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Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
ISSN 2231-2935
Review Article
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A systematic review on: Buccoadhesive drug delivery systems
1
2
Ravi Kumar Reddy J* , Indira Muzib Y
1
Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India
2
Sri Padmavati Mahila Visvavidyalayam, Tirupati, Andhra Pradesh, India
ABSTRACT
Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein
drug molecules. Buccal cavity was found to be the most convenient and easily accessible site for the delivery of
therapeutic agents for both local and systemic delivery as retentive dosage forms delivery. Buccal delivery offers a
safer mode of drug utilization, since drug absorption can be promptly terminated in cases of toxicity by removing
the dosage form from the buccal cavity. Since the above reasons, delivery of the desired drug as buccoadhesive
drug delivery systems has been subject of interest since last 3 decades. However, the need for safe and effective
buccal permeation, absorption enhancers is a crucial component for a prospective future in the area of buccal
drug. Transmucosal is relatively new drug delivery strategy; in this traditional polymers are replaced by novel bioadhesive polymers such as thiomers (e.g.chitosan) and lectins etc to overcome limitations of traditional polymers.
Some of the buccoadhesive products like Nitrostat , Buccastem, Striant, Suscard are commercially available in the
market to play a vital role in the treatment of various diseases. The buccoadhesive products are increasing day by
day in the market, so they have steady growth rate of above 10 % in the world market. This article describes physiological barriers for the oral mucosa, Theories of mucoadhesion, components of drug permeation, general considerations in dosage form design, recent developments in the buccal drug delivery systems, which will be useful
to circumvent the difficulties associated with the formulation design for further research in buccal drug delivery.
Keywords Adhesive polymers; buccal drug delivery; mucoadhesion; thiomers; transmucosal.
INTRODUCTION
Buccal, sublingual, palatal and gingival (Amir H S et al.,
2001) regions shows effective drug delivery in oral cavity. Buccal and sublingual route of drug delivery are
most widely in which local and systemic effects are
treated. The permeability of oral mucosa denotes the
physical nature of the tissues. The permeable part is
sublingual mucosa and buccal mucosa is thinner part
and in which there is a high blood flow and surface
area; it is a feasible site when a rapid onset of action is
desired. For the treatment of acute disorders sublingual route is a preferred one; however its surface
washed with saliva which makes formulations in the
oral cavity hard in nature (Satheesh M N V et al., 2009;
Yajaman S et al., 2006).
Various newer researches are carried out their research work recent days in the buccal delivery, like
antihypertensive,
anti-anginal,
analgesic,
antiinflammatory, anti-asthmatic, anti-infective, anti* Corresponding Author
Email: [email protected]
Contact +91-8565-249309
Received on: 19-07-2012
Revised on: 28-11-2012
Accepted on: 05-12-2012
neoplastic, hormonal and ophthalmic drugs. In this
article various developments in formulations of buccal
dosage forms, physiological barriers for permeation,
theories of mucoadhesion in consolidate, future trends
were described. Even many reviews are available in
this area of work, but this article gives a comprehensive data on buccal drug delivery from the year 1990 to
2012. Literature review is collected from publications
of various online sources includes Science direct, Pub
med, Med know, Google Scholars etc.
Overview of the oral mucosa
The oral mucosa is composed of an outermost layer of
stratified squamous epithelium. Below this lies a
basement membrane, a lamina propria followed by the
submucosa as the innermost layer. The epithelium is
similar to stratified squamous epithelia found in the
rest of the body in that it has a mitotically active basal
cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where
cells are shed from the surface of the epithelium. The
epithelium of the buccal mucosa is about 40-50 cell
layers thick, while that of the sublingual epithelium
contains somewhat fewer. The epithelial cells increase
in size and become flatter as they travel from the basal
layers to the superficial layers. The lining of the oral
cavity is referred to as the oral mucosa, and includes
the buccal, sublingual, gingival, palatal and labial mu-
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
143
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
cosa. The buccal, sublingual and the mucosal tissues at
the ventral surface of the tongue accounts for about
60% of the oral mucosal surface area. The top quarter
to one-third of the oral mucosa is made up of closely
compacted epithelial cells. The primary function of the
oral epithelium is to protect the underlying tissue
against potential harmful agents in the oral environment and from fluid loss. Beneath the epithelium are
the basement membrane, lamina propia and submucosa. The oral mucosa also contains many sensory receptors including the taste receptors of the tongue (Gandhi R.E and Robinson J.R, 1988; Harris D and Robinson J
R, 1992; Amir H S et al., 1998).
