and is typically found in roots or rhizomes. Inulins are polymers mainly

comprised of fructose units and typically have a terminal glucose. The fructose units

in inulins are joined by a beta-[2-1] glycosidic link49

. Inulin passes through the

stomach and duodenum undigested and is highly broken down by the gut bacterial

flora.

Figure 3.11: Chemical structure of inulin

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InulinHP (inulin with a high degree of polymerization) was formulated as a

biodegradable colon-specific coating by suspending it in Eudragit RS films76

. The in

vitro degradability for the prepared films was studied by incubating them in faecal

degradation medium and it was observed that inulin resists hydrolysis and digestion in

the upper gastro-intestinal tract, but gets fermented by the colonic microflora. Inulin

hydrogels have been developed as carriers for colonic targeting of drugs77

. The

enzymatic digestibility of the prepared inulin hydrogels was assessed by in vitro study

using inulinase preparation derived from Aspergillus niger. The data obtained

suggested that inulinase enzymes are able to diffuse into the inulin hydrogel networks

causing bulk degradation.

The azo-polysaccharide gels were synthesized by radical crosslinking of a

mixture of methacrylated inulin or methacrylated dextran and N,N′-bis

(methacryloylamino) azobenzene (B(MA)AB). Increasing the amount of B(MA)AB

resulted in denser azo-inulin and azo-dextran networks. However, the degradation of

azo-dextran gels by dextranase seemed to be more pronounced than the degradation of

the azo-inulin gels by inulinase78

.

Francesco Castelli et al.79

derivatized inulin with methacrylic anhydride (MA)

and succinic anhydride (SA) to obtain a methacrylated/succinilated derivative (INU-

MA-SA) able to produce a pH sensitive hydrogel after UV irradiation using diflunisal

as a model drug. The hydrogel have a better drug release at both investigated pHs (4.0

and 7.4), however a faster and more complete release behaviour was observed at pH

7.4.

Giovanna Pitarresi et al.80

synthesized macromolecular derivatives based on

inulin which are able to complex with iron and useful in the treatment of iron

deficiency anaemia. Carboxylated or thiolated/carboxylated inulin derivatives were

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obtained by single or double step reactions, respectively. They stated that both the

complexes showed an excellent biodegradability in the presence of inulinase. They

concluded that thiolated derivative INU–SA–Cys showed greater mucoadhesive

properties than polyacrylic acid chosen. Fares et al.81

used inulin and poly(acrylic

acid) grafted inulin copolymer to enhance the dissolution of poorly water-soluble

drug, irbesartan and to control its release rate, respectively.

3.4.3.5 Karaya gum

Gum Karaya is an extract of Sterculia urens tree belonging to the family

Sterculiaceae. It is used as a suspending or stabilizing agent, thickener, emulsifier and

laxative in foods, and as a denture adhesive. Powdered gum karaya is white to greyish

white in colour having a high molecular weight of about 9,500,000. On hydrolysis, it

yields galactose, rhamnose and galacturonic acid. Gum Karaya occurs as a partially

acetylated derivative49

.

Sujja-areevath et al. evaluated the use of four natural hydrophilic gums,

carrageenan (C), locust bean (LB), karaya (K) and xanthan (X) gums as mini-matrix

formulations enclosed in a hard gelatin capsule82

. The release profiles showed that

drug release was sustained up to 77% for diclofenac from mini-matrices containing

LB, X and K, while C did not exhibit sufficient sustained release. The amount of gum

present played important role in determining the drug release rate. Similar kind of

study was reported by Sujja-areevath et al.83

. Directly compressed matrices containing

xanthan gum and karaya gum were prepared to control the release of caffeine and

diclofenac sodium84

. Drug release from xanthan and karaya gum matrices depend on

agitation speed, solubility and proportion of drug. Both xanthan and karaya gums

produced near zero order drug release with the erosion mechanism playing a dominant

role, especially in karaya gum matrices.

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Figure 3.12: Chemical structure of karaya gum

Modified gum karaya (MGK) was evaluated as carrier for dissolution

enhancement of poorly soluble drug, nimodipine (NM)85

. The advantages of MGK

over the parent gum karaya (GK) were illustrated by differences in the in vitro

dissolution profiles of respective solid mixtures prepared by co-grinding technique.

The dissolution rate of NM was increased as the MGK concentration increased and

optimum ratio was found to be 1:9 w/w ratio (NM:MGK).

