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Chapter 3 Review of Literature
Biopolymers Based Drug Delivery Systems
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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.