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www.wjpps.com Vol 4, Issue 07, 2015. 475

Kaundalet al . World Journal of Pharmacy and Pharmaceutical Sciences

A REVIEW ON MUCOADHESIVE BUCCAL TABLETS PREPARED

USING NATURAL AND SYNTHETIC POLYMERS

Ankaj Kaundal*, Pravin Kumar and Archana Chaudhary

Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog (H.P)-177101.

ABSTRACT

Nature has provided us a wide variety of materials to help improve and

sustain the health of all living things either directly or indirectly. In

recent years there has been an important development in different

dosage forms for existing and newly designed drugs and natural

products, and semi-synthetic as well as synthetic excipients often need

to be used for a variety of purposes. Gums and mucilages are widely

used natural materials for conventional and novel dosage forms. With

the increasing interest in polymers of natural origin, the pharmaceutical

world has compliance to use most of them in their formulations.

Buccal mucosa is the preferred site for both systemic and local drug

action. The mucosa has a rich blood supply and it relatively permeable.

Buccal transmucosal delivery helps to bypass first- pass metabolism by allowing direct access

to the systemic circulation through the internal jugular vein. This article briefly describes

isolation of mucilage, the basis, requirements, the standards of an ideal mucoadhesive buccal

drug delivery advantages, limitations, mechanism of mucoadhesion, structure of buccal

mucosa, theories of mucoadhesion, investigated buccal tablets containing natural polymer,

evaluation parameters, commercially available buccal adhesive tablets etc.

KEYWORDS:Natural polymers,Mucoadhesion, Theories, Factors affecting mucoadhesion,

Oral mucosa, evaluation, mucoadhesive tablets, buccal drug delivery.

INTRODUCTION

A large number of plant-based pharmaceutical excipients are available today. Many

researchers have explored the usefulness of plant-based materials as pharmaceutical

excipients. The reason for increase in importance of natural plant based material is that plant

resources are renewable and if cultivated or harvested in a sustainable manner can provide a

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Article Received on

11 May 2015,

Revised on 02 June 2015,

Accepted on 23 June 2015

*Correspondence for

Author

Ankaj Kaundal

Department of

Pharmaceutics, Laureate

Institute of Pharmacy,

Kathog (H.P)-177101.

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constant supply of raw materials. However, substances from plant origin also pose several

potential challenges such as being synthesized in small quantities and present in mixtures that

are structurally complex, which may differ according to the location of the plants as well as

other variables such as the season. This may result in a slow and expensive isolation and

purification process (Avachat et. al, 2010; Punitha and Girish, 2010).

Natural polysaccharides such as gums and mucilages abundantly found in many higher plants

have been extensively used for the development of dosage forms (Kumar et. al, 2012;

Narkhede et. al, 2010). Mucilages are naturally occurring, high-molecular-weight

(approximately 200,000), polyuronides consisting of sugar and uronic acid units. These are

esters of sulphuric acid, wherein ester group is a polysaccharide complex. Chemically,

mucilages resemble gums and pectins but differ in their physical properties. Gums swell in

water to form sticky, colloidal dispersions and pectins gelatinize in water, while mucilages

form slippery, aqueous colloidal dispersions (Sangwan et. al, 2011; Malviya et. al, 2011;

Shanmugam et. al, 2005; Shirke and Shirsath, 2012).

Bioadhesion may be defined as the state in which two materials, at least one of which is of

biological nature, are held together for extended periods of time by the interfacial forces. For

drug delivery system, the term bioadhesion implies attachment of a drug carrier system to a

specific biological location. If the biological source is epithelial tissue or the mucous coat, the

phenomenon is referred to as mucoadhesion (Joshi et. al, 2012; Gremiao et. al, 2010; Tangri

and Madhav, 2011). Mucoadhesion is believed to occur in three stages: wetting,

interpenetration and mechanical interlocking between mucin and polymer (Roychowdhary et.

al, 2011).

Buccal drug delivery was introduced by Orabase in 1947, when gum tragacanth was mixed

with dental adhesive powder to supply penicillin to the oral mucosa (Sudhakar et al., 2006).

Buccal route of drug delivery is a good alternative, amongst the various routes of drug

delivery. Oral route is perhaps the most preferred for the patients. Within the oral mucosal

cavity, the buccal region offers an attractive route of administration for systemic drug

delivery. However, oral administration of drugs has disadvantages such as hepatic first pass

metabolism and enzymatic degradation within the GI tract, that prohibit oral administration

of certain classes of drugs especially peptides and proteins. Buccal routes of drug delivery

offer distinct advantages over oral administration for systemic drug delivery. These

advantages include possible bypass of first pass effect, avoidance of pre-systemic elimination

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within the GI tract, these factors make the oral mucosal cavity a very attractive and feasible

site for systemic drug delivery. Considering the low patient compliance of rectal, vaginal,

sublingual and nasal drug delivery for controlled release, the buccal mucosa has rich blood

supply and it is relatively permeable. The buccal mucosa lines the inner cheek and buccal

formulations are placed in the mouth between the upper gingival (gums) and cheek to treat

local and systemic conditions.