Baljit Singh et al.86

synthesized sterculia gum and PAAm based hydrogels by

using N,N′-MBAAm as crosslinker and ammonium persulfate as initiator. The release

of drug, ranitidine from the hydrogels occurred through Fickian diffusion mechanism

in distilled water and in pH 2.2 buffer, and through non-Fickian diffusion mechanism

in pH 7.4 buffer. Baljit Singh et al.87

carried out the modification of sterculia gum to

develop the novel wound dressing for the delivery of antimicrobial agent (tetracycline

hydrochloride). The drug release behaviour of sterculia crosslinked PVA (sterculia-cl-

PVA) hydrogels were studied in the simulated wound fluid. Researchers also studied

the use of karaya gum as a potential thickening agent88

and as a carrier for anti-

diarrhoeal drug in combination with poly vinyl pyrrolidone (PVP)89

.

3.4.3.6 Locust bean gum

Locust bean gum is a galactomannan vegetable gum extracted from the seeds of the

Carob tree. It forms a food reserve for the seeds and helps to retain water under arid

conditions. It is used as a thickener and gelling agent in food technology. It is also

called Carob Gum or Carubin. It consists of a (1→4)-linked β-D-mannopyrannose

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backbone with branchpoints from their 6-positions linked to α-D-galactose (i.e. 1→6-

linked α-D-galactopyranose)49

. The use of locust bean gum as a carrier for

formulating colon targeted drug delivery systems has also been investigated90

.

Honey locust gum (HLG) obtained from Gleditsia triacanthos was

investigated as a hydrophilic matrix material for theophylline drug release91

. The

matrix tablets containing hydroxyethylcellulose and hydroxypropyl methylcellulose

as sustaining polymers at the same concentrations were prepared and a commercial

sustained release (CSR) tablet containing 200 mg theophylline was examined for

comparison of HLG performance. dissolution studies in distilled water, pH 1.2 HCl

buffer and pH 7.2 phosphate buffer revealed that no significant difference was found

between CSR tablet and the matrix tablet containing 10% HLG in each medium

(P > 0.05) and these tablets showed zero-order kinetic model in all the mediums.

Guar gum and Locust bean gum matrix tablets were compared with matrices

obtained with scleroglucan92

. Furthermore, the polymers were chemically crosslinked

with glutaraldehyde to obtain a network suitable as a matrix for modified drug release.

The delivery of the model molecules from the Guar gum and Locust bean gum gels,

and from tablets prepared from the freeze-dried hydrogels of the three polymers was

evaluated, and a comparison with the tablets prepared with the not-crosslinked

polymers was carried out.

S. Maiti et al.93

prepared carboxymethyl derivative of locust bean gum,

evaluated its gelling ability with different concentrations (1-5% w/v) of aluminum

chloride (AlCl3) and utilized for the development of glipizide-loaded beads.

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Figure 3.13: Chemical structure of locust bean gum

C. Vijayaraghavan et al.94

evaluated locust bean gum and chitosan in ratios of

2:3; 3:2 and 4:1 (F1, F2 and F3) as a mucoadhesive component in buccal tablets and

to compare the bioavailability of a propranolol hydrochloride buccal tablet with the

oral tablet in healthy human volunteers. The study indicated that, locust bean gum and

chitosan in a weight ratio of 2:3 (F1) not only releases the drug unidirectionally from

the dosage form, but also gives buccal tablets which are sufficiently mucoadhesive for

clinical applications.

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3.5 DRUG PROFILES

3.5.1 Metoprolol tartrate95-98

Figure 3.14: Chemical structure of metoprolol tartrate

Molecular formula : (C15H25NO3)2 . C4H6O6

Molecular weight : 684.81 g/mole

IUPAC name : (2RS)-1-[4-(2-Methoxyethyl)phenoxy]-

3-[(1-methylethyl)amino]propan-2-ol

hemi-(2R,3R)-tartrate

Description : A white crystalline powder.

Solubility : Soluble in water, and freely soluble in methanol, in

ethanol (95) and in acetic acid (100).

Storage : Well-closed light resistant containers

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Preparations : Metoprolol tartrate tablets, metoprolol tartrate ER

tablets, metoprolol tartrate IV injection.

Usual dose range : 50-100 mg BID

Absorption : Rapidly and almost completely absorbed from the GI

tract

Bioavailability : Oral bioavailability is about 70 - 80%.

