Advances in Natural Polymers as Pharmaceutical Excipients
Ikoni J Ogaji*, Elijah I Nep and Jennifer D Audu-Peter
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of Jos, PMB 2084 JOS, 930003, Plateau State, Nigeria
Dr. Ikoni J Ogaji
Department of Pharmaceutics and
Faculty of Pharmaceutical Sciences
of Jos, PMB 2084 JOS, 930003
Plateau State, Nigeria GSM: +234 802 363
4482 E-mail: email@example.com
Received November 07, 2011; Accepted January 16, 2012; Published January
Citation: Ogaji IJ, Nep EI, Audu-Peter JD (2012) Advances in Natural Polymers
as Pharmaceutical Excipients. Pharm Anal Acta 3:146. doi:10.4172/2153-
Research in natural polymeric materials has witnessed growing interest and attention. This is attributable to
a number of factors which include their relative abundance, low cost, and biodegrable and eco-firendly profiles.
This article reviews the current applications of natural polymeric materials in pharmaceutical formulations. The
pharmaceutical applications of some of the traditional and commercially available natural polymers were discussed.
Emerging potential pharmaceutical excipients of natural origins were also discussed. The increasing research
interests in this group of materials are indications of their increasing importance. It is believed that as technology and
testing techniques advance, more understanding of their physicochemical nature would be gained that can enable
them to be tailored for wider Pharmaceutical applications than their synthetic counterparts.
Drugs are hardly administered as such but are almost always
formulated into a suitable dosage form with the aid of excipients,
which serve various functions such as binding, lubricating, gelling,
suspending, flavoring, sweetening and bulking agent among others
. The International Pharmaceutical Excipients Council defines
excipients as substances, other than the active drug substances of
finished dosage form, which have been appropriately evaluated for
safety and are included in a drug delivery system to either aid the
processing of the drug delivery system during its manufacture; protect,
support orenhance stability, bioavailability, or patient acceptability;
assist in product identification; or enhance any other attributes of
the overall safety and effectiveness of the drug delivery system during
storage or use . Excipients play a critical role in the creation of
medicines, helping to preserve the efficacy, safety, and stability of active
pharmaceutical ingredients (APIs) and ensuring that they deliver their
promised benefits to the patients. Optimal use of excipients can provide
pharmaceutical manufacturers with cost-savings in drug development,
enhanced functionality and help in drug formulations innovation.
Excipients are the largest components of any pharmaceutical
formulation. They can be of natural or synthetic origin and synthetic
excipients have become commonplace in today’s pharmaceutical
dosage forms . It is common knowledge that both synthetic and
semi-synthetic products have enjoyed a long history of use, frequently
offering unique properties and advantages over naturally derived
compounds, including a low sensitivity to various ingredients or
moisture, resulting in more efficient and effective pharmaceutical
products . But despite the many potential benefits of synthetic
excipients, manufacturers must still address a number of challenges
before their current universe of implementation can be expanded.
The terms ‘synthetic’ and ‘semi-synthetics are both broadly used to
distinguish this family of excipients from those extracted from natural
sources. Semi-synthetic typically refers to a substance that is naturally
derived but has been chemically modified. Most excipients in use today
fall into this category and there must be the ‘natural’ to obtain the
‘semi-synthetic’ excipients. In contrast, ‘synthetic’ ‘is usually defined as
a pure synthetic organic chemical that is derived from oil or rock .
Lipids, carbohydrates and proteins are natural polymeric materials.
Natural polysaccharides, as well as their derivatives, represent a group
of polymers that are widely used in pharmaceutical formulations and
in several cases their presence plays a fundamental role in determining
the mechanism and rate of drug release from the dosage form. These
naturally occurring polymers have been employed as excipients in the
pharmaceutical industry in the formulation of solid, liquid and semisolid
dosage forms in which they play different roles as disintegrates,
binders, film formers, matrix formers or release modifiers, thickeners
or viscosity enhancers, stabilizers, emulsifiers, suspending agents
and muco adhesives [4,5]. Specifically, they have been used in the
formulation and manufacture of solid monolithic matrix systems,
implants, films, beads, micro particles, nanoparticles, inhalable and
injectable systems as well as viscous liquid formulations [5-7].
Their growing role and application in the pharmaceutical industry
may be attributable not only to the fact that they are biodegradable
and toxicologically harmless raw materials of low cost and relative
abundance compared to their and synthetic counter parts [8,9], but
also because natural resources are renewable and if cultivated or
harvested in a sustainable manner, they can provide a constant supply
of raw material . Furthermore, their extensive applications in drug
delivery have been realized because as polymers, they offer unique
properties which so far have not been attained by any other materials
. They can be tailored for many applications based on the very
large chains and functional groups which can be blended with other
low- and high–molecular-weight materials to achieve new materials
with various physicochemical properties. Consequently, many of the
widely used excipients today are chemical modifications of the natural
excipients to overcome some of their disadvantages.
A couple of review articles on natural gums are available in
literatures [12,13]. Some of the reviews covered the chemical structure,occurrence and production of exudate gums, their size and relative
importance of the various players on the world market and focused
on their application in food and other areas . Due to the growing
interest in the use of natural polymeric materials as pharmaceutical
excipients, as demonstrated by the number of published scientific
papers, it is difficult to cover all that might be available in a single article.
It is intended in this review to discuss the uses of natural polymers as
excipients in pharmaceutical formulations. Specific mention is made
of some of the natural products already in use as pharmaceutical
excipients and those being researched for this purpose.
Natural Polymeric Materials
Natural polymers are obtained from different sources and this
review will attempt to briefly discuss them according to their sources.
Mention is made of those that are relevant to the current topic.
Polysaccharides of the plant cell wall
Natural polymers which have their origin from the plant cell wall
mainly include cellulose, hemicelluloses and pectin.
Cellulose: In higher plants, cellulose is an essential structural
component and represents the most abundant organic polymer
. Cellulose is a linear unbranched polysaccharide consisting of
β-1, 4-linked D-glucose units and many parallel cellulose molecules
which form crystalline micro fibrils. The crystalline micro fibrils are
mechanically strong and highly resistant to enzymatic attack and
are aligned with each other to provide structure to the cell wall .
Cellulose is insoluble in water and indigestible by the human body.
It is however digested by herbivores and termites. Cellulose obtained
from fibrous materials such as wood and cotton can be mechanically
disintegrated to produce powdered cellulose which has been used
in the pharmaceutical industry as filler in tablets. High quality
powdered cellulose when treated with hydrochloric acid produces
microcrystalline cellulose which is preferred over powdered cellulose
because it is more free-flowing containing non-fibrous particles. It is
consequently employed as diluents or filler/binder in tablets for both
granulation and direct compression processes . The molecular
structure of cellulose is shown in figure 1.
Figure 1:Molecular structure of powdered cellulose (n ≈ 500) or microcrystalline
cellulose (n ≈ 220).
The formation of derivatives of cellulose is made possible by the
hydroxyl moieties on the D-glucopyranose units of the cellulose polymer
to give a variety of derivatives. Cellulose derivatives can be made by
etherification, esterification, cross-linking or graft copolymerization
. Etherification yields derivatives such as hydroxyl-propyl-methylcellulose
and carboxyl-methyl-cellulose, while esterification results
in derivatives which include cellulose nitrate, cellulose acetate and
cellulose acetate phthalate. These derivatives have found application in
membrane controlled release systems such as enteric coating and the
use of semi-permeable membranes in osmotic pump delivery systems.
They have also enjoyed wide use and application in monolithic matrix
systems. Extensive studies conducted on these derivatives have proven
their ability to sustain the release of medicaments and most of these
derivatives have been employed for this purpose [17,18].
Hemicellulose: Bound to the surface of cellulose microfibrils
are complex polysaccharides which themselves do not form micro
fibrils. These bound polysaccharides are called hemicelluloses and
include xyloglycans, xylans, mannans and glucomannans, and β-(1→3,
1→4)-glucans . They can be extracted from the plant cell wall with
the aid of strong alkali.