Isolation of Mucilage

The mucilage was isolated from the branches and stem by washing properly with distilled

water to remove any dust and adhered particles. After that bark of stem and branches was

peeled off and was cut into small pieces. These pieces were soaked in distilled water for 24 h.

After 24 h, material was squeezed through 8 fold muslin cloth to separate the marc from

filtrate. Then acetone was added to the filtrate in a ratio (1:2) to precipitate the mucilage. The

precipitated mucilage was separated by decantation and washed several times with acetone.

The mucilage was dried in hot air oven at 40C and powdered. The powdered mucilage was

passed through British standard sieve (BSS) 80 (mesh size) and kept in a desiccator for the

further studies (Kumar and Kulkarni 2012).

Structure and function of oral mucosal membrane: The outermost layer of oral mucosa is

stratified squamous epithelium and below it, there is a basement membrane called lamina

propria which is followed by the sabmucosa. It also contains many sensory receptors

including the taste receptors of the tongue.. Lamina propria, consist of collagen fibers a

supporting layer of connective tissues, blood vessel and smooth muscles. The epithelium may

consist of a single layer (stomach, small and large intestine, bronchi) or multiple layers

(esophagus, vagina). The upper layer contains goblet cells, which secrete mucus components

directly onto the epithelial surface. Tissue have moist surface due to mucus which is a,

viscous, gelatinous secretion and this mucus composed of glycoproteins, lipids, inorganic

salts, and up to 95% water. Mucin (Glycoproteins) are the most important components of

mucus and it is also responsible for gelatinous structure, cohesion, and antiadhesive

properties. Mucin consist of three dimensional network with large number of loops. The main

functions of the mucus are to protect and lubricate the supporting epithelial layer.

Permeability: The permeability of the buccal mucosa is estimated to be 4-4000 times greater

than the skin. In general, the permeabilities of the oral mucosa decrease in the order of

sublingual greater than buccal, and buccal greater than palatal. This rank order is based on the

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relative thickness and degree of keratinization of these tissues, with the sublingual mucosa

being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the

palatal intermediate in thickness but keratinized. The permeability barrier property of the oral

mucosa is predominantly due to intracellular materials derived from the so called

membrane coating granules(MCGS). Recent evidence has shown that passive diffusion is

the primary mechanism for the transport of drugs across the buccal mucosa while carrier

mediated transport has been reported to have a small role. In buccal mucosa two routes of

passive transport are found one involves the transport of compounds through the intercellular

space between the cells (paracellular) and other involves passage into and across the cells

(transcellular). Another barrier to drug permeability across buccal epithelium is enzymatic

degradation.

Role of Saliva

a. Protective fluid for all tissues of the oral cavity.

b. Continuous mineralization / demineralization of the tooth enamel.

c.

To hydrate oral mucosal dosage forms.

Role of Mucus

a. Made up of proteins and carbohydrates.

b. Cell-cell adhesion

c. Lubrication

d.

Bioadhesion of mucoadhesive drug delivery systems

Buccal Drug Delivery and Mucoadhesive property

For the development of Buccal drug delivery systems, mucoadhesion of the device is the

important criteria. For proper and good mucoadhesion, mucoadhesive polymer have been

utilized in many different dosages form such as tablets, patches, tapes, films, semisolids and

powders. Many studies showed that addition of various polymers to drug delivery systems

such as gums, increased the duration of attachment of the formulations to the mucous surface

and also increased the efficacy. The polymers should possess following general

physiochemical features so as to serve as mucoadhesive polymers

Predominantly anionic hydrophilicity with numerous hydrogen bond-forming groups.

Polymer and its degradation products should be non-toxic, non-irritant and free from

leachable impurities.

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Should have good spreadability, wetting, swelling and solubility and biodegradability

properties.

pH should be biocompatible and should possess good viscoelastic properties.

Should possess peel, tensile and shear strengths at the bioadhesive range. (Roychowdharyet. al, 2011).

Oral mucosal sites

Within the oral mucosal cavity, delivery of drugs is classified into three categories,

1) Sublingual delivery: is the administration of the drug via the sublingual mucosa (the

membrane of the ventral surface of the tongue and the floor of the mouth) to the systemic

circulation.

2) Buccal delivery: is the administration of drug via the buccal mucosa (the lining of the

cheek) to the systemic circulation.

3)Local delivery: for the treatment of conditions of the oral cavity, principally ulcers, fungal

conditions and periodontal disease. These oral mucosal sites differ greatly from one another

in terms of anatomy, permeability to an applied drug and their ability to retain a delivery

system for a desired length of time.

Mechanism of mucoadhesionMucoadhesion has the following mechanism,

a. intimate contact between a bioadhesive and a membrane (wetting or swelling

phenomenon)

b. penetration of the bioadhesive into the tissue or into the surface of the mucous membrane

i.e. interpenetration.

Mucoadhesion Theories

Although the chemical and physical basis of mucoadhesion are not yet well understood, there

are six classical theories adapted from studies on the performance of several materials and

polymer-polymer adhesion which explain the phenomenon.