Distribution : Widely distributed, about 12% protein-bound

Elimination : About 95% in urine. Half life of 3-7 h

Therapeutic uses : Hypertension, angina, and post-MI

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3.5.2 Diltiazem hydrochloride95, 99-100

Figure 3.15: Chemical structure of diltiazem hydrochloride.

Molecular formula :C22H26N2O4S, HCl

Molecular weight :451.0 gm.

IUPAC name :2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-

methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-

benzothiazepin-3-yl acetate hydrochloride.

Description : A white, odorless, crystalline powder.

Solubility : Freely soluble in water, in methanol and in methylene

chloride, slightly soluble in ethanol.

Storage : In an airtight container, protected from light.

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Preparations : Diltiazem tablets, diltiazem SR tablets, diltiazem ER

capsules.

Usual dose range : 30 to 60 mg QID.

Absorption : Rapidly and completely absorbed from the GI tract.

Bioavailability : Oral bioavailability is about 40 - 50%.

Distribution :At therapeutic concentration, diltiazem is

approximately 80% bound to plasma proteins.

Elimination : Half-life of is approximately 3-4 h.

Therapeutic uses : It is an effective calcium channel blocker, used in the

treatment of angina, hypertension and myocardial

infarction.

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3.5.3 Metoprolol succinate95, 97, 101

Figure 3.16: Chemical structure of metoprolol succinate

Molecular formula : (C15H25NO3)2 . C4H6O4

Molecular weight : 652.81 g/mole

IUPAC name :2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-

methylethyl)amino]-, (+/-)-, butanedioate (2:1) (salt)

Description : A white to off-white crystalline powder.

Solubility : It is very soluble in water, Soluble in methanol;

sparingly soluble in ethanol; slightly soluble in

isopropanol and in dichloromethane; very slightly

soluble in ether and in acetone.

Storage : Well-closed light resistant containers

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Preparations : Metoprolol tartrate tablets, metoprolol tartrate ER

tablets, metoprolol tartrate IV injection.

Usual dose range : 50-100 mg per day

Absorption : Rapidly and almost completely absorbed from the GI

tract

Bioavailability : Oral bioavailability is about 50 - 60%.

Distribution : Wide. About 11% protein-bound

Elimination : About 95% in urine. Half life of 3-7 h

Therapeutic uses : Hypertension, angina, and heart failure

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3.5.4 Galantamine hydrobromide95, 102-104

Figure 3.17: Chemical structure of galantamine hydrobromide

Molecular formula : C17H21NO3 . HBr

Molecular weight : 368.27 g/mole

IUPAC name :(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-

11-methyl-6H-benzofuro[3a,3,2ef][2]benzazepin-6-ol

hydrobromide

Description : A white to almost white powder.

Solubility : It is slightly soluble in water; fairly soluble in hot

water; freely soluble in alcohol, acetone, and

chloroform; less soluble in benzene

Storage :Keep container tightly closed in a dry and well

ventilated place.

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Preparations : Galantamine tablets, galantamine capsules,

galantamine oral solution.

Usual dose range : 8-32 mg per day

Absorption : It is well absorbed and almost completely absorbed

following oral administration

Bioavailability : Oral bioavailability is about 90%.

Distribution : Wide. About 18% plasma protein-bound

Elimination : About 95% in urine. Half life of 6 h

Therapeutic uses : for the treatment of mild to moderate Alzheimer’s type

dementia

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3.6 POLYMER PROFILES

3.6.1 Kondagogu gum105-109

Kondagugu gum [KG] is the dried exudates obtained from tree Cochlospermum

gossypium which belongs to the family Bixaceae. KG is a high molecular weight

complex acetylated polysaccharide consisting mainly of D-galacturonic acid, D-

galactose and L-rhamnose.

Figure 3.18: Cochlospermum gossypium tree

KG exudate is produced by trees as a natural defense mechanism, particularly

in semi-arid regions. When the plants bark is injured, an aqueous gum solution is

exuded to seal the wound, preventing infection and dehydration of the plant. The

solution dries in contact with air and sunlight to form hard, glass like lumps, which

can easily be collected.