The oral mucosae in general is a somewhat leaky epithelia intermediate between that of the epidermis and
intestinal mucosa. It is estimated that the permeability
of the buccal mucosa is 4-4000 times greater than that
of the skin. As indicative by the wide range in this reported value, there are considerable differences in
permeability between different regions of the oral cavity because of the diverse structures and functions of
the different oral mucosa. In general, the permeabilities of the oral mucosae decrease in the order of sublingual greater than buccal, and buccal greater than
palatal.This rank order is based on the relative thickness and degree of keratinization of these tissues, with
the sublingual mucosa being relatively thin and nonkeratinized, the buccal thicker and non-keratinized,
and the palatal intermediate in thickness but keratinized (Sevda S and Atilla H A, 2001; Squier C A et al.,
1997; Haas J and Lehr C.M, 2002).
Physiological barriers for oral transmucosal drug delivery
The environment of the oral cavity presents some significant challenges for systemic drug delivery. The drug
needs to be released from the formulation to the delivery site (e.g. buccal or sublingual area) and pass
through the mucosal layers to enter the systemic circulation. Certain physiological aspects of the oral cavity
play significant roles in this process, including pH, fluid
volume, enzyme activity and the permeability of oral
mucosa. For drug delivery systems designed for extended release in the oral cavity (e.g. mucodhesive
systems), the structure and turnover of the mucosal
surface is also a determinant of performance. The principle physiological environment of the oral cavity, in
terms of pH, fluid volume and composition, is shaped
by the secretion of saliva. Saliva provides a water rich
environment of the oral cavity which can be favorable
for drug release from delivery systems especially those
based on hydrophilic polymers. However, saliva flow
decides the time span of the released drug at the delivery site. This flow can lead to premature swallowing
of the drug before effective absorption occurs through
the oral mucosa and is a well accepted concept as “saliva wash out”. However, there is little research on to
what extent this phenomenon affects the efficiency of
oral transmucosal delivery from different drug delivery
144
systems and thus further research needs to be conducted to better understand this effect (Herrera J.L et
al., 1988; Slomiany B.L et al., 1996).
Drug permeability through the oral (e.g. buccal/sublingual) mucosa represents another major physiological barrier for oral transmucosal drug delivery.
The oral mucosal thickness varies depending on the
site as does the composition of the epithelium. The
relative impermeability of the oral mucosa is predominantly due to intercellular materials derived from the
so-called membrane coating granules Q (MCGs). MCGs
are spherical or oval organelles that are 100 - 300 nm
in diameter and found in both keratinized and nonkeratinized epithelia. They are found near the upper,
distal, or superficial border of the cells, although a few
occur near the opposite border (Gilles P et al., 1996).
Another factor of the buccal epithelium that can affect
mucoadhesion of drug delivery systems is the turnover
time. The turnover time for the buccal epithelium has
been estimated 3-8 days compared to about 30 days
for the skin which may change permeability characteristics frequently (Gandhi R.B et al., 1994).