Electronic theory

Electronic theory is based on the premise that both mucoadhesive and biological materials

possess opposing electrical charges. Thus, when both materials come into contact, they

transfer electrons leading to the building of a double electronic layer at the interface, wherethe attractive forces within this electronic double layer determines the mucoadhesive strength.

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Adsorption theory

According to the adsorption theory, the mucoadhesive device adheres to the mucus by

secondary chemical interactions, such as in van der Waals and hydrogen bonds, electrostatic

attraction or hydrophobic interactions. For example, hydrogen bonds are the prevalent

interfacial for

Absorption theory

According to this theory, after an initial contact between two surfaces, the material adheres

because of surface force acting between the atoms in two surfaces. Two types of chemical

bonds resulting from these forces can be distinguished as primary chemical bonds of covalent

nature and Secondary chemical bonds having many different forces of attraction, including

electrostatic forces, Vander Walls forces, hydrogen and hydrophobic bonds.

Diffusion theory

According to this theory, the polymer chains and the mucus mix to a sufficient depth to create

a semi permanent adhesive bond. The exact depth to which the polymer chain penetrates the

mucus depends on the diffusion coefficient and the time of contact. The diffusion coefficient

in terms depends on the value of molecular weight between cross linking and decreases

significantly as the cross linking density increases.

Wetting theory

The wetting theory postulates that if the contact angle of liquids on the substrate surface is

lower, then there is a greater affinity for the liquid to the substrate surface. If two substrate

surfaces are brought in contact with each other in the presence of the liquid, the liquid may

act as an adhesive among the substrate surface.

Cohesive theoryThe cohesive theory proposes that the phenomena of bioadhesion are mainly due to

intermolecular interaction amongst like molecule. Based upon the above theories, the process

of bioadhesion can broadly be classified into two categories namely chemical (electron and

absorption theory) and physical (wetting, diffusion and cohesive theory).

Factors affecting mucoadhesion

The mucoadhesion of a drug carrier system to the mucous membrane depends on the

following mentioned factors.

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Polymer based factors

a. Molecular weight of the polymer

As compared to ions, the molecules penetrate rapidly, through oral mucosa. The molecular

weight and size is important in the penetration through the oral mucosa, especially in case of

hydrophilic molecule having a molecular weight of below 100 Dalton can cross the oral

mucosa very rapidly. As the molecular weight increases, thepenetration reduces. (Shijith et.

al, 2013; Hussain et. al, 2013)

b. Concentration of polymer used

An optimum concentration of a mucoadhesive polymer is required to produce maximum

bioadhesion. It is found that, in highly concentrated system, adhesive strength drops

significantly beyond the optimum level because the coiled molecules become separated from

the medium so that the chains available for interpenetration become limited.

c. Flexibility of polymer chains

It is critical for interpenetration and entanglement. Due to the cross-linking of water-soluble

polymers, the mobility of character polymer chains decrease and thus the valuable length of

the chain that can penetrate into the mucus layer also decreases, which results in the reduced

bioadhesive strength.

d. Swelling factor

Swelling characteristics are related to the mucoadhesive polymer and its environment.

Swelling depends on polymer concentration, ionic strength, and presence of water.

e. Stereochemistry of polymer

Spatial conformation of a molecule is also important factor which can affect the

mucoadhesion. The helical conformation of dextran may shield many adhesively activegroups, primarily responsible for adhesion, unlike PEG polymers, which have a linear

conformation.

Physical factors

a. pH of polymer-Substrate interface

pH can influence the formal charge on the surface of the mucus as well as certain ionizable

mucoadhesive polymers. Mucus have a different charge density depending on pH due to the

difference in dissociation of functional groups on the carbohydrate moiety and the amino

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acids of the polypeptide backbone. Some studies had shown that the pH of the medium is

important for the degree of hydration of cross-linked polyacrylic acid polymers, showing

consistently increased hydration from pH 4 through pH 7, and then a decrease at alkaline pH

levels.

b. Applied strength

To place a solid mucoadhesive system, it is necessary to apply a defined strength. Depending

on the type of polymer, the adhesion strength increases with the applied strength or with the

duration of its application, up to an optimum level. The initial pressure applied to the

mucoadhesive tissue at the contact site, can affect the depth of interpenetration. If high

pressure is applied for a sufficiently long period of time, polymers become mucoadhesive

even though they do not have attractiveinteractions with mucin.

c. Contact time

Contact time between the mucoadhesive and mucus layer determines the extent of swelling

and interpenetration of the mucoadhesive polymer chains. More mucoadhesive strength

increases as the initial contact time increases.

Physiological factors

a.