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Figure 3.19: Kondagogu gum exudate obtained from trees

Figure 3.20: Chemical structure of kondagogu gum

Figure 3.21: Structural assignment of kondagogu gum

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The physicochemical analysis and chemical analysis of various grades of

kondagogu are given in table 3.2, 3.3 and 3.4 respectively

Table 3.2: Physico-chemical properties of kondagogu gum

Parameter Kondagogu grade

KG I KG II KG III

Moisture (%) 15.25 16.97 15.88

Ash (%) 7.3 9.4 7.3

Nitrogen (%) 1.00 0.8 0.90

Protein (%) 6.3 5.0 5.6

Volatile acidity (%) 15.9 16.5 16.0

Tannin (%) 0.073 0.103 0.150

Specific rotation [α] + 53.5 + 53.5 + 53.5

Water-binding capacity mlg-1

gum

35.1 48.7 47.3

Research work done on kondagogu gum

Swati Malik et al.110

carried out microwave-assisted grafting of gum

kondagogu onto poly (acrylamide) by employing two-level, four-factor full factorial

experimental design. Gum kondagogu-g-poly(acrylamide) was characterized by

Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray

diffraction and scanning electron microscopy. They stated that microwave power,

microwave exposure time and the concentration of ammonium persulfate had

significant synergistic effect on grafting efficiency, while the concentration of gum

kondagogu had no significant effect. The optimal calculated parameters were

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microwave power-40%, microwave exposure time-120 s, concentration of ammonium

persulfate-10 mmol and concentration of gum kondagogu 3% (w/v).

V.G.M. Naidu et al.111

prepared polyelectrolyte complexes (PEC) of gum

kondagogu (GKG) and chitosan by mixing polymeric solutions of different

concentrations (0.02–0.18% w/v). The complex formed were loaded with diclofenac

sodium, and the release of the drug was measured in vitro and in vivo, along with the

measurement of particle size, zeta potential, complex formation, flow properties, and

loading efficiency. Maximum yield of PEC was observed at gum kondagogu

concentrations above 80%. The PEC showed lower release of diclofenac sodium in

0.1 N HCl as compared to phosphate buffer (pH 6.8). They stated that increasing the

concentration of gum kondagogu in PEC led to an increase in drug release.

V.T.P. Vinod et al.112

reported an environmentally benign method for the

synthesis of noble metal nanoparticles using aqueous solution of gum kondagogu

(Cochlospermum gossypium). Both the synthesis, as well as stabilization of colloidal

Ag, Au and Pt nanoparticles has been accomplished in an aqueous medium containing

gum kondagogu. The colloidal suspensions so obtained were found to be highly stable

for prolonged period, without undergoing any oxidation. SEM–EDXA, UV–vis

spectroscopy, XRD, FTIR and TEM techniques were used to characterize the Ag, Au

and Pt nanoparticles. Their approach exemplified a totally green synthesis using the

plant derived natural product (gum kondagogu) for the production of noble metal

nanoparticles and the process was also be extended to the synthesis of other metal

oxide nanoparticles.

Aruna Jyothi Kora et al.113

developed a facile and ecofriendly method for the

synthesis of silver nanoparticles from silver nitrate using gum kondagogu

(Cochlospermum gossypium) a natural biopolymer, as a reducing and stabilizing

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agent. The influence of different parameters such as gum particle size, concentration

of gum, concentration of silver nitrate and reaction time on the synthesis of

nanoparticles was studied. The synthesized nanoparticles were characterized using

UV–visible spectroscopy, transmission electron microscopy, X-ray diffraction and

thermogravimetric analysis. A possible mechanism involved in the reduction and

stabilization of nanoparticles has been investigated using Fourier transform infrared

spectroscopy and Raman spectroscopy. The synthesized silver nanoparticles had

significant antibacterial action on both the Gram classes of bacteria. They concluded

that, as the silver nanoparticles are encapsulated with functional group rich gum, they

can be easily integrated for various applications.

Vinod VTP et al.114

explored gum kondagogu (Cochlospermum gossypium),

an exudates tree gum from India for its potential to decontaminate toxic metals (Pb2+

and Cd2+). Optimum biosorption of metals were determined by investigating the

contact time, pH, initial concentration of metal ions and biosorbent dose at 25 ± 2 °C.

The maximum metal biosorption capacity for gum kondagogu was observed for Pb2+

(48.52 mg g−1) and Cd2+ (47.48 mg g−1) as calculated by Langmuir isotherm model.

Kinetic studies showed that the biosorption rates could be described by pseudo-

second-order expression. The metal interactions with biopolymer were assessed by

FT-IR, SEM–EDXA and XPS analysis. They suggested that mechanism of metal

binding by the biopolymer involves micro-precipitation, ion-exchange and metal

complexation.