Hemicelluloses have β-(1→4)-linked backbones with an equatorial
configuration. In contrast to cellulose which is crystalline and
unbranched, hemicellulose is amorphous and branched. Although the
xyloglycans have similar backbone as cellulose, they contain xylose
branches on 3 out of every 4 glucose monomers, while the β-1,4-linked
D-xylan backbone of arabinoxylan contains arabinose branches .
Glucomannan is mainly a straight-chain hydrocolloidal
polysaccharide of the mannan family with about 8% branching
through β-(1→6)-glucosyl linkages. The component sugars are β-(1→4)-
linked D-mannose and D-glucose in a ratio of 1.6:1 which may differ
depending on the source . The component sugars may contain
acetyl side branches on some of the backbone units which contribute
to the solubility and swelling capacity of the glucomannans. The acetyl
groups consequently enhance the solubility of the glucomannans as
natural polysaccharides possessing the highest viscosity and waterholding
capacity. Konjakglucomannan is the most commonly used
type of glucomannan obtained by extraction from the tubers of
Amorphophalluskonjac K. Koch (Fam. Ulmaceae). Konjacglucomannan
has been investigated as an effective excipient in controlled release drug
delivery devices in combination with other polymers or by modifying
its chemical structure. Combination of konjacglucomannan and
xanthan gum in matrix tablets has been shown to effectively retard
drug release by stabilisation of the gel phase of the tablets by a network
of intermolecular hydrogen bonds between the two polymers .
Pectins: Pectins are non-starch, linear polysaccharides extracted
from the plant cell walls. They are predominantly linear polymers of
mainly (1–4)-linked D-galacturonic acid residues interrupted by 1,2-
linked L-rhamnose residues with a few hundred to about one thousand
building blocks per molecule (molecular structure is shown in figure
2), corresponding to an average molecular weight of about 50, 000 to
about 180,000 . Being soluble in water, pectin is not able to shield
its drug load effectively during its passage through the stomach and
small intestine. It was found that a coat of considerable thickness
was required to protect the drug core in simulated in vivo conditions . Hence the focus was shifted to the development of less soluble
derivatives of pectin which get degraded by the colonic micro flora.
Calcium salts of pectin reduced their solubility by forming an eggbox
configuration. To overcome the drawback of high solubility of
pectin, mixed films of pectin with ethyl-cellulose were investigated as a
coating material for colon-specific drug delivery. These films combined
the colon specific degradation properties of pectin with the protective
properties of the water insoluble ethyl cellulose .
Figure 2:Molecular structure of powdered cellulose (n ≈ 500) or microcrystalline
cellulose (n ≈ 220).
Polymeric hydrogels are widely used as controlled-release matrix
tablets. Some researchers  investigated the high-methoxy-pectin
for its potential value in controlled-release matrix formulations.
The effects of compression force, ratio of drug to pectin, and type of
pectin on drug release from matrix tablets were also investigated. The
results of the in vitro release studies showed that the drug release from
compressed matrix tablets prepared from pectin can be modified by
changing the amount and type of pectin in the matrix tablets. A very
low solubility pectin-derivative (pectinic acid, degree of methoxylation
4%) was found to be well suited as an excipient for pelletisation by
extrusion/spheronisation. The capacity as an extrusion aid was found
to be high. Formulations containing only 20% pectinic acid resulted
in nearly spherical pellets. All pectinic acid pellets were mechanically
stable. They possessed an aspect ratio of approximately 1.15–1.20
and released 30–60% of a low solubility model drug within 15 min
in simulated gastric fluid (0.1M HCl) and intestinal fluid (phosphate
buffer pH 6.8) .
Micro particulate polymeric delivery systems have been reported as
a possible approach to improve the low bioavailability characteristics
observed in standard ophthalmic vehicles (collyria) . In this context
pectin microspheres of piroxicam were prepared by the spray drying
technique. In vivo tests in rabbits with dispersions of piroxicam-loaded
microspheres also indicated a significant improvement of piroxicam
bioavailability in the aqueous humour (2.5–fold) when compared with
commercial piroxicameye drops.
Investigation on the suitability of amidated pectin as a matrix patch
for transdermal chloroquine delivery has been reported . This
was in an effort to mask the bitter taste of chloroquine when orally
administered. The results suggested that the pectin-chloroquine patch
matrix preparation has potential applications for the transdermal
delivery of chloroquine and perhaps in the management of malaria.
Calcium pectinate nanoparticles to deliver insulin were prepared as a
potential colonic delivery system by ionotropic gelation .
In relation to cosmetics, using citronellal as a model compound,
pectin gel formulations were evaluated for controlled fragrance release
by kinetic and static methods. These formulations showed a prolonged
duration of fragrance release and limitation of fragrance adsorption
to the receptor skin layers. The increase in pectin concentrations
suppressed the fragrance release by a diffusion mechanism, thereby
proving that pectin/calcium micro particles are promising materials for
controlled fragrance release . Drug delivery systems utilizing pectin
is discussed by various researchers [30-35].
Gums and mucilages
Gums are natural plant hydrocolloids that may be classified as
anionic or nonionic polysaccharides or salts of polysaccharides .
They are translucent, amorphous substances usually produced by plants
as a protective after injury. Gums, mucilage, pectins and celluloses
are classified as substances that are condensations of pentoses and or
hexoses. When gum is hydrolyzed, it yields large proportion of sugars
and complex organic acid nucleus. It is by means of these organic acids
that they do form salts with calcium or magnesium. According to Claus
and Tyler  it is difficult to distinguish between gums and mucilage.
In their opinion, one attempt is to refer to gums as water soluble
and mucilage as water insoluble and the other approach is to refer to
mucilage as pathological product and gums as physiological products.
Gums and mucilage are produced in various ways by the plant.
These substances can be formed from middle lamella as in the algae;
cell wall as in the seed epidermis, seed endodermis, cells in the bark;
special secretory cells as in the squill; in the schizogenous sacs as in the
young stem of Rhamnuspurshiana, or by lysiogenous metamorphosis
of the cell walls as in tragacanth and acacia .
Gums have found pharmaceutical application since the early 1800
having gums like tragacanth, acacia, sterculia appearing in the United
States Pharmacopoeia of 1820 and sodium alginate and agar in the
1947 National Formulary. The gums have been used as suspending
agents for insoluble solids in mixtures, as emulsifying agents for oils
and resins and as adhesive in pill and troche masses. Some gums are
used as demulcent and emollient in hand lotion while others are used
as protective colloid and as binding and disintegrating agents in tablet
Google scholar entries on gums hit 7,500 in 2010 and were 8,260
a year later, showing the continuous interest in the use of these
materials. There were 453 articles in the Wolter Kluwer’s database
while in Pubmed the number was 7,979 scholarly articles on gums and
mucilage, showing the importance of gums in pharmacy. It seems that
gums and mucilage are the most highly investigated in the recent time
as potential pharmaceutical excipients.
Gums are naturally occurring components in plants, which are
essentially cheap and plentiful. They have diverse applications as
thickeners, emulsifiers, viscosifiers, sweeteners etc. in confectionary,
and as binders and drug release modifiers in pharmaceutical dosage
forms. However, most of the gums in their putative form are
required in very high concentrations to successfully function as
drug release modifiers in dosage forms due to their high swellability/
solubility at acidic pH. Hence, gums need to be modified to alter their
physicochemical properties. For example, the modification of gums
through derivatisation of functional groups, grafting with polymers,
cross-linking with ions and other approaches as well as the factors
influencing these processes in the pursuit of making them suitable
for modifying the drug release properties of pharmaceutical dosage
forms and for other purposes have been discussed with respect to
optimization of their performance .
Oral sustained release matrix tablets of water-insoluble drug,
flurbiprofen was designed with natural gums and evaluated for the
drug release characteristics using response surface methodology
. The central composite design for two factors at five levels each
was employed to systematically optimize drug release profile. In their
work matrix tablets were prepared by direct compression technique.