Theories of mucoadhesion
The most widely investigated group of mucoadhesives
used in buccal drug delivery systems are hydrophilic
macromolecules containing numerous hydrogen bondforming groups. The presence of hydroxyl, carboxyl or
amine groups on the molecules favors adhesion. They
are called "wet" adhesives as they are activated by
moistening and will adhere nonspecifically to many
surfaces. Unless water uptake is restricted, they may
over hydrate to form slippery mucilage. For dry or partially hydrated dosage forms two basic steps in mucoadhesion have been identified. Step one is the "contact stage" where intimate contact is formed between
the mucoadhesive and mucous membrane. Within the
buccal cavity the formulation can usually be readily
placed into contact with the required mucosa and held
in place to allow adhesion to occur. Step two is the
"consolidation" stage where various physicochemical
interactions occur to consolidate and strengthen the
adhesive joint, leading to prolonged adhesion (Lee J W
et al., 2000; Smart J.D, 2005).
Mucoadhesion is a complex process and numerous
theories have been presented to explain the mechanisms involved. These theories include mechanicalinterlocking, electrostatic, diffusion-interpenetration,
adsorption and fracture processes, whilst undoubtedly
the most widely accepted theories are founded upon
surface energy thermodynamics and interpenetration/diffusion. The wettability theory is mainly applicable to liquid or low viscosity mucoadhesive systems
and is essentially a measure of the spreadability of the
drug delivery system across the biological substrate.
The electronic theory describes adhesion occurs by
means of electron transfer between the mucus and the
mucoadhesive system arising through differences in
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
their electronic structures. The electron transfer between the mucus and the mucoadhesive results in the
formation of a double layer of electrical charges at the
mucus and mucoadhesive interface. The net result of
such a process is the formation of attractive forces
within this double layer. According to fracture theory,
the adhesive bond between systems is related to the
force required to separate both surfaces from one
another. This "fracture theory" relates the force for
polymer detachment from the mucus to the strength
of their adhesive bond. The work of fracture has been
found to be greater when the polymer network strands
are longer or if the degree of cross-linking within such
as system is reduced (Andrews G.P et al., 2009; Madsen F et al., 1998). According to adhesion theory, adhesion is defined as being the result of various surface
interactions (primary and secondary bonding) between
the adhesive polymer and mucus substrate. Primary
bonds due to chemisorption result in adhesion due to
ionic, covalent and metallic bonding, which is generally
undesirable due to their permanency. The diffusioninterlocking theory proposes the time-dependent diffusion of mucoadhesive polymer chains into the glycoprotein chain network of the mucus layer. This is a twoway diffusion process with penetration rate being dependent upon the diffusion coefficients of both interacting polymers (Ugwoke M.I et al., 2005; Dodou D et
al., 2005; Ahagon A et al., 1975).
Components of drug permeation
In order for a drug to be absorbed across mucosal epithelia it must first diffuse across a layer of mucus, and
any associated unstirred water layer. A number of
drugs, such as testosterone and the tetracycline antibiotics have been shown to be highly bound to mucus
and to exhibit significantly increased diffusion coefficients and lag times in mucus compared to those which
are not bound. It is not known how many drugs are
similarly affected, although determining the potential
role of mucus in limiting absorption is likely to become
of increasing importance as the requirement to deliver
therapeutics peptides and proteins via mucosal surfaces becomes of greater significance. Selected components of the absorption process are being investigated
in isolation to determine the role of mucus. Diffusion
of model compounds through native and partially purified mucus collected from different regions are being
examined in vitro in the presence and absence of compounds known to reduce or promote structure in the
mucus gel. The epithelium of the small intestine regulates some very diverse absorptive and secretory
processes. Many of the secretions delivered into the
intestinal lumen are synthesized and assembled within
the intestinal epithelial cells. These secretions include
mucus, which is provided by the goblet cells. In order
for a drug (or nutrient) molecule to be absorbed it
must diffuse across this layer. Factors that affect the
turnover of mucus within the gastrointestinal tract and