Mucin turnover rate

The natural turnover of mucin molecules from the mucus layer is important for at least two

reasons. Firstly, the mucin turnover is expected to limit the residence time of the

mucoadhesives on the mucus layer. No matter how high the mucoadhesive strength, they are

detached from the surface due to mucin turnover. Secondly, mucin turnover results in

substantial amounts of soluble mucin molecules. These molecules interact with

mucoadhesives before they have chance to interact with the mucus layer. Surface fouling is

unfavorable for mucoadhesion to the tissue surface. Mucin turnover may depend on the other

factors such as the presence of food. The gastric mucosa accumulates secreted mucin on the

luminal surface of the tissue during the early stages of fasting. The accumulated mucin is

subsequently released by freshly secreted acid or simply by the passage of ingested food; the

exact turnover rate of the mucus layer remains to be determined.

b. Diseased state

The physiochemical properties of the mucus are known to change during disease conditions

such as the common cold, gastric ulcers, ulcerative colitis, cystic fibrosis, bacterial, and

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fungal infections of female reproductive tract, and inflammatory conditions of the eye. The

exact structural changes taking place in mucus under these conditions are not clearly

understood. If mucoadhesive polymers are to be used in the disease states, the mucoadhesive

property needs to be evaluated under the same conditions. (Patel et. al, 2011; Sharma et. al,

2012; Shijith et. al, 2013)

Limitations of Buccal Drug Delivery System

a. Drugs which irritate oral mucosa or have bitter taste, or cause allergic reactions,

discoloration of teeth cannot be formulated.

b. If formulation contains antimicrobial agents, affects the natural microbes in the buccal

cavity.

c.

The patient cannot eat/drink/speak.

d. Only those drugs which are absorbed by passive diffusion can be administered by this

route.

e. Drugs which are unstable at buccal pH cannot be administered by this route.

f.

Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug

g. Low permeability of the buccal membrane, specifically when compared to the sublingual

membrane. (Gandhi et. al, 2011)

Formulation of Buccal Drug Delivery System

Formulation design

a. General criteria for selection of drug candidate

Buccal adhesive drug delivery systems with the size 13 cm2and a daily dose of 25 mg

or less are preferable. (James and Boylan 2001)

The maximal duration of buccal delivery is approximately 48 hr (Alur et. al, 1999).

Drug must undergo first pass effect or it should have local effect in oral cavity.

Drugs with biological half life 2-8 hr will in general be good candidates for sustained

release dosage forms.

Local drug irritation caused at the site of application is to be considered while selecting

the drug.

b. Pharmaceutical considerations

Great care needs to be exercised while developing a safe and effective buccal adhesive drug

delivery device. Factors influencing drug release and penetration through buccal mucosa,

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organoleptic factors, and effects of additives used to improve drug release pattern and

absorption, the effects of local drug irritation caused at the site of application are to be

considered while designing a formulation. (Metia and Bandyopadhyay 2008; Tanabe et.

al, 2008; Malik et. al, 2007)

c. Buccal adhesive polymers

Polymer is a generic term used to describe a very long molecule consisting of structural units

and repeating units connected by covalent chemical bonds. The term is derived from the

Greek words: polys meaning many, and meros meaning parts (Rathbone et al., 1996).

The key feature that distinguishes polymers from other molecules is the repetition of many

identical, similar, or complementary molecular subunits in these chains. These subunits, themonomers, are small molecules of low to moderate molecular weight, and are linked to each

other during a chemical reaction called polymerization.

Instead of being identical, similar monomers can have varying chemical substituent. The

differences between monomers can affect properties such as solubility, flexibility, and

strength. The term buccal adhesive polymer covers a large, diverse group of molecules,

including substances from natural origin to biodegradable grafted copolymers and thiolated

polymers. Bioadhesive formulations use polymers as the adhesive component. These

formulations are often water soluble and when in a dry form attract water from the biological

surface and this water transfer leads to a strong interaction. These polymers also form viscous

liquids when hydrated with water that increases their retention time over mucosal surfaces

and may lead to adhesive interactions. (Munasur et. al, 2006).Bioadhesive polymers should

possess certain physicochemical features including hydrophilicity, numerous hydrogen bond-

forming groups, flexibility for interpenetration with mucus and epithelial tissue and visco-

elastic properties (Batchelor et. al, 2004).

d. Ideal characteristics

Polymer and its degradation products should be non-toxic, non-irritant and free from

leachable impurities.

Should have good spreadability, wetting, swelling and solubility and biodegradability

properties.

pH should be biocompatible and should possess good viscoelastic properties.

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Should adhere quickly to buccal mucosa and should possess sufficient mechanical

strength.

Should possess peel, tensile and shear strengths at the bioadhesive range.

Polymer must be easily available and its cost should not be high.

Should show bioadhesive properties in both dry and liquid state.

Should demonstrate local enzyme inhibition and penetration enhancement properties.

Should demonstrate acceptable shelf life.

Should have optimum molecular weight.

Buccal mucoadhesive dosage forms may be classified into three types,

a single layer device with multidirectional drug release.

An dosage form with impermeable backing layer which is superimposed on top of an

drug loaded bioadhesive layer, creating a double layered device and preventing loss from

the top surface of the dosage form into the oral cavity.

Unidirectional release device, the drug is released only from the side adjacent to the

buccal mucosa.