Xanthan and acacia gums were taken as the independent variables.
Fourier transform infrared spectroscopy was employed to study the
stability of drug used and the interactions between polymers and
drug. Percent drug release in 2 and 8 hours were taken as response
variables (Y1 and Y2, respectively). These workers found that the gums
have significant effect on the drug release. Polynomial mathematical
models, generated for the response variables using multiple linear
regression analysis, were found to be statistically significant (P < 0.05).Contour plots were drawn to depict the relationship between response
variables and independent variables. These workers concluded that the
formulated matrix tablets followed zero-order kinetics with negligible
drug release in 0.1N HCl at pH 1.2. Their objective of a formulation
that would avoid the gastric effects of flurbiprofen was achieved.
The mechanical and disintegration properties of paracetamol tablets
formulated with Delonixregia seed gum (DRSG) as a binder have
been studied . Tragacanth (TRG) and acacia (ACG) were used for
comparison. Results showed that an increase in concentration of the
binder increased the tensile strength while the brittle fracture index
(BFI) was reduced. The crushing strength - friability/disintegration
time ratio was ranked in the order: DRSG > ACG > TRG at 1%, w/w
binder concentration. The ranking of high binder concentrations was
ACG > TRG > DRSG. The results suggested that Delonixregia seed
gum may be useful as a binder at low concentration and as sustained
release matrix at high concentration. Another natural gum, damar was
investigated as a novel micro encapsulating material for sustained drug
delivery . Micro particles were prepared by oil-in-water emulsion
solvent evaporation method employing ibuprofen and diltiazem
hydrochloride as model drugs. Micro particles were evaluated for
particle size, encapsulation efficiency and in vitro drug release kinetics.
The effect of different gum: drug ratios and solubility of drug on micro
particle properties was principally investigated. Gum damar produced
discrete and spherical micro particles with both drugs. With a freely
water soluble drug (diltiazem hydrochloride), gum damar produced
bigger (45-50 μm) and rapid drug releasing micro particles with low
encapsulation efficiencies (44-57%). Conversely, with a slightly watersoluble
drug (ibuprofen), small (24-33 μm) micro particles with good
encapsulation (85-91%) and sustained drug delivery were achieved. An
increase in gum: drug ratio resulted in an increase in particle size and
encapsulation efficiency but decreased the drug release rate in all cases.
Drug release profiles of all micro particles followed zero order kinetics.
Seaweed gums are typified by the carrageenans, agar and the
Alginates: Alginates are natural polysaccharide polymers isolated
from the brown sea weed (Phaeophyceae). Alginic acid can be
converted into its salts, of which sodium alginate is the major form
currently used. They are linear polymers consisting of D-mannuronic
acid and L-guluronic acid residues arranged in blocks in the polymer
chain. These homogeneous blocks (composed of either acid residue
alone) are separated by blocks made of random or alternating units of
mannuronic and guluronic acids. Alginates offer various applications
in drug delivery, such as in matrix type alginate gel beads, in liposomes,
in modulating gastrointestinal transit time, for local applications and
to deliver the bio molecules in tissue engineering applications .
Bio-adhesive sodium alginate microspheres of metoprolol tartarate
for intranasal systemic delivery were prepared to avoid the first-pass
effect, as an alternative therapy to injection, and to obtain improved
therapeutic efficacy in the treatment of hypertension and angina pectoris.
The microspheres were prepared using emulsification-cross linking
method. In vivo studies indicated significantly improved therapeutic
efficacy of metoprolol from microspheres. There was sustained and
controlled inhibition of isoprenaline-induced tachycardia as compared
with oral and nasal administration of drug solution .
A new insert, basically consisting of alginates with different
hydroxyl-ethyl-cellulose content was developed to maintain a constant
drug level over a certain period in the eye that was not possible with
conventional eye drop application. This study showed good tolerance
of the new calcium-alginate-insert applied to the ocular surface for
controlled drug release . In order to achieve a 24h release profile of
water soluble drugs, sodium alginate formulation matrices containing
xanthan gum or zinc acetate or both were investigated. The release of
the drug from the sodium alginate formulation containing only xanthan
gum was completed within 12h in the simulated intestinal fluid, while
the drug release from the sodium alginate formulation containing only
zinc acetate was completed within 2h in the same medium. Only the
sodium alginate formulation, containing both xanthan gum and zinc
acetate achieved a 24h release profile, either in the simulated intestinal
fluid or in the pH change medium (pH 1.2). The helical structure
and high viscosity of xanthan gum possibly prevented zinc ions from
diffusing out of the ranitidine hydrochloride sodium alginate-xanthan
gum-zinc acetate matrix so that zinc ions react with sodium alginate to
form zinc alginate precipitate with a cross-linking structure. The crosslinking
structure might control a highly water-soluble drug release for
In a comparative study, alginate formulation appeared to be better
than the poly-lactide-co-glycoside (PLG) formulation in improving
the bioavailability of two clinically important antifungal drugs
clotrimazole and econazole. The nanoparticles were prepared by the
emulsion-solvent-evaporation technique in case of PLG and by the
cation-induced controlled gelling in case of alginate .
Carageenans: The carrageenans are sulphated marine
hydrocolloids obtained by extraction from seaweeds of the class
Rhodophyceae, represented by Chondruscrispus, Euchemaspinosum,
Gigartinaskottsbergi, Gigartinastellata, Iradaealaminariodes. These are
red seaweeds growing abundantly along the Atlantic coasts of North
America, Europe and the western Pacific coast of Korea and Japan [45-
47]. Carrageenan is not assimilated by the human body. It provides
only bulk but no nutrition. Carrageenan has been categorized into
3: kappa (κ), iota (ι) and lambda (λ). Lambda (λ-type) carrageenan
produces viscous solutions but does not form gels. While the Kappa
(κ-type) carrageenan forms a brittle gel, the iota (ι-type) carrageenan
produces elastic gels . Studies have shown that the carrageenans are
suitable in the formulation of controlled release tablets [49-51].
Gum agar: Gum agar is extracted from the red-purple marine algae
of the Rhodophyceae class. The species include Gelidiumcartilagineum
and Gracilariaconfervoides which grow abundantly in the waters along
the coast of Japan, New Zealand, South Africa, Southern California,
Mexico, Chile, Morocco, and Portugal [46, 52, 53].
Natural polysaccharide gums have also been obtained as
carbohydrate fermentation products including Xanthan gum, produced
in pure culture fermentation by the bacteria Xanthomonascampestris.
It was originally obtained from the rutabaga plant . Gellan gum is
a microbial polysaccharide obtained by fermentation by Pseudomonas
elodea [53,54]. Pullulan is an extracellular homo-polysaccharide of
glucose produced by many species of the fungus Aureobasidium,
specifically A. pullulans.
Xanthan gum: Xanthan gum, a complex microbial exopolysaccharide
produced from glucose fermentation by Xanthomonas
campestrispv. Campestris, a plant bacterium. It has a molecular weight
of about 2 million . The gum consists of D-glucosyl, D-mannosyl,
and D-glucuronyl acid residues in a molar ratio of 2:2:1. It also contains O-acetyl and pyruvyl residues in variable proportions . Xanthan
gum is an acidic polysaccharide gum of penta-saccharide subunits.
The penta-saccharide subunits form a cellulose backbone with trisaccharide
The applications of xanthan gum have been widely researched. It is
non-toxic and has been approved by the Food and Drug Administration
(FDA) for use as food additive without quantity limitations .
Xanthan gum has been used in a wide range of industries including
food, oil recovery, cosmetics and pharmaceutical industries. This wide
application is due to its superior rheological properties. It is used as
stabilizer for emulsions and suspensions. The gum forms highly
viscous solutions which exhibit pseudoplasmic flow behavior .