other mucosal surfaces have not been extensively investigated, although it has recently been shown that
amino acids exert differential activity in promoting
mucus output. The physiological mechanisms which
control this junction are at present unknown, although
initial studies suggest the involvement of chloride
channels. It is the purpose of work in this area to establish whether amino acids promote mucus secretion at a
number of different mucosal epithelia and to examine
the effects on mucus output of putative antagonists to
amino acids. Implications of these findings for drug
delivery will be determined (Sze P. W. C. and Lee S. Y,
1995; Hassan EE and Gallo JM, 1990). Some permeation enhancers and their mechanisms which are commonly using in the buccal drug delivery system given in
Table 1
Formulation design for buccal delivery
For mucosal and transmucosal administration, conventional dosage forms are not able to assure therapeutic
Table 1: Penetration enhancers and their mechanism of action (Chinna Reddy P et al., 2011)
Category
Surfactants
Bile salts
Fatty acids
Cyclodextrins
Chelators
Positively charged
Polymers
Cationic
Compounds
Examples
Anionic: Sodium lauryl sulfate
Cationic: Cetyl pyridinium chloride
Nonionic: Poloxamer, Brij, Span, Myrj, Tween
Sodium glycol deoxycholate,
Sodium glycocholate, Sodium tauro deoxycholate, Sodium tauro cholate
Oleic acid, Caprylic acid, Lauric acid, Lyso phosphatidyl choline, Phosphatidyl choline
α, β, γ, Cyclodextrin, methylated β –cyclodextrins
EDTA, Citric acid, Sodium salicylate, Methoxy
salicylates
Chitosan, Trimethyl chitosan
Poly-L-arginine, L-lysine
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
Mechanism of action
Perturbation of intercellular
Lipids and protein domain integrity
Perturbation of intercellular
Lipids and protein domain integrity
Increase fluidity of phospholipid
domains
Inclusion of membrane
Compounds
Interfere with Ca+
Ionic interaction with negative
charge on the mucosal surface
Ionic interaction with negative
charge on the mucosal surface
145
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
drug levels in the mucosa and circulation because of
the physiological removal of the oral cavity (washing
effect of saliva and mechanical stress), which take the
formulation away from the mucosa, resulting in a very
short exposure time and unpredictable distribution of
the drug on the site of action/absorption. To obtain the
therapeutic action, it is therefore necessary to prolong
and improve the contact between the active substance
and the mucosa. To fulfill the therapeutic requirements, formulations for buccal administration should
contain: mucoadhesive agents, to maintain an intimate
and prolonged contact of the formulation with the absorption site; penetration enhancers, to improve drug
permeation across mucosa (transmucosal delivery) or
into deepest layers of the epithelium (mucosal delivery), enzyme inhibitors, to protect the drug from the
degradation by means of mucosal enzymes and solubility modifiers to enhance solubility of poorly soluble
drugs (Clark MA et al., 2000; Miller N. S et al., 2005).
General considerations in dosage form design:
Physiological aspects
Constant flow of saliva and mobility of the involved
tissues challenge drug delivery to the oral cavity. The
residence time of drugs delivered to the oral cavity is
typically short; in the range of <5–10 min. Buccal mucoadhesive formulations are expected to overcome
this problem. Bioadhesive polymers offer a means by
which a delivery system is attached to the buccal mucosa, and hence, provide substantially longer retention
times at the absorption site. They also provide a means
to confine and maintain high local concentrations of
the drug and/or excipient(s) to a defined, relatively
small region of the mucosa in order to minimize loss to
other regions and limit potential side effects.
The buccal mucosa is a very suitable region for bioadhesive system application because of its smooth and
relatively immobile surface, as well as direct accessibility. However, there are some inherent limitations associated with buccal drug delivery, including short residence time, small absorption area, and barrier properties of the buccal mucosa. The size of a buccal dosage
form is restricted by the very limited area available for
application of the delivery system. This size restriction,
in turn, limits the amount of drug that can be incorporated in the dosage forms. In general, a buccal delivery
device that is 1–3 cm in size and a drug with a daily
dose requirement of 25 mg or less would be preferred.
In addition, an ellipsoid shape appears to be most acceptable, and the thickness of buccal delivery devices is
usually limited to a few millimeters (Rathbone M. J et
al., 1994; Anders R et al., 1989).