Table 1: Research work on Buccoadhesive tablets

Active ingredient Polymers used Investigators [Ref.]Propranolol HCl HPMC and PC Akbari et. al, 2004

Piroxicam HPMC and CP 940 Jug et. al, 2004

Chlorpheniramine

maleatePolyoxyethylene Tiwari et. al,1999

Losartan

potassimHPMC and Sodium alginate S. Velmurugan et. al, (2013)

Nebivolol Carbapol 934P S. B. Shirsand et. al, (2013)

Curcumin Ethyl cellulose K. Gowthamarajan et.al, (2012)

Piroxicm HPMC K4M K. A. Reddy et. al, (2012)

Simvastain Sod. CMC and HPMC K4M B. A. Goud et. al, (2011)

Lisinopril Carbopol 934p and HPMC K4M G. Aditya et. al, (2010)Piroxicam HPMC K4M S. Velmurugan et. al, (2010)

Timolol maleate HPMC K4M and Carbapol 934 S. Bhanja et.al, (2010)

Glipizide HPMC K15M D. Mahalaxmi et. al, (2010)

Diltiazem HCl Carbapol-934 and HPMC R. Manivannan et. al, (2008)

Prednisolone HPMC S. M. Samani et. al, (2005)

Chlophenaramine

maleateHakea gibbosa gum H. H. Alur et. al, (1999)

Clotrimazole HPC-M R. Khanna et. al, (1996)

Tizanidine HCl Sodium alginate Patil et. al, (2011)

Fluvastatin Tamarind, xanthan gum and gellan gum Shah et. al, (2012)Salbutamol sulfate Caesalpinia pulcherrima seeds mucilage Jeevanandham et. al, (2010)

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Diltiazem Sinapis albaseeds mucilage Bandyopadhyay and Sudhakar (2008)

NitrendipineZizyphus maurtiana, Tamrarind seed, Sodium

CMC AND HPMC K15MBangale et. al, (2011)

Chlophenaramine

maleateJack fruit mucilage Patel et, al, (2012)

Domperidone Taro gum Singh et. al, (2011)Theophylline Caesalpinia pulcherrima seeds mucilage Senthil et. al, (2010)

Ciprofloxacin HCl Tamarind seed, HPMC K100 and Xanthan gum Chandramouli et. al, (2012)

Terbutaline sulphateZizyphus maurtiana, Aegle marmelos and HPMC

K4MChanda et. al, (2008)

Metoprolol tartrateSodium CMC, gum karaya, xanthan gum and

locust bean gumHirlekar et. al, (2010)

Diclofenac Aegle marmelos fruit gum Kharwade et. al, (2011)

Rosiglitazone

maleateCarbopol 934P and HPMC Bahera et. al, (2012)

RepaglinideCarbopol 934P and HPMC K4M, Sodium CMC

and HECSatyabrata et. al, (2010)

DomperidoneCarbopol 934P, methocel K4M, methocel

E15LV and chitosanGanesh et. al, (2008)

Lisinopril Carbopol 934P, HPMC and HEC Aditya et. al, (2010)

Hydrocortisone

acetateHPMC, carbopol 974P and polycarbophyl Ceshel et. al, (2001)

Atenolol HPMC, carbopol and mannitol Shirsand et. al, (2012)

Tizanidine HCl HPMC K4M and sodium CMC Shanker et. al, (2009)

Propranolol HCl Sodium CMC and carbopol 934 Patel et. al, (2007)

Ciprofloxacin HClCarbopol 934P, HPMC 15cps, methocel K4M

and sodium CMCIslam et. al, (2011)

Ketoprofen Chitosan and sodium alginate Miyazaki et. al, (1994)

NifedipineChitosan, polycarbophil, Sodium alginate,gellan

gumRemunan et. al, (1998)

Nystain Carbomer, HPMC Labot et. al, (2002)

Buprenorphine HEMA and Polymeg Cassidy et. al, (1993)

Morphine Sulphate Carbomer and HPMC Anlar et. al, (1994)

Lidocaine CP-934, HPC-H Nagai and Machida (1993)

Ergotamine Tartrate PVA Tsutsumi et. al, (2002)

Table 2: Commercially available buccal adhesive formulations

Commercial name Bioadhesive polymer Company Dosage form

Buccastem PVP, Xanthum gum, Locust bean gum Rickitt Benckiser Tablet

Suscard HPMC Forest Tablet

Gaviscon liquid Sodium alginate Rickitt Benckiser Oral liquid

Orabase Pectin, gelatin ConvaTech Oral paste

Corcodyl gel HPMC Glaxosmithkline Oromucosal gel

Corlan pellets Acacia Celltech Oromucosal pellets

Fentanyl Oralet CP 934, Sodium CMC Lexicomp Lozenge

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Miconaczole Lauriad Modified starch, CP-934 Bioalliance Tablet

EmezineTM CP 934 and PVP K-30 BDSI's Tablet

BEMA Fentanyl . BDSI's Tablet

Straint SR CP 974, HPMCK4M Ardana Tablet

Zilactin . Zila Buccal film

Luborant Sodium CMC Antigen Artificial salivaSaliveze Sodium CMC Wyvern Artificial saliva