The literatures are littered with uses of xanthan as a pharmaceutical
Gellan gum: DeacylatedGellan gum (Gellan) is an anionic
microbial polysaccharide, secreted from Sphingomonas elodea,
consisting of repeating tetrasaccharide units of glucose, glucuronic
acid and rhamnose residues in a 2:1:1 ratio: [→3)–β–D–glucose–(1→4)–
β–D–glucuronic acid–(1→4)– β–D–glucose–(1→4)–ᾳ–L–rhamnose–
(1→]. In the native polymer two acyl substituents, L-glyceryl at O(2)
and acetyl at O(6), are present on the 3-linked glucose. On average,
there is one glyceryl per repeating unit and one acetyl for every two
repeating units. DeacylatedGellan gum is obtained by alkali treatment
of the native polysaccharide. Both native and deacylatedGellan gum
are capable of physical gelation . To induce Gellan gelation it is
necessary to warm up preliminarily a concentrated water solution of
the polysaccharide: when the temperature is decreased, the chains
undergo a conformational transition from random coilsto double
helices (Coil-Helix Transition). Then a rearrangement of the double
helices occurs leading to the formation of ordered junction zones (Sol-
Gel Transition)  thus giving a thermo-reversible hydrogel .
Much stronger physical thermo-reversible hydrogels are also obtained
by addition of mono and divalent ions to Gellan solutions , or in
acidic conditions .
The physical gelation properties make this polysaccharide
suitable as a structuring and gelling agent in food industries. Gellan
is also exploited in the field of modified release of bioactive molecules.
Aqueous solutions of Gellan are used as in situ gelling systems, mainly
for ophthalmic preparation and for oral drug delivery . Physical
Gellan hydrogels, prepared with mono or divalent cations, are
used also for the preparation of tablets, beads  or microspheres.
Interpenetrating polymer networks  or co-cross linked polymer
networks  based on Gellan and other polysaccharide systems have
also been developed as drug delivery matrices.
Chemical hydrogels of Gellan are usually prepared via chemical
cross linking of preformed physical networks, in order to enhance
their mechanical properties, and to obtain slower drug release profiles.
The aim of the present work was the development of a novel Gellan
chemical hydrogel, with tunable physicochemical properties, obtained
by cross linking the polymer chains with L-lysine ethyl ester moieties.
As a first step, amidation of Gellan carboxyl groups in the presence
of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
N-hydroxy-succinimide (NHS) was carried out it is well known that
EDC and NHS have the ability to mediate the amide bond formation
between amino and carboxyl groups. Ethyl ester of L-lysine (Lys)
was used in order to protect the carboxyl group, thus avoiding the
intermolecular reaction among the L-lysine molecules. Chemical
hydrogels with different cross linking degrees were prepared, and their physico-chemical and rheological properties were studied and
compared with the corresponding physical gels. The new networks,
that were also investigated as matrices for modified oral release, using
model molecules with different steric hindrance, can be proposed as
carriers for the delivery of high molecular weight drugs such as proteins.
Furthermore, the observed peculiar mechanical and rheological
properties can be properly modulated in order to give matrices suitable
for the depot systems [71,72].
Pullulan: Insulin (Ins) spontaneously and easily complexed with the
hydrogel nanoparticle of hydrophobized cholesterol-bearing pullulan
(CHP) in water. The complexed nanoparticles (diameter 20–30 nm)
thus obtained formed a very stable colloid. The thermal denaturation
and subsequent aggregation of Ins were effectively suppressed upon
complexation. The complexed Insulin was significantly protected from
enzymatic degradation. Spontaneous dissociation of Insulin from the
complex was barely observed, except in the presence of bovine serum
albumin. The original physiological activity of complexed Insulin
was preserved in vivo after i.v. injection . Figure 3 shows the
microscopic view of pullulan in the solid and in the presence of water.
Figure 3:Molecular structure of powdered cellulose (n ≈ 500) or microcrystalline
cellulose (n ≈ 220).
Natural gums have also been obtained from animal sources.
Examples include chitin and chitosan. Chitin is a structural
polysaccharide which takes the place of cellulose in any species of lower
plants and animals. It therefore occurs in fungi, yeast, green, brown and
red algae and form the main component of the exoskeleton of insects
and shells of crustaceans . Chitin is insoluble in water but when
treated with strong alkali, it forms the water-soluble polysaccharide chitosan which is the only polysaccharide carrying a positive charge
Plants, which form the sources of exudate gums, when cut give
a viscous, sticky fluid which exudes from the incision and tends to
cover and seal the opening. Gum exudates are therefore believed to be
produced by plants in order to seal-off infected sections of the plant
and prevent loss of moisture due to physical injury or fungal attack
. The fluid eventually dries to a brittle, translucent, glassy, hard
mass. These gum exudates are secreted by various organs of the plant.
They include tragacanth gum and acacia gum or gum Arabic.
Acacia gum: Acacia gum or gum Arabic is the dried gummy exudate
from the stems and branches of Acacia Senegal (Fam. Leguminosae)
and other related African species of acacia [74,75]. Gum arabic is
a branched molecule of 1, 3-linked β-Dgalactopyranosyl units. It
consists of monosaccharide sugarss such as arabinose, glucuronic acid
and rhamnose. Studies recorded success with gum Arabic as a matrix
microencapsulating agent for the enzyme, endoglucanase . In this
study gum Arabic was shown to give slow release endogucanase from
the formulation. In another study gum arabic was used as an osmotic
suspending and expanding agent to prepare monolithic osmotic tablet
systems . There was zero order release of the active for up to 12
hours at a pH of 6.8. Heterogeneity of Acacia senegal gum by sodium
sulfate –induced precipitation has been studied .
Tragacanth gum: Gum tragacanth is a branched, heterogeneous,
and anionic carbohydrate which consists of two major fractions:
tragacanthin (water-soluble) and bassorin (water-swellable) .
It is not understood yet if the two polysaccharides are in a physical
mixture or chemically bonded to each other, although easy separation
procedures favor the former hypothesis. Bassorin and tragacanthin
composition differ particularly in terms of their uronic acid and
methoxyl content ; it has been suggested that bassorin is a complex
structure of polymethoxylated acids and on demethoxylation, probably
yields tragacanthin . Gum tragacanth has been known and used for
thousands of years. It is defined by the Food Chemical Codex as the
dried gummy exudation obtained from different species of Astragalus
(fam. Leguminosae) . It has been classified as generally recognized
as safe at the 0.2–1.3% level in food stuffs in the USA since 1961 and
has the number E413 in the list of additives approved by the Scientific
Committee for Food of the European Community. The capacity of gum
tragacanth to extensively modify the rheology of aqueous media even
at fairly low concentration is the most important factor in evaluating
tragacanth and is regarded as a measure of its quality and also a guide to
its behavior as a suspending agent, stabilizer, and emulsifier . A few
studies have been devoted to functional properties of gum tragacanth,
and most of the works on structural and functional properties of the
gum as well as its application in various fields have been done. Recently
the flow behavior of six species of Iranian gum tragacanth dispersions
was investigated at different temperatures and ionic strengths, within
a concentration range (0.05–1.5% w/w) using a controlled shear rate
rheometer. The steady shear measurements showed that all of the gum
dispersions had shear-thinning natures. The power law model was used
to describe the rheological properties of dispersions and Arrhenius
model was used to evaluate the temperature effect. The workers carried
out composition analysis; surface tension measurement, particle size
analysis, and color measurement of all the species were also carried out.
Their results indicated that the six species of gum tragacanth studied
exhibited significantly different physicochemical properties .
Mucilage gums: Many seeds contain polysaccharide food reserves
which produce intracellular seed gums usually obtained by extraction
from the seeds. Guar gum is obtained from the ground endosperms
or seeds of the plant Cyamopsistetragonolobus (Fam. Leguminosae).
Locust bean gum is obtained from the endosperms of the hard
seeds of the locust bean tree (Carob tree), Ceratoniasiliqua (Fam.