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3.6.2 Ghatti gum115-117

Gum ghatti [GG] is a complex non-starch polysaccharide obtained as amorphous

translucent mucilage from wounds in the bark of Anogeissus latifolia tree which is

found in the deciduous forests of India and Sri Lanka. It has been widely employed in

food, pharmaceuticals, paper and other industries primarly due to its emulsification

and thickening property. It is a high molecular weight complex polysaccharide that

occurs in nature as a mixed calcium, magnesium, potassium, and sodium salt; upon

hydrolysis it yields L-arabonose, D-galactose, D-mannose, D-xylose, L-rhamnose,

and D-glucuronic acid.

Figure 3.22: Anogeissus latifolia tree

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Figure 3.23: Ghatti gum exudate obtained from trees

Figure 3.24: Structural assignment of ghatti gum

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GG exudate is produced by trees as a natural defense mechanism, particularly

in semi-arid regions. When the plants bark is injured an aqueous gum solution is

exuded to seal the wound, preventing infection and dehydration of the plant. The

solution dries in contact with air and sunlight to form hard, glass like lumps, which

can easily be collected.

Ghatti gum is a high-arabinose, protein rich, acidic heteropolysaccharide,

occurring in nature as mixed calcium, magnesium, potassium, and sodium salt [12-

14,16]. The primary structure of this gum is composed of sugars such as, L-arabinose,

D-galactose, D-mannose, D-xylose, and D-glucuronic acid in a molar ratio of

48:29:10:5:10 and<1% of rhamnose, which is present as non-reducing end-groups.

The gum ghatti with a CAS number 9000-28-6 is recognized as “generally recognized

as safe” (GRAS) and approved as a food ingredient by the Food and Drug

Administration, USA, under the function of emulsifier and emulsifier salt.

Table 3.3: Physico-chemical properties of ghatti gum

Parameter Values

pH 4-4.5

Ash (%) 2.5

Moisture (%) NMT 10

Optical rotation -30 to -40º

Anand et al.118

stated that gum ghatti (Anogeissus latifolia) or Indian gum is a

complex non-starch polysaccharide. It has been widely employed in food,

pharmaceuticals, paper and other industries primarily due to its excellent

emulsification and thickening property. Other applications of gum ghatti are

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inadequately investigated owing to lack of information on it. Thy stated that

researchers in recent years have shown a great interest in exploring its molecular

structure and functional properties.

Ji Kang et al.119

described the fractionation, chemical and physical

characterization of processed gum ghatti, and identified the source of its surface

activity. They stated that rheologically gum ghatti and its fractions exhibited

Newtonian flow behavior until gum concentrations reached 20% (w/v), at which point

gum ghatti showed some shear thinning.

Priti Rani et al.120

grafted polyacrylamide chains (PAM) onto the backbone of

gum ghatti by microwave assisted method. The grafting of the PAM chains on the

polysaccharide backbone was confirmed through intrinsic viscosity study, FTIR

spectroscopy, elemental analysis (C, H & N) and SEM morphology study. The

intrinsic viscosity of gum ghatti appreciably improved on grafting of PAM chains,

thus resulting grafted product with potential application as superior viscosifier.

Robert R. et al.121

did a 90-day toxicity study following Organization for

Economic Co-operation and Development (OECD) guidelines. Male and female

Sprague–Dawley rats were exposed to 0 (control), 0.5, 1.5 and 5% gum ghatti in AIN-

93M basal diet. In a second 90-day study, increased cecal weights were present in

Sprague–Dawley females exposed to 5% gum ghatti in AIN-93M and NIH-07 basal

diets. In the second study, a few statistically significant alterations in clinical

chemistry were considered sporadic and unrelated to treatment. They concluded that

ghatti gum did not show any toxic effects in the animals selected.

Cheryl A. et al.122

stated that gum ghatti is a food additive in some parts of the

world, serving as an emulsifier, a stabilizer, and a thickening agent. To evaluate its

genotoxic potential, they conducted good laboratory practice compliant in vitro and in

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vivo studies in accordance with the Organisation for Economic Co-operation and

Development (OECD) guidelines. They found no evidence of toxicity or mutagenicity

in a bacterial reverse mutation assay using five tester strains evaluating gum ghatti up

to 6 mg/plate, with or without metabolic activation. Gum ghatti also did not induce

chromosome structural damage in a chromosome aberration assay using Chinese

hamster ovary cells.