Tibozole Polycarbophil and CP 934P Tibotec Tablet

(Asija et. al, 2014; Bobade et. al, 2013)

METHODS OF EVALUATION

Evaluation of Buccoadhesive Dosage Form

I n Vitro/ Ex vivomethods

Tensile strength Shear strength

Other methods

Adhesion weight method

Fluorescent probe method

Flow channel method

Mechanical spectroscopic method

Falling liquid film method

Colloidal gold staining method

Iscometric method

Thumb method

Adhesion number

Electrical conductance

I n vivo method

Radioisotopes

Gamma scintigraphy

Pharmaco scintigraphy

Electron paramagnetic resonance

Isolated loop technique (Bobade et. al, 2013)

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Table 3: Patent Literature Instances on Mucoadhesive Microparticle Drug Delivery

Systems (Swain et. al, 2012)

S.

No.

Types of

Formulation

Patent

Number

Title of the

Patent

Year of

Patent

Criteria of the Selection of

Patent

1.

Multiparticulate US0281007A1

Mucoadhesiveoral formulations

of high

permeability

and high

solubility drugs.

December

2007

To increase the oral

bioavalability of BCS Class-1

drugs

2.

Multiparticulate US5571533 A

Controlled release

mucoadhesive

pharmaceutical

composition

for the oraladministration

of furosemide

November

1996

To reduced or elminaes the

diuresis peak or reduces

intersubject response

variability with theconventional treatment.

3. Microspheres US6235313B1

Bioadhesive

microspheres

and their use as

drug delivery

and imaging

systems

May 2001

To establish a correlation

between the chemical

nature, the surface morphology

and the dimensions

of drug loaded microspheres

on one hand and bioadhesive

forces on the other hand.

4.

Nanoparticle US6235313B1

Bioadhesive

microspheresand their use as

drug delivery

and imaging

systems

May 2003

Site specific controlled release

delivery over a extended

period of time for active

ingredients or sensory

markers

5. Nanoparticles US6565873B1

Multicomponent

Biodegradable

bioadhesive

controlled

release system for

oral care

products.

July 2003

Nanoparticle encapsulated in a

moisture sensitive

microparticle.

6. Multiparticulate US0027780A1Multiparticulate

formulation

February

2003

Nanoparental multiparticulate

formulation capable of

transporting therapeutic

prophylactic and diagnostic

agent across mucosal

memberanes

7. Multiparticulate US0026082A1

Multiparticle

pharmaceutical

dosage form

containing a

mucoadhesively

February

2007

Pharmaceutical dosage form

containing a mucoadhesively

formulated peptide or protein

active substances

method said pharmaceutical

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formulated

peptide or protein

active

substances

method said

pharmaceuticaldosage form.

dosage form.

8. Nanocomposite US0232899A1

Mucoadhesive

nanocomposite

delivery system.

September

2009

Delivery of the drug by adding

wih chitosan or silica

nanocomposite during the in-

situ gellation of colloidal

silica.

9.


Multiparticulate

form of

administration,

comprising

nucleic acidcontaining

mucoadhesive

active ingradients

and method for

producing

said form of

administration.

November

2009

The invention relates to

multiparticulate pharmaceutica

l formcomprising mucoadhesively

formulated nucleic acid

ingradients and to process

for producing the

pharmaceutical form.

10.


Bioadhesive

polymers

April

2011

To improved bioadhesive

properties

To increased residence time attissue surface and increased the

bioavailability of a drug.

11. Nanoparticles US0323977A9

Mucoadhesive

nanoparticles

for Cancer

treatment

December

2010

Chitosan, glyceryl mono fatty

acid and cancer therapeutics

agent based nanoparticles

target to the cancer.

12. Tablet US0260824A1

Bioadhesive rate

controlled

oral dosages

formulations

October

2008

Polymers with improved

bioadheive properties and

methods for improving

bioadheive of polymer and also

see the release pattern of drug

from monolithic system.

13.


Pantoprazole

Multiparticulate

formulations

August

2007

To avoid sticking to

nasogastric and gastronomy

tubes with the subcoating of

hypermellose.

14.Semisolid Dosages

formUS0240111A1

Semisolid

mcoadhesive

formulations

October

2006

To improve the technical and

organoleptic characteristics by

vaginal applications using two

bioadhesive gelling polymers

with active ingredient

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15.

Mucoadhesive

DevicesUS0196440A1

Drug delivery

devices and

methods of

making and using

thereof

September

2005

To compare the mucoadhesive

drug delivery devices between

one or more biocomptable

purified proteins, solvents and

mucoadhesive agents

Table 4: Patents/ applications on transmucosal/ bioadhesive systems

PUBLICATION NUMBER TITLEPUBLICATION

DATEASSIGNEE

(IN) 226662

Multiparticulate pharmaceutical dosage

form containing a mucoadhesively

formulated peptide or protein active

substances method for producing said

pharmaceutical dosage form.