Locust bean gum: It is also called carob gum, as it is derived
from the seeds of the leguminous plant carob, Ceratoniasiliqua Linn
(Fam. Caesalpiniaceae). Locust bean gum has an irregularly shaped
molecule with branched β-1, 4-D-galactomannan units (See figure 4
for molecular structure). This neutral polymer is only slightly soluble
in cold water; it requires heat to achieve full hydration and maximum viscosity. Cross-linked galactomannan however led to water-insoluble
film forming product-showing degradation in colonic microflora
The colon-specific drug delivery systems based on polysaccharides,
locust bean gum and chitosan in the ratio of 2:3, 3:2 and 4:1, were
evaluated using in vitro and in vivo methods Core tablets containing
mesalazine with average weight of 80mg were prepared by compressing
the materials using 6-mm round, flat, and plain punches on a single
station tablet machine. The formulated core tablets were compression
coated with different quantities of locust bean gum and chitosan. The
in vitro studies in pH 6.8 phosphate buffer containing 2%w/v rat caecal
contents showed that the cumulative percentage release of mesalazine
after 26 hr was 31.25 ± 0.56, 46.25 ± 0.96, and 97.5 ± 0.26, respectively.
The in vivo studies conducted in nine healthy male human volunteers
for the various formulations showed that the drug release was initiated
only after 5hr, which is the transit time of small intestine. In vitro drug
release studies and in vivo studies revealed that the locust bean gum
and chitosan as a coating material applied over the core tablet was
capable of protecting the drug from being released in the physiological
environment of stomach and small intestine and was susceptible to
colonic bacterial enzymatic actions with resultant drug release in the
colon (Figure 4).
Figure 4:Molecular structure of powdered cellulose (n ≈ 500) or microcrystalline
cellulose (n ≈ 220).
Guar gum: Guar gum, obtained from the ground endosperms of
Cyamposistetragonolobus, consists of chiefly high molecular weight
hydrocolloidal polysaccharide, composed of galactan and mannan
units combined through glycosidic linkages and shows degradation in
the large intestine due the presence of microbial enzymes. The structure
of guar gum is a linear chain of β-D-mannopyranosyl units linked
(1→4) with single member α-D-galacto-pyranosyl units occurring as
side branches. It contains about 80% galactomannan, 12% water, 5%
protein, 2% acid soluble ash, and 0.7% fat. Guar gum has a molecular
weight of approximately 1 million, giving it a high viscosity in solution.
This galactomannan is soluble in cold water, hydrating quickly to
produce viscous pseudo plastic solutions that although shear-thinning
generally have greater low-shear viscosity than other hydrocolloids.
This gelling property retards release of the drug from the dosage form,
and it is susceptible to degradation in the colonic environment.
Guar gum is a non-ionic polysaccharide that is found abundantly in
nature and has many properties desirable for drug delivery applications.
However, due to its high swelling characteristics in aqueous solution,
the use of guar gum as delivery carriers is limited. Guar gum can be
modified by derivatization, grafting and network formation to improve
its property profile for a wide spectrum of biomedical applications.
Guar gum and its derivatives in various forms such as coatings,
matrix tablets, hydrogels and nano/micro particles can be exploited as
potential carriers for targeted drug delivery . An oral controlled
drug delivery systems for highly water-soluble metroprolol using
guar gum (30 (M1), 40 (M2) or 50% (M3) as a carrier in the form of a
three-layer matrix tablet was formulated by wet granulation technique
using starch paste as a binder. Three-layer matrix tablets of metoprolol
tartrate were prepared by compressing on both sides of guar gum
matrix tablet granules of metoprolol tartrate M1, M2 or M3 with either
50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3)
of guar gum granules as release retardant layers. Both the matrix and
three-layer matrix tablets were evaluated for hardness, thickness, drug
content uniformity, and subjected to in vitro drug release studies. The
amount of metoprolol tartrate released from the matrix and threelayer
matrix tablets at different time intervals was estimated by using
a HPLC method. Matrix tablets of metoprolol tartrate were unable to
provide the required drug release rate. However, the three-layer guar
gum matrix tablets (TL2M3) provided the required release rate on par
with the theoretical release rate for metoprolol tartrate formulations
meant for twice daily administration. The three-layer guar gum matrix
tablet (TL2M3) showed no change either in physical appearance, drug
content or in dissolution pattern after storage at 40°C/75% RH for 6
months. The FT-IR study did not show any possibility of metoprolol
tartrate/guar gum interaction with the formulation excipients used in
the study. The results indicated that guar gum, in the form of threelayer
matrix tablets, is a potential carrier in the design of oral controlled
drug delivery systems for highly water-soluble drugs such as metoprolol
tartrate . Similar results was obtained with guar gum at 65,75, and
85% in a three layer tablet of tri-metazidinedihydrochloride controlled
release formulation .
A novel tablet formulation for oral administration using guar gum
as the carrier and indo-methacin as a model drug has been investigated
for colon-specific drug delivery using in vitro methods. Drug release
studies under conditions mimicking mouth to colon transit have
shown that guar gum protects the drug from being released completely
in the physiological environment of stomach and small intestine.
Studies in pH 6.8 phosphate buffered saline (PBS) containing rat
caecal contents have demonstrated the susceptibility of guar gum to
the colonic bacterial enzyme action with consequent drug release. The
pre-treatment of rats orally with 1 ml of 2% w/v aqueous dispersion
of guar gum for 3 days induced enzymes specifically acting on guar
gum thereby increasing drug release. A further increase in drug release
was observed with rat caecal contents obtained after 7 days of pretreatment.
The presence of 4% w/v of caecal contents obtained after
3 days and 7 days of enzyme induction showed biphasic drug release
curves. The results illustrated the usefulness of guar gum as a potential
carrier for colon-specific drug delivery. The scientists concluded on the
study that the use of 4% w/v of rat caecal contents in PBS, obtained
after 7 days of enzyme induction provided the best conditions for in
vitro evaluation of guar gum . Poly-acryl-amide-grafted-guar gum
(pAAm-g-GG) was prepared by taking three different ratios of guar
gum to acrylamide (1:2, 1:3.5 and 1:5). Amide groups of these grafted
copolymers were converted into carboxylic functional groups. Fourier
transform infrared (FTIR) spectroscopy and differential scanning
calorimetry were used to characterize copolymers. Tablets were
prepared by incorporating an antihypertensive drug viz., diltiazem
hydrochloride. In-vitro drug release was carried out in simulated
gastric and intestinal conditions. Effect of drug loading on release
kinetics was evaluated. Release continued up to 8 and 12 h, respectively,
for pAAm-g-GG and hydrolyzed pAAm-g-GG copolymers. Nature of
drug transport through the polymer matrices was studied by comparing
with Higuchi, Hixson-Crowell and Kopcha equations. The researchers
found out that the drug release dissolution-controlled in case of
unhydrolyzed copolymer while in the hydrolyzed copolymers, drug
release was swelling-controlled initially (i.e., in 0.1N HCl), but at later
stage, it became dissolution-controlled in pH 7.4. These observations
led to the conclusion that Hydrolyzed pAAm-g-GG matrices are pH
sensitive , which positioned them as potential materials for intestinal
drug delivery .
Grewia gum: Grewia genus is today placed by most authors
in the Family Malvaceae, in the expanded sense as proposed in the
Angiosperm Phylogeny Group (APG). Formerly it was placed in either
the linden Family (Tiliaceae) or the Spermamanniaceae. However,
these were both not monophylectic with respect to other Malvales.
Grewia and similar genera have been merged into the Malvaceae.
Together with the bulk of the former spermanniaceae, Grewia is in the Family Grewiodeae and therein the tribe Grewieae, of which it is the
type genus .
The genus was named by the father of modern taxonomy, Carolus
Linnaeus (1707-1778), in honor of the Nehemiah Grew (1641-1712).
Grew, from England, was one of the leading plant anatomists and
microscope researchers of his time, and his study of pollen laid the
groundwork for modern-day palynology . Briefly, Carl Linnaeus
(Latinized as Carolus Linnaeus, also known after his ennoblement as
Carl von Linne  who lived from 23 May 1707 – 10 January 1778) was
a Swedish botanist, physician, and zoologist, who laid the foundations
for the modern scheme of binomial nomenclature. He is known as the
father of modern taxonomy, and is also considered one of the fathers of
modern ecology . About 150 species of Grewia have been confined
and most of them were said to be in Africa -.