Pathological aspects
Many diseases can affect the thickness of the epithelium, resulting in alteration of the barrier property of
the mucosa. Some diseases or treatments may also
influence the secretion and properties of the mucus, as
146
well as the saliva. Changes at the mucosal surface due
to these pathological conditions may complicate the
application and retention of a bioadhesive delivery
device. Therefore, understanding the nature of the
mucosa under relevant disease conditions is necessary
for designing an effective buccal delivery system. In
addition, drugs with the potential of changing the physiological conditions of the oral cavity may not be suitable for buccal delivery (Khanvilkar K et al., 2001).
Pharmacological aspects
A buccal dosage form may be designed to deliver a
drug to the systemic circulation, or merely indicated
for local therapy of the oral mucosa. Selection of dosage forms is affected by the intended application, target site of action, drug characteristics, and the site to
be treated (periodontal pockets, gingival, teeth, buccal
mucosa, or systemic) (Ch’ng H. S et al., 1985).
Pharmaceutical aspects
Regardless of dosage form types, the drug must be
released from the delivery system and subsequently
taken up by the oral mucosa. Poor drug solubility in
saliva could significantly retard drug release from the
dosage form. Cyclodextrin has been used to solubilize
and increase the absorption of poorly water-soluble
drugs delivered via the buccal mucosa. Other factors
affecting both drug release and penetration through
buccal mucosa must also be considered in the formulation design. In addition to the physicochemical characteristics required for desirable drug release and absorption, organoleptic properties of the drug or the
delivery device should also be considered, since the
buccal delivery systems are to be exposed to a highly
developed sensory organ (Park H et al., 1985; Andrews
G.P et al., 2009). Some commercially available bioadhesive buccal formulations are listed in Table 2
Table 2: Dosage forms developed for the buccal
mucosal drug delivery systems
Dosage forms developed
Solutions, Tablets, Lyophilized tablets, Chewing gum, Bioadhesive
tablets, Solutions spray, Laminated systems and patches, Hydrogels, Adhesive films,
Hollow fibres, Microspheres, Liposomes
Commercially available
bioadhesive buccal delivery systems
Bioadhesive tablets
Sublingual mucosal delivery of nitroglycerine: Susadrin®
Buccal mucosal delivery of
Prochloroperazine: Buccastem® Chewing gum
Bucccal mucosal delivery of
nicotine: Nicorette ®
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
Recent developments in buccal drug delivery systems
Since few decades lot of developments were taken
place in the pharmaceutical field towards delivery of
drugs. In this developments buccal drug delivery also
made a significant mark, here listed some of the advances which recently focused by researchers. Commercial formulations or under clinical trials formulation
intended for buccal delivery are represented in Table 3
Micro/nano-particulates
These are typically delivered as an aqueous suspension
but can also be applied by aerosol or incorporated into
a paste or ointment. Particulates have the advantage
of being relatively small and, therefore, more likely to
be acceptable to the patient. However, the dose of
drug retained on the buccal mucosa and, therefore,
delivered may not be consistent relative to a singleunit dosage form such as a patch or buccal tablet. Polymeric microparticles (23-38 μm) of Carbopol®, polycarbophil, chitosan or Gantrez® were found to be capable of adhering to porcine oesophageal mucosa, with
particles prepared from the polyacrylic acids exhibiting
greater mucoadhesive strength during tensile testing
studies whereas, in "elution" studies, particles of chitosan or Gantrez were seen to persist on mucosal tissue
for longer periods of time (Kockisch S et al., 2003;
Kockisch S et al., 2004).
Holpuch and co-workers (Holpuch A.S et al., 2010) explored the use of nanoparticles for local delivery to the
oral mucosa. Two types of nanoparticles were studied
in a proof of concept study which were solid lipid nanoparticles incorporating either idarubicin or BODIPY®
FL C12 as model fluorescent probes and polystyrene
nanoparticles (FluoSpheres®) in monolayer-cultured
human oral squamous cell carcinoma (OSCC) cell lines
and normal human oral mucosal explants. The results
demonstrated that OSCC cells internalized solid lipid
nanoparticles. The observed penetration of nanoparticles through the epithelium and basement membrane
into the underlying connective tissue suggested the
possibility of oral transmucosal nanoparticle delivery
for systemic therapy.