01-09-2009Rohm GMBH &

co. KG

(IN) 212177Mucoadhesive granules and a process

for the preparation of the same 08-11-2008

Reckitt & colman

products limitedLondon

(IN) 225506Mucoadhesive polymers, use thereof

and method for producing the same02-13-2009

Andreas

bernkopschnurch,

Austria.

1530/CHE/2006 A

(1530/CHE/2006)

Controlled release mucoadhesive

matrix formulation containing

tolterodine and a process for its

preparation

11-28-2008

Kulkarni giriraj

tirupatirao, JSS

college of

pharmacy, IN

392/CHE/2007 A(392/CHE/2007)

A film forming, release modifying and

mucoadhesive agent derived from a

natural source and its use thereof inlocal drug delivery system for

treatment of periodontitis gingivitis

and other oral infections

11-28-2008

Kulkarni giriraj

tirupatirao JSScollege of

pharmacy, IN

9095/DELNP/2007 A

(9095/DELNP/2007)

Mucoadhesive xyloglucan-containing

formulations useful in medical devices

and in pharmaceutical formulations

01-18-2008Alfa wassermann

SPA italy

968/CHE/2004 A

(968/CHE/2004)

Mucoadhesive buccal composition

containing nicotine useful for smoking

cessation and a process for its

preparation

07-20-2007The mainpal

college, IN

7704/DELNP/2006 A

(7704/DELNP/2006)

Controlled release formulations of

enzymes microorganisms, and

antibodies with mucoadhesive

polymers

06-15-2007Amano enzyme,

USA

IN/PCT/2001/60/DELOral mucoadhesive compositions

containing gastrointestinal actives03-11-2005

The Procter &

Gamble

company. US

1026/MUM/2001 A

(1026/MUM/2001)

Process for manufacture of

mucoadhesive buccal bilayered novel

delivery tablets of diclofenac

09-15-2006

K M Kundnani

College

of pharmacy, IN

00527/KOL/2003A(527/KOL/2003)

Preparation of new oral sustaineddiltiazem tablet using extract of

03-03-2006 Jadavpuruniversity, IN

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fenugreek as a mucoadhesive agent

528/KOL/2003A

Preparation of new oral sustained

diltiazem tablet using extract of

ocimum basilicum as a mucoadhesive

agent

03-03-2006Jadavpur

university, IN

1932/DELNP/2005 A A film-shaped therapeutic system 09-26-2008LTS lohmanntherapie-system