There were ten (10) citations in International Pharmaceutical
Abstracts (IPA) database on grewia Family a year ago, in EBSCO
there are thirty-six (36) while in PubMed there were thirty-eight (38)
citations in 2010 on Grewia.
Increased interest on Grewia mollisas a potential pharmaceutical
excipient has been on since the last decade and has been investigated for
its phytochemical, toxicological and histopathological properties .
In their work they used soxhlet extraction to obtain the crude materials
from the stem bark of the plants along with those of Boswelliadalziellii,
paarophacurcas and Pterocarpuserinaceus claimed to be of medicinal
values in Nigeria. The study showed that tannins, saponins, flavonoids,
glycosides, balsam, phenols, terpenes, steroids were present while
alkaloids were absent. The study further demonstrated that the plant is
safe for human consumption with LD 50 of 1500 mg/kg body weight.
The extracts showed no structural effects on the liver and heart.
The actual investigation on the pharmaceutical uses of Grewia
mollis was documented in the early 2000’s [93-98]. The scientists
investigated some physicochemical and rheological characteristics as
well as water vapor permeability of the aqueous-based films. The gum
was investigated for its binding properties in sodium salicylate tablets
 and the effect of granulating fluid on the release profile of drug
containing the gum . Other workers  also found that method
of incorporating the gum into tablet formulation had effect on tablet
properties, where they discovered that incorporation by activation with
water produced better tablet properties than when incorporate by wet
granulation or direct compression. Scientists  evaluated the gum
by acid treatment, heating and some modification showed reduced
viscosity and improved drug release from tablets. More recently
other researchers  investigated the binding property of the gum
in comparison with both untreated gum and gelatin in paracetamol
tablet formulations. Compression properties of the formulations were
analyzed using density measurements and assessed by compression
equation of Heckel. The mechanical properties of the formulations
were assessed using crushing strength and friability as well as crushing
strength friability ratio. The drug release properties of the tablets
formed were assessed using disintegration and dissolution times.
Tablet formulations containing treated grewia gum exhibited low
onset of plastic deformation, while that of untreated gum and gelatin
were relatively high onset of deformation. The friability of paracetamol
tablet formulation increased with increase in acid concentration and
treatment time. The crushing strength, disintegration and dissolution
times decreased with increase in acid concentration and treatment time.
Tablets containing untreated gum possessed high crushing strength,
disintegration and dissolution times and low friability compared to
those containing gelatin and the treated gum. Depending on the desired
onset of action of medicament acid treated grewia gum can be used
in formulation of conventional tablets especially if the formulation
does not require sustained release . Advancement in technology
and analytical tools will continue to aid the understanding of natural
polymers and better position them for use as pharmaceutical excipients.
Grewia gum was extracted from the inner stem bark of Grewia mollis
and characterized by several techniques such as gas chromatography
(GC), gel permeation chromatography (GPC), scanning electron
microscopy (SEM), differential scanning calorimetry (DSC) and
thermo gravimetric analysis of the extracted sample. Spectroscopic
techniques such as x-ray photoelectron spectroscopy (XPS), Fouriertransformed
infrared (FT-IR), solid-state nuclear magnetic resonance
(NMR), and 1H and 13C NMR and NIR techniques were also used
to characterize the gum [103,104]. The gum is a typically amorphous
polysaccharide gum containing glucose, rhamnose, galactose,
arabinose and xylose as neutral sugars. It has an average molecular
weight of 5925 kDa expressed as the pullulan equivalent. The gum
slowly hydrated in water, dispersing and swelling to form a highly
viscous dispersion exhibiting pseudo plastic flow behavior. Fractions
of the gum obtained by centrifugation successively at 4500 rpm for
30 minutes with average molecular weights between 230 and 235 kDa
showed improved aqueous solubility that was useful in delivering more
solids to the substrate when used as a film coating agent .
Okra gum: Okra is a tall erect annual plant botanically known as
Abelmoschusesculentus (Fam. Malvaceae). It is widely cultivated and
grown in most tropical part of Nigeria. Okra has been used as food and
soup in Africa  and Asia  and has been a subject of research
in agriculture and food [105,107-119]. Okra is known for its viscous
mucilaginous solution which results when it is crushed and extracted
in water . The potential of okra gum as a pharmaceutical excipient
has received attention in literatures as a binder [121,122], control
release , film coating , bio-adhesive  and suspending
[126-128] agent. Okra gum has been evaluated as a controlled-release
agent in modified release matrices, in comparison with sodium carboxymethyl-
cellulose (NaCMC) and hydroxyl-propyl-methyl-cellulose
(HPMC), using Paracetamol as a model drug. Tablets were produced
by direct compression and the in-vitro drug release was assessed in
conditions mimicking the gastro intestinal system, for 6 h. Okra gum
matrices provided a controlled-release of Paracetamol for more than 6
h and the release rates followed time-independent kinetics. The release
rates were dependent on the concentration of the drug present in the
matrix. The addition of tablet excipients, lactose and Avicel, altered
the dissolution profile and the release kinetics. Okra gum compared
favorably with NaCMC, and a combination of Okra gum and NaCMC
or on further addition of HPMC resulted in near zero order release
of paracetamol from the matrix tablet. The results indicated that Okra
gum matrices was useful in the formulation of sustained-release tablets
for up to 6h .
Kyaha gum: Khaya gum is obtained by extraction from
Khayasenegalensis and Khayagrandifoliola (Fam. Meliaceae).
The comparative binding effects of khaya gum obtained from
Khayasenegalensis and Khayagrandifoliola in paracetamol tablet
formulation were evaluated . The mechanical properties of the
tablets were assessed using the tensile strength (T), brittle fracture index
(BFI) and friability (F) of the tablets while the drug release properties
were assessed using disintegration and dissolution times. The tensile
strength, disintegration and the dissolution times of tablets increased
with the increase in binder concentration while F and BFI decreased.K. senegalensis gum produced strong tablets with long disintegration
and dissolution times compared to K. grandifoliola gum. The results
showed that K. senegalensis will be more appropriate as a binding agent
than K. grandifoliola when high mechanical strength and slow release
profiles of tablets are desired.
Moringaoleifer gum: A natural gum obtained from plant
Moringaoleifera gum was extracted by using water as solvent and
precipitated using acetone as non-solvent. Physical characteristics
such as, solubility, swelling index, loss on drying, and pH were studied.
Diclofenac sodium was used as model drug for the formulation of
gels. Seven batches of drug loaded gels with concentration of mucilage
ranging from 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, and 8.5 were formulated by
using glycerin as plasticizer and methyl paraben as preservative. The
pH, viscosity, and in vitro diffusion profiles were studied. The gels
prepared with 8.0% of mucilage were found to be ideal and comparable
with a commercial preparation .
Irvingiagabonensis:Irvingiagabonensis (AubryLecomte ex
O’Rorke) Baill. Commonly known as ‘African mango’ or ‘bush mango’
is a tree of 15-40 m, with a bole slightly buttressed [132-135]. The
plant is a wild forest tree [134,136] with dark green foliage and yellow
fragrant flowers and occurs in the wild lowland forest; 2-3 trees occur
together and in some areas, it is reported to be widespread. I.gabonensis
is largely distributed in Africa [137-140]. The fruit is spherical with
smooth yellow fibrous mesocarp and hard endocarp when ripe. The seed
from the plant has been of interest in the food [136,141-143], beverages
[144-146], medical [135,147-152] and pharmaceutical [153-162] as
well as cosmetic circles . The seed of the plant contains lipids and
polymeric constituents [105,137,146,164-167]. Both the lipids (dika
fat) and the polymeric (gum) components are of importance to the
pharmaceutical scientists as excipients in Africa and the developing
world. The mucilage from the kernel has been used as binding agent
in tablet formulation , as emulsifying and suspending agent
[105,168]. On the other hand, the lipid has been employed in tableting
as lubricant [162,169], sustained release ingredient [154,155,170],
microencapsulation , as suppository base [158,159,172] and as
a component of film coating operation . The lipids component
of I.gabonensis seeds have been traditionally extracted using n-hexane
 or other organic solvents ; and more recently an enzymatic
approaches for extracting the lipid components have been investigated
. The polymeric component of the seed has been extracted from
aqueous dispersion using petroleum ether  or diethyl ether .