Monti and co-workers (Monti D et al., 2010) produced
an atenolol containing microsphere using Poloxamer
407 and evaluated the formulation in vivo in rabbits
against marketed tablet formulation as a reference.
After administration of the microsphere formulations,
the atenolol concentration remained higher than the
reference tablet during the entire elimination phase
showing a sustained release profile from the microspheres; the concentrations at 24 h were 0.75 ± 0.1 μg
/ml vs 0.2 ± 0.1 μg /ml for the microspheres and marketed tablet, respectively. Moreover, the absolute bioavailability of microsphere formulations was higher
than that of reference tablets in spite of a lower drug
dose in the former, suggesting a possible dose reduction by atenolol microparticles via orotransmucosal
administration (Laitinen R et al., 2009; Turunen E et al.,
2010).
Delivery of proteins and peptides
The buccal mucosa represents a potentially important
site for controlled delivery of macromolecular therapeutic agents, such as peptides and proteins. With the
right dosage form design and formulation, the permeability and the local environment of the mucosa can
be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery
of potent peptide and protein drug molecules. A variety of proteins/peptides with or without penetration
enhancer were studied by different scientists using
different animal models like dogs, rabbits, rats, pigs
and humans. Some of those examples are given in Table 4.
Alginate Raft System
The effects of alginate molecular structure and formulation variables on the physical characteristics of alginate raft systems.
Bacterial Cellulose
The effects of pH, salt, heating and freezing on the
physical properties of bacterial cellulose.
Bioadhesive Films
Mechanical characterization of Tetracaine containing
bioadhesive films for percutaneous local anesthesia.
Biogels
Characterization of binary drug delivery platforms.
Blood Plasma Gels
Functional properties of heat induced gels form liquid
and spray dried porcine blood plasma as influenced by
pH.
Bones
Increase in bone calcification in young rats fed bread
highly fortified with calcium. Stylianopoulous, Effects
of fortification and enrichment of maize tortillas on
growth and brain development of rat throughout two
generations.
Bones Substitute
A new inject able bone substitute combining poly (Ecaprolactone) microparticles with biphasic calcium
phosphate granules. Injectable bone substitute using a
hydrophilic polymer.
Carbopol Organogels
Controlled release of Tetracycline from Carbopol organogels.
Cellulose Films
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
147
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
Table 3: Commercial formulations or under clinical trials formulation intended for buccal delivery (Chinna
Reddy P et al., 2011; Alagusundaram M et al., 2011)
Manufacturer
Wyeth Pharma
Ceuticals
Product
Insulin Buccal Spray
ORALGEN (US)
ORALIN (Canada)
Heparin Buccal Delivery System
Fentanyl Buccal Delivery Systems
Testosterone Buccal Tablet (Straint)
Desmopressin Buccal Tablet
Androdiol Buccal Tablets (Cyclo-Diol SR)
Norandrodiol Buccal Tablets (Cyclo-Nordiol SR)
Pilocarpine Buccal Tablet (PIOLOBUC)
Prochlorperazine Buccal Tablet (Buccastem)
Glyceryl Trinitrate (Suscard Buccal Tablet)
Oral Transmucosal Fentanyl Citrate Solid Dosage
Form (ACTIQ)
Lorazepam Buccal Tablets (Temesta Expidet)
Oxazepam Buccal Tablets (Seresta Expidet)
IVAX Corporation
Estrogen Buccal Tablet
Regency Medical research
Vitamins Trans Buccal Spray
Nicotine Mucoadhesive Tablet (Nicorette)
Nicotine Chewing Gum (Nicotinell)
Triamcinolone acetonide(Aftach)
Prochlorperazine Bioadhesive Buccal Tablet (Tementil)
Prochlorperazine Bioadhesive
Buccal controlled release Tablet (Buccastem)
Buprenorphine HCl Tablets (Subutex)
Generex Biotechnology Corporation
Columbia Laboratories Inc.