AG, Germany

7324/DELNP/2007 ANew pharmaceutical compositions

useful in the treatment of pain10-26-2007

Orexo ab,

Sweden

WO 2008/106659

Methods of treating bipolar disorder

and memory and/or cognitive

impairment associated therewith

04-09-2008

Memory

pharmaceuticals

corporation, NJ

WO 2008/134540Compositions and methods for

transmucosal delivery of domperidone06-11-2008

Aronchick craig,

PA

WO 2008/099397

Compositions and methods for

enhancing

transmucosal delivery

21-08-2008 Derma-young ltd.Israel

WO 2008/085764

Storage and dispensing devices for

administration of oral transmucosal

dosage forms

17-07-2008

Acelrx

Pharmaceuticals

Inc., CA

WO 2008/075102

Pharmaceutical compositions for

transmucosal delivery of a

therapeutically active agent on the

basis of submicron particles

26-06-2008Pharmakodex

limited, UK

WO 2007/125545 Transmucosal composition 08-11-2007Panacea biotec

ltd, IN

WO 2007/103931Nanofluidized B-12 composition and

process for treating pernicious anemia13-09-2007

Health plus

international,

Inc., US

WO 2007/081949Small-volume oral transmucosal

dosage forms19-07-2007

Acelrx

pharmaceuticals,

Inc., CA

WO 2007/081948Bioadhesive drug formulations for oral

transmucosal deliver19-07-2007

Acelrx

pharmaceuticals,

Inc., USA

WO 2007/070632 Abuse resistant transmucosal drugdelivery device 21-06-2007

BDS

international,Inc., NC

WO 2007/058923

Composition of fentanyl citrate oral

solid

transmucosal dosage form, dextrose

monohydrate as major excipient and

binding material therefore and methods

of producing them

24-05-2007 Innozen, Inc., CA

WO 2006/119286Edible film for transmucosal delivery

of nutritional supplements09-11-2006 Innozen, Inc., CA

WO 2006/117803 Transmucosal drug delivery systems 09-11-2006Devarajan,

padma,

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venkitachalam,

IN

WO 2006/089082

Transmucosal administration of drug

compositions for treating and

preventing disorders in animals

24-08-2006

Velcera

pharmaceuticals,

PN

WO 2006/088473

Microcapsules and nanocapsules forthe

transmucosal delivery of therapeutic

and diagnostic agents

24-08-2006

Koritala,

panduranga rao,

US

WO 2005/016321

Adhesive bioerodible transmucosal

drug delivery

system

24-02-2005 QLT Inc., US

WO 2005/011617

Transmucosal dosage forms for brain-

targeted steroid chemical delivery

systems

10-02-2005Ivax corporation,

US

WO 2004/069198Sugar-free oral transmucosal solid

dosage forms and uses there of 19-08-2004Cephalon, Inc.,

US

WO 2004/064811A composition material for

transmucosal delivery05-08-2004

Magle holding

AB, Sweden

WO 2004/024124 Modified release oral dosage form 25-03-2004 Smithkline, UK

WO 2003/101357 Transmucosal delivery of cannabinoids 11-12-2003University of

Mississippi, US

WO 2003/092661

Multi-phasic delivery via transmucosal

absorption of appetite suppressants and

craving reduction medicaments

13-11-2003NPD Intelect,

L.L.C, US

WO 2003/092591Multi-phasic delivery via transmucosal

absorption of antiemetic medicaments

13-11-2003NPD Intelect,

L.L.C, US

WO 2002/076211 Nicotine-containing oral dosage form 03-10- 2002Smithkline

beecham, UK

WO 2002/067903

Compositions and methods of

manufacture for oral dissolvable

dosage forms

06-09- 2002Cephalon, Inc.,

US

WO 2002/030451Compositions and methods for

reducing GnRH induced bone loss18-04-2002

Atossa

healthcare, Inc,

US

WO 2001/030288Oral transmucosal drug dosage using

solid solution03-05-2001

Anesta

corporation, US

WO 2000/059423Oral transmucosal delivery of drugs orany other ingredients via the inner

buccal cavity

12-11-2000Watson

pharmaceuticals,

Inc., US

WO 2000/032171Autoahesive oral transmucosal

delivery dosage form08-06-2000

Controlled

therapeutics ltd.,

Scotland

WO 1993/023011 Transmucosal drug delivery device 25-1-1993

Minnesota

mining and

manufacturing

company, US

WO 1991/003271 Apparatus for administeringmedicaments to mucosal tissue 21-03-1991 University ofUtah, US

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WO 1991/003236 Transmucosal dosage form 21-03-1991University of

Utah, US

US 6,375,963

Bioadhesive hot-melt extruded film for

topical and mucosal adhesion

applications and drug delivery and

process for preparation thereof

23-04-2002

M. A. Repka, S.

L. Repka and J.

W. McGinity, US

US 6,228,383Use of fatty acid esters as bioadhesive

substances08-05-2001 Hansen et al, US

US 5,672,356

Bioadhesive pharmaceutical

composition for the controlled release

of active principles

30-09-1997Adir et

compagnie, FR

US 20090246256Compositions and methods for

transmucosal delivery of lofexidine01-10- 2009

Abeer M. Al-

Ghananeem, US

US 20090214604

Method of obtaining hydrogels of

cyclodextrins with glycidyl ethers,

compositions thus obtained and

applications thereof

27-08-2009

Universidade de

santiago de

compostela,

Spain

US 20090110717 Transmucosal composition 30-04-2009

Singh Amarjit,

Singh Sarabjit,

Puthli Shivanand,

IN

US 20080152695

Oral/buccal transmucosal delivery

methods for electrolyte compositions

including xylitol

26-06-2008

Clark Richard,

Durschlag

Maurice, US

US 20070293581

Methods for buccal, lingual or

sublingual dosing regimens of

epinephrine for the treatment ofallergic emergencies

20-12-2007Hill Malcolm,

US

US 20070292479Film-shaped drug forms for use in the

oral cavity (wafers)20-12-2007

Podhaisky Hans-

Pete, Bracht

Stefan, US

US 20060073189

Chewing gums, lozenges, candies,

tablets, liquids,and sprays for efficient

delivery of medications and dietary

supplements

06-04-2006 NPD, LLC, US

US 20060013864Transmucosal pharmaceutical

administration form19-01-2006

Hoffmann et. al.,

US

US 20040241223 Oral dosage forms for macromoleculardrugs

02-12- 2004 David Barman,US

US 20030219472

Compositions and method for

transmucosal drug delivery and

cryoprotection

27-11-2003Pauletti et. al.,

US

US 20030124179

Transdermally administered tolterodine

as antimuscarinic agent for the

treatment of overactive bladder

03-07-2003Pharmacia AB,

Sweden

CONCLUSION

Mucoadhesive drug delivery system utilize the property of bioadhesion of certain watersoluble polymer whichbecome adhesive on hydration and hencecan be used for targeting a

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drug to aparticular region of the body for an extended period of time. Many potential

mucoadhesive systems are being investigated whichmay find their way into the market in

near future.The main objective of usingbioadhesive systems orally would beachieved by

obtaining a substantial increase in residence time of the drug for local drug effect and to

permit once daily dosing. The natural mucoadhesive polymer as a carrier for buccal drug

delivery can be used to improve the health of all living things and to minimize the unwanted

effect of synthetic polymers. Researchers will motivate for the establishment of some more

naturally occurring polymer and the scenario of pharmaceutical development will change

with fewer side effects due to biodegradability of natural occurring polymer.

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