None of the extraction processes described in the literature provided
for simultaneous extraction of the lipid and polymer component
until recently . This was to overcome adverse environmental
consequences of disposal of organic solvents used in its extraction
and also address worker’s safety concerns and cost of extraction. A
lot have appeared in literature on the application of both the gum and
the fat from this plant. The mucilage extracted from the kernels of
Irvingiagabonensis was evaluated for use as suspending and emulsifying
agent . The rheological behavior of the mucilage was studied
and compared to that of tragacanth. As a suspending agent, Irvingia
mucilage was compared to tragacanth at various concentrations
(0.5, 1.0, 1.5 and 2.0% w/v) in the formulation of sulphanilamide
suspensions. At all concentrations the formulated suspensions with
Irvingia mucilage gave higher Hu (final sedimentation height) and F
(sedimentation volume) values. As an emulsifying agent, the properties
of Irvingia mucilage was compared to tragacanth and acacia gum. The
emulsions prepared with 0.6, 1.0, and 1.5% tragacanth and Irvingia
‘cracked’ within six days while that with 12.5% w/v acacia started
showing signs of creaming at the tenth day. The emulsion prepared
with 2.0% w/v Irvingia mucilage was however stable throughout the six
weeks of study. The results indicate that Irvingia mucilage performed
better than acacia and tragacanth even at lower concentrations in the
formulation of emulsions and suspensions.
The potential of irvingia fat as a suppository base has been evaluated
[158,172]. The binding effects on metronidazole tablets , sustained
release profiles on some tablets [154,155] as well as lubricating potential
in tablet formulations  incorporating irvingia gum have been
Hakeagibbosa gum: The muco adhesive and sustained-release
properties of the water-soluble gum obtained from Hakeagibbosa
(hakea), for the formulation of buccal tablets. Flat-faced tablets
containing hakea were formulated using chlorpheniramine maleate
(CPM) as a model drug had been investigated . In the study
two types of tablets were prepared: uncoated tablets (type I) and
tablets in which all but one face of the type I tablet was coated with
hydrogenated castor oil (Cutina) using a compression coating
technique (type II). FTIR, differential scanning calorimetry (DSC),
UV spectroscopy, and acid–base titrations were used to evaluate the
properties of the formulations. Mathematical modeling of the CPM
release data was developed to elucidate the mechanism of drug release.
The muco adhesive strength was evaluated by quantitating the force
of detachment. Finally, the rates of water uptake and erosion were
determined for the buccal tablets. The time required for 90% of the
CPM to be released in vitro (t90%) was used as a basis for comparison.
For formulations that did not contain hakea, the t90% was 14min for
both directly compressed and wet granulated tablets, whereas the t90%
for wet granulated tablets containing 2 or 32mg hakea/tablet was 36
and 165min, respectively. Directly compressed tablets containing 2, 12,
22, and 32mg hakea/tablet displayed t90% values of 48, 120, 330, and
405min, respectively. DSC, FTIR, UV spectroscopy and acid–base
titration experiments suggested the absence of chemical interactions.
The force of detachment for directly compressed and wet granulated
tablets increased from 0.70 ± 0.3 to 4.08 ± 0.52 N and from 0.65 ± 0.28
to 3.94 ± 0.31 N as the amount of hakea per tablet was increased from
0 to 32 mg, respectively, at a 5 N attachment compression force. The
workers concluded that hakea, may not only be utilized to sustain the
release of CPM from a unidirectional-release buccal tablet, but it also
exhibited excellent mucoadhesive properties. The mechanism by which
CPM release was sustained was more likely due to slow relaxation of
the hydrated hakea.
Psyllium mucilage: Psyllium mucilage is obtained from the seed
coat of Plantagoovata (Fam. Plantaginaceae) by milling the outer layer
of the seeds . Psyllium has been evaluated for its tablet binding
properties . Hydrogels of psyllium and methacrylamide prepared
using N,N’-methylene-bis-acryl-amide as cross-linker and loaded with
insulin showed controlled release of the active ingredient .
Other natural gums and mucilage:Sterculiafoetida gum has been
investigated as a swelling and erosion modulator in controlled release
matrix tablets of diltiazem hydrochloride . The pharmaceutical uses
of other gums have been explored. These include Colocassiaesculenta
, seeds of Linumusitatissimum , malva nut gum .
Inulin is a naturally occurring storage polysaccharide found in
many plants such as onion, garlic, artichoke, and chicory. Chemically,
it belongs to the gluco-fructans and consists of a mixture of oligomers and polymers containing 2 to 60 (or more) β-2-1 linked D-fructose
molecules. Most of these fructose chains have a glucose unit as the
initial moiety. The inulin has been incorporated into Eudragit RS films
for preparation of mixed films that resisted degradation in the upper
GIT but digested in human fecal medium by the action of Bifidobacteria
and Bacteroids . Various inulin hydrogels have been developed
that serve as potential carriers for the introduction of drugs into the
colon . Vinyl groups were introduced in inulin chains to form
hydrogels by free radical polymerization. Inulin was reacted with
glycidylmethacrylated in N,N-dimethylformamide in the presence of
4-dimethylaminopyridine as catalyst. 1H and 13C NMR spectroscopy
were used for the characterization of the obtained reaction product and
revealed the conversion of the incorporated vinyl groups into covalent
crosslink’s upon free radical polymerization of aqueous solutions of the
derivatized inulin .
Starch whether in the native or modified form has been used as
one of the key pharmaceutical excipients in pharmaceutical tablet
and capsule formulations. It serves various functions such as bulking,
binder, disintegrant or aiding drug delivery. Microcapsules containing
a protein and a proteinase inhibitor were prepared to deliver proteins
or peptidic drugs orally . Starch/bovine serum albumin mixedwalled
microcapsules were prepared using interfacial cross-linking
with terephthaloyl chloride. The microcapsules were loaded with native
or amino-protected aprotinin by incorporating protease inhibitors in
the aqueous phase during the cross-linking process. The protective
effect of microcapsules with aprotinin for bovine serum albumin was
revealed in vitro.
Acetylation of starch considerably decreases its swelling and
enzymatic degradation . Starch-acetate (SA) based delivery
systems for controlled drug delivery has been reported . These
workers reported that acetylated of potato starch substantially retard
drug release compared to that of natural potato starch film.
Tablet film coating with amylose-rich maize starch has been
investigated . These workers carried out a study on the use of
aqueous –based amylose-rich starch (Hylon VII™) film coating of the
tablets. Using a side vented pan coating system, they investigated the
influence of plasticizer concentration, temperature of coating pan and
the spray rate of the coating solution. In their study they observed
that at low spray rates, the temperature of the coating pan did not
affect the roughness of the coated tablet but at high spray rates, high
temperatures gave smooth films. The dissolution rate of all Hylon
VII™ –coated tablets was rapid in an acid medium, releasing 75% of
the drug. Other works on the use of amylose and native starches as
film forming agent in pharmaceutical film coatings have been reported
[189-192]. A combination of amylose and ethyl-cellulose aqueous and
non-aqueous based coatings for colon drug delivery has been reported
[189-191,193]. Some workers  sourced and obtained cellulose
and microcrystalline cellulose from maize cobs and they compared the
tablet properties of paracetamol tablets made by direct compression
with microcrystalline cellulose (MCC) as sole excipients with a multiexcipient
formula in wet granulation and found that the former
possesses better tablet properties apart from the added advantages of
direct compression and fewer ingredients. Scientists have evaluated
the physicochemical and powder properties of alpha- and microcrystalline
cellulose derived from maize cobs and they found that it has
comparable attributes to Avicel® as a pharmaceutical excipient .