Ergo Pharm
Cytokine Pharma Sciences Inc.
Britannia Pharmaceuticals Ltd
Pharmax Limited
Cephalon, Inc.
Leo Pharmaceuticals
Teijin Ltd.
Rhone-Poulenc Rorer
Reckitt Benckiser
Reckitt Benckiser
Present status
Commercially available
Clinical Trials Completed
Clinical Trials Completed
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Under Phase III clinical
trials
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Commercially available
Table 4: Few Buccal adhesive formulations of proteins/ peptides
Protein/peptide drug
Buserelin
Calcitonin
Glucose like peptide
Gonadotropin
Oxytoxin
Protrelin (TRH)
Dosage form
Patch
Tablet
Tablet
Tablet
Patch
Patch
Enhancer
SGDC
No enhancer
STC
SC, SDC
No enhancer
Citric acid, Sodium 5Methoxy salicylate
Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl cellulose as coating material for diffusion pellets.
Properties of sprayed films.
Poly saccharides gels
As a result of huge interest in the research of bucal
drug delivery, currently some formulation developments are seen, such as lipophilic gel, buccal spray and
phospholipid vesicles have been recently proposed to
deliver peptides via the buccal route. In particular,
some authors proposed the use of cubic and lamellar
liquid crystalline phases of glyceryl monooleate as buccal drug carrier for peptide drugs. A novel liquid aerosol formulation (Oralin, Generex Biotechnology) has
148
Animal model
Pig, rat
Rabbits
Human
Dog
Rabbit
Human
Rats
% increase in bioavailability
12.7%
37%
4 – 23%
-Slight increase
Increase in plasma
thyrotropin concentration
been developed recently. Phospholipid deformable
vesicles, transfersomes, have been recently devised for
the delivery of insulin in the buccal cavity.
Research carried out so far
A review of literature survey has been carried out
through various Indian and international journals that
are view the Formulation design for buccal delivery,
recent developments in buccal drug delivery and related aspects. Some of the important works are revealed here, over the last few decades pharmaceutical
scientists throughout the world are trying to explore
buccoadhesive and buccal drug delivery as an alternative to injections. Among the various transmucosal
sites available, mucosa of the buccal cavity was found
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
to be the most convenient and easily accessible site for
the delivery of therapeutic agents for both local and
systemic delivery as retentive dosage forms
Bottenburg et al., developed a bioadhesive fluoride
containing slow release tablet from modified starch,
polyacrylic acid, polyethylene glycol and sodium carboxymethyl cellulose (Na CMC). The fluoride release
from the tablet was evaluated in healthy human volunteers and found that fluoride levels sustained significantly longer than those obtained with the administration of toothpaste having four times the fluoride content (Bottenberg P et al., 1991).
Anders and Merkle, developed and evaluated laminated mucoadhesive patches of protirelin for buccal
drug delivery. The patches consisted of laminates of an
impermeable backing layer and a hydrocolloid polymer
layer containing the drug. The duration of mucosal
adhesion in vivo was found to be dependent on the
type of polymer used, its viscosity grade, the polymer
load per patch and drying procedure for the preparation (Anders R et al., 1989).
Ali et al., prepared buccoadhesive films of triamcinolone acetonide, for the treatment of oral lesions using
propylene glycol as plasticizer & different bioadhesive
polymers. The films were evaluated on the basis of
their physical characteristics, bioadhesive performance, release characteristic, surface pH, folding endurance and stretchability. The optimized film exhibited an in vitro adhesion time of 3.24 h and drug release of 89.98% in 3.5 h (Ali J et al., 1998).
