Buccal Drug Delivery System: A Review

 

Jalpa G. Patel*, Sweta S. Solanki, Karan B. Patel, Manish P. Patel, Jayvadan K.Patel

Department of Pharmaceutics, Nootan Pharmacy College, Visnagar-384315, Gujarat, India 

*Corresponding Author E-mail: jalpa.patel132@gmail.com

ABSTRACT:

The buccal region of the oral cavity is an attractive target for administration of the drug of choice, particularly in overcoming deficiencies associated with the latter mode of administration. Problems such as high first-pass metabolism and drug degradation in the gastrointestinal environment can be circumvented by administering the drug via the buccal route. Moreover, rapid onset of action can be achieved relative to the oral route and the formulation can be removed if therapy is required to be discontinued. It is also possible to administer drugs to patients who unconscious and less co-operative. To prevent accidental swallowing of drugs adhesive mucosal dosage forms were suggested for oral delivery, which included adhesive tablets, adhesive gels, adhesive patches and many other dosage forms with various combinations of polymers, absorption enhancers. In addition to this, studies have been conducted on the development of controlled or slow release delivery systems for systemic and local therapy of diseases in the oral cavity.

 

 

INTRODUCTION:

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 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. The buccal route provides one of the potential routes for typically large, hydrophilic and unstable proteins, oligonucleotides and polysaccharides, as well as conventional small drug molecules ¹.

Received on 20.09.2012

Oral mucosal sites ^{1, 5}

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.

Components or structural features of oral cavity (Figure 1)

·        Oral cavity is that area of mouth delineated by the lips, cheeks, hard palate, soft palate and floor    of mouth. The oral cavity consists of two regions.

·        Outer oral vestibule, which is bounded by cheeks, lips, teeth and gingival (gums).

·        Oral cavity proper, which extends from teeth and gums back to the fauces (which lead to       pharynx) with the roof comprising the hard and soft palate.

·        The tongue projects from the floor of the cavity.

 

 

 

Physiological aspects and functions of oral cavity

·         As a portal for intake of food material and water.

·         Helps in chewing, mastication and mixing of food stuff.

·         Helps to lubricate the food material and bolus.

·         To identify the ingested material by taste buds of tongue.

·         To initiate the carbohydrate and fat metabolism.

·         To aid in speech and breathing process.

 

Advantages of buccal drug delivery ^{2, 3, 4}

·        Bypass of the gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally administered drugs that otherwise undergo hepatic first-pass metabolism.

·        Improved patient compliance due to the elimination of associated pain with injections. 

·        Sustained drug delivery. 

·        A relatively rapid onset of action can be achieved relative to the oral route and the formulation can be removed if therapy is required to be discontinued. 

·        Increased ease of drug administration 

·        The large contact surface of the oral cavity contributes to rapid and extensive drug absorption 

·        Extent of perfusion is more therefore quick and effective absorption.

·        Nausea and vomiting are greatly avoided.

·        Used in case of unconscious and less cooperative patients.

·        Drugs, which show poor bioavailability via the oral route, can be administered conveniently. Ex; Drugs, which are unstable in the acidic environment of the stomach or are destroyed by the enzymatic or alkaline environment of the intestine.

 

Limitations of buccal drug delivery: ^{2, 3, 4}

·        Drugs which irritate oral mucosa or have bitter taste, or cause allergic reactions, discoloration of teeth cannot be formulated.

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

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

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

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

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

 

Overview of buccal mucosa:

A.     Structure^{1, 2}

 

Figure 2: Cross section of oral mucosa

 

The cross section of oral mucosa is shows in figure-2 is anatomically divided into

1) Epithelium

2) Basement membrane and Connective tissues

1) Epithelium: ^{1, 6}

The epithelium consists of approximately 40–50 layers of stratified squamous epithelial cells having thickness 500-800µm¹. The epithelium of the oral mucosa serves as a protective covering for the tissues and a barrier to the entry of foreign materials. These functions are reflected in the organization of the epithelium in which individual epithelial cells are closely opposed and stratified so there are a number of layers that show a sequence of differentiation. The uppermost layers form a surface that is resistant to physical insult and to penetration by foreign substances [6]. Membrane Coating Granules (MCG) are spherical or oval organelles (100–300 nm in diameter). MCGs discharge their contents into the intercellular space and thus form the permeability barrier. Major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids ¹ increase in size and become flattened as they progressively mature and migrate from the basal layer towards the epithelial surface, showing increasing levels of protein tonofilaments and declining levels of some cytoplasmic organelles⁶.

 

2) Basement Membrane and Connective Tissue ^{1, 6}

The basement membrane (BM) is a continuous layer of extracellular materials and forms a boundary between the basal layer of epithelium and the connective tissues. This basal complex anchors the epithelium to the connective tissue and supplements the barrier function of the superficial layers of the epithelium to prevent some large molecules from passing the oral mucosa. The bulk of connective tissue consists of a collagen fiber network, the organization of which determines mechanical stability, resistance to deformation, and extendibility of the tissue. Most likely, the connective tissue, along with the basement membrane, is not considered to influence the diffusion of most compounds of pharmacological interest although these two regions may limit the movement of some macromolecules and complexes.

 

B. Environment⁷

The oral cavity is marked by the presence of saliva produced by the salivary glands and mucus which is secreted by the major and minor salivary glands as part of saliva.

 

Role of Saliva:

·        Protective fluid for all tissues of the oral cavity.

·        Continuous mineralization / demineralization of the tooth enamel. 

·        To hydrate oral mucosal dosage forms.

 

Role of Mucus:

·        Made up of proteins and carbohydrates.

·        Cell-cell adhesion 

·        Lubrication 

·        Bioadhesion of  mucoadhesive drug delivery system

 

Routes of drug transport ^{1, 9}

A=Transcellular route

B= Paracellular route

FIGURE 3 : ROUTES OF DRUG TRANSPORT

 

There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa.

1) Trans cellular (intracellular, passing through the cell)

2) Para cellular (intercellular, passing around the cell).

Permeation across the buccal mucosa has been reported to be mainly by the para cellular route through the intercellular lipids produced by membrane granules