Other work on MCC and cellulose derived from maize cobs have been
Dextran hydrogels have been shown to be the promising carrier for
the delivery of drugs to colon [198-200].
Cyclo dextrins (CyDs) are cyclic oligosaccharides consisting of six
to eight glucose units joined through α-1, 4glucosidic bonds. CyDs
remain intact during their passage through stomach and small intestine.
However, in the colon, they undergo fermentation from the presence of
vast colonic micro flora into small saccharides and thus absorbed from
these regions [201,202]. CyDs form inclusion complexes with drug
molecules because the interior of the molecule is relatively lipophilic
while the exterior is hydrophilic . It has been investigated through
a study in healthy human volunteers that β CyDs are degraded to a
very small extent in the small intestine but are completely digested in
large intestine. Most bacterial strains that are isolated from human
beings are capable of degrading CyDs. This has been proved by their
ability to grow on cyclo dextrins by utilizing them as the sole carbon
source and by the stimulation of cyclo dextrinase activity as low as 2–4
hr of exposure to CyDs. This property of the drug may be exploited
for the formation of colon targeted drug delivery systems. Several CyD
conjugates have been prepared and the enantio selective hydrolysis has
been described. Formulation of pro-drug of CyDs with drug molecules
can provide a versatile means for construction of not only colon
targeted delivery systems, but also delayed release systems. Biphenyl
acetic acid (BPAA), an anti-inflammatory drug, was conjugated with
α-, β- and γ -CyDs and in vivo release pattern was investigated in rat
after oral administration. The CyD pro-drug maintained the physical
integrity in stomach and small intestine which is reflected from the
observations that the absorption of pro-drugs from upper GIT was
negligible, and after 6 hr most of the pro-drug approached the caecum
and colon. The α- and γ -CyD amide pro-drugs were hydrolyzed to the
maltose conjugate in the colon while the α- and γ -CyD ester pro-drugs
produced BPAA in the caecum and colon. The anti-inflammatory
effect of the α- and γ -CyD ester pro-drugs was assessed and compared
with those of BPAA alone and the drug CyD complex prepared by the
kneading method in a molar ratio of 1:1. In the case of β-CyD complex,
a rapid anti-inflammatory response was observed from the small
intestine after a fast dissolution of the complex. In sharp contrast, the γ
-CyD ester pro-drug required a fairly long lag time to exhibit the drug
activity, because BPAA was produced after the pro-drug had reached
the caecum and colon [203,204]. Some investigators  prepared two
CyD conjugates: ester and amide conjugates. They showed that ester
conjugate released the drug preferentially when incubated with the
contents of caecum or colon, whereas no appreciable drug release was
observed on incubation with the contents of either stomach or intestine
in intestinal or liver homogenates or in rat blood. Systemic side effects of
prednisolone were significantly reduced when conjugated with α-CyD
. The lower side effect of the conjugate was attributed to passage
of the conjugate through the stomach and small intestine without
significant degradation or absorption, followed by the degradation of
the conjugate site-specifically in the large intestine.
Curdlan is a neutral, essentially linear (1”3)-β-glucan which may
have a few intra- or inter-chain (1”6) linkages. Curdlan’s unusual rheological properties among natural and synthetic polymers underlie
its use as a thickening and gelling agent in foods. Apart from being
tasteless, colourless and odourless, the main advantages are that in
contrast to cold-set gels and heat-set gels, the heating process alone
produces different forms of curdlan gel with different textural qualities,
physical stabilities and water-holding capacities . Gels of variable
strength are formed depending on the heating temperature, time of
heat-treatment and curdlan concentration. The safety of curdlan has
been assessed in animal studies and in vitro tests and it is approved
in food use in Korea, Taiwan and Japan as an inert dietary fibre. It is
registered in the USA as a food additive (Figure 5).
Figure 5:Molecular structure of powdered cellulose (n ≈ 500) or microcrystalline
cellulose (n ≈ 220).
Among these macromolecules, scleroglucan (Sclg) also seems to
be potentially useful for the formulation of modified release dosage
forms and numerous studies have been devoted to this specific
topic . Scleroglucan (Sclg) is a branched homo polysaccharide
consisting of a main chain of (1-3)-linked b-D glucopyranosyl units
bearing, every third unit, a single b-D-glucopyranosyl unit linked (1-
6). This polysaccharide is resistant to hydrolysis and its solutions show
an interesting rheological behaviour: viscosity remains practically
constant, even at high ionic strength, up to pH-12 and to 90oC.
Interest in this polysaccharide was first aroused in 1967 .
Sclg is a general term used to designate a class of glucans of similar
structure produced by fungi, especially those of the genus Sclerotium.
The commercial product is termed Scleroglucan, but it is also known
with other names according to the company that produces the
polysaccharide (e.g., Actigum, Clearogel, Polytetran, Polytran FS,
Sclerogum). Because of its peculiar rheological properties and its
resistance to hydrolysis, temperature and electrolytes, Sclg has various
industrial applications, especially in the oil industry for thickening,
drilling muds and for enhanced oil recovery and in food industry
[209, 210]. In pharmaceutical products, Sclg may be used as a laxative
in tablet coatings and in general to stabilize suspensions. Recently
carboxymethyl derivative of scleroglucan (Scl-CM) with a 65±5%
carboxylic group degree of derivatization (DD) was synthesized and
characterized. Aqueous solutions of the polymer underwent to a sharp
transition toward a gel like behavior in the presence of divalent ions
such as Ca+2. Physical hydrogels with different Scl-CM/Ca+2 ratios
were prepared and characterized for their rheological behavior. Their
potential as drug delivery systems were also evaluated. To this end
three non-steroidal anti-inflammatory drugs (NSAIDs) were loaded
into the hydrogels obtained with 2% w/v solution of Scl-CM and 0.05
and 0.1 M CaCl2. The release rate of the drugs was critically related to
the salt concentration. By an appropriate combination of the hydrogels
prepared using different amounts of salt, it was possible to obtain a
system able to release diclofenac with zero-order kinetics. Primary skin
irritation tests showed a good biocompatibility of the new polymer, as
well as of its hydrogels. These results suggested a potential of the new
hydrogels for the development of modified delivery systems in oral and
topical formulations [211,212].
Rosin is a low molecular weight (400 Da) natural polymer
obtained from the oleoresin of Pinussoxburghui, Pinuslongifolium
and Pinustoeda. It has as components abietic and pimaric acids. Rosin
and its derivatives have enjoyed growing roles in Pharmacy. They
have been investigated for microencapsulation, film-forming and
coating properties, and as matrix materials in tablets for sustained and
controlled release [213,214].
Studies on the film forming and coating properties of rosin and
the glycerol ester of maleic rosin showed that rosin has excellent film
forming properties with good to be used as coating materials for
pharmaceutical products as well as in sustained-release drug delivery
systems. The rosin films were biodegradable and biocompatible .
Derivatives of rosin have been synthesized by reaction with polyethylene
glycol 200 and maleic anhydride. The derivative proofed suitable for
sustaining drug release from matrix tablets and pellets . Rosin
nanoparticles loaded with hydrocortisone retarded the release of the
active and demonstrated the potential of rosin production of effective
nanoparticulate drug delivery systems .
The research into and use of excipients from natural sources
was reviewed and were discussed according to their classes. Natural
polymeric excipients and their modifications have continued to
dominate the research efforts of scientists in finding cheap, less
expensive, biodegradable, ecofriendly excipients. Some of these
excipients have obvious advantages over their synthetic counterparts
in some specific delivery systems due to their inherent characteristics.
If the current vigorous investigations on the use of natural polymeric
materials are sustained and maintained, it is probable that there would
be a breakthrough that will overcome some of the disadvantages of
this class of potential pharmaceutical excipients that would change the
landscape of the preferred pharmaceutical excipients for drug delivery
in the future.
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