Nakhat P D et al., has developed buccoadhesive bilayered tablets of terbutaline sulphate. They reported
that the carbopol 934P alone has maximum strength of
bioadhesion and it get decrease with the decrease in
carbopol content. Results demonstrated that effective
design and stability of buccoadhesive tablets was been
made possible with carbopol 934P and methocel K4M
in ratio of 1:1 (Nakhat P D et al., 2007).
Han-Gon Choi et al., has formulated buccoadhesive
tablets of omeprazole using bioadhesive polymers and
alkali materials. Magnesium oxide is acts as a stabilizer
among different ones because of its strong water
proofing effect in omeprazole buccal adhesive tablets.
Two tablets composed as tablets containing Omeprazole which are attached to the cheeks of human and
using human saliva they are stabilized for 4 h period
(Han-Gon C et al., 2000).
M Alagusundaram, et al., has formulated novel transbuccoadhesive bilayer tablets of Famotidine an H2receptor antagonist used as an antiulcerative agent.
The buccoadhesive tablets were prepared by direct
compression method using bioadhesive polymers like
sodium alginate, SCMC, HPMC-K100M, PVP-K30 either
alone or in combinations with EC as a backing layer.
The prepared formulations were evaluated for their
physicochemical characteristics (Alagusundaram M et
al., 2011).
Bhupinder Singh et al., Atenolol mucoadhesive tablets
are formulated by method using direct compression
and characterized for strength of bioadhesion and release parameters. A non-fickian kinetic release is exhibited following zero order with that of compressed
matrices. An excellent control release and strength of
bio adhesion were made possible with this study (Bhupinder S et al., 2006).
Rajeshwar Kamal Kant Arya et al., their work involving
mainly on preparation and characterization on mucoadhesive microspheres using Famotidine as drug for
gastric residence time. Polymers SCMC for mucoadhesion are used in case of microspheres with a release
controlling polymer sodium alginate. The shape and
surface morphology of prepared microspheres were
characterized by optical and scanning electron microscopy, respectively. In-vitro drug release studies were
performed and drug release evaluated (Rajeshwar K K
et al., 2010).
Future Trends
The future challenge in the development of buccoadhesive dosage forms is to modify the permeability barrier of the mucosa using safe and effective penetration
enhancers (Gupta S.K et al., 2011). Mucoadhesive drug
delivery systems available in the market include attach
tablet (Triamcinolone acetonide), suradrin tablet (Nitroglycerin), Buccostem tablet (prochlormperazine
maleate). Salcoat powder sprays (Beclomethazone
dipropionate. Rhinocort powder spray (Beclomethazone Dipropionate) and sucralfate (Aluminum hydroxide). Though there are only a few mucoadhesive formulations available currently, it can be concluded that
drug delivery using mucoadhesive formulations offers a
great potential both for systemic and local use in the
near future (Gupta A et al., 1992).
Various strategies are being employed to achieve oral
absorption of peptides. These strategies include manipulation of the formulation (e.g. inclusion of penetration enhancers or protease inhibitors etc.), maximizing
retention of the delivery system at the site of absorption, and alteration of the peptide so as to optimize
affinity for endogenous transport systems, build in
chemical and metabolic stability, minimize the size and
optimize the balance between lipophilicity and hydrogen bonding potential (Smart JD, 1991).
Conclusion
Due to the ease of access and avoidance of the hepatic
metabolism, oral transmucosal drug delivery offers a
promising alternative to overcome the limitations of
conventional oral drug delivery and parental administration. The buccal route in particular, present favourable opportunities and many formulation approaches
have been explored for such an application; although
the current commercially available formulations are
©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences
149
Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151
mostly limited to tablets and films. Oral mucoadhesive
dosage forms will continue be an exciting research focus for improving drug absorption especially for the
new generation of the so called "biologics", although,
the palatability and irritancy and formulation retention
at the site of application need to be considered in the
design of such medicines
Chinna Reddy P, Chaitanya K.S.C., Madhusudan Rao Y.
A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation
methods. 2011; 19: 385-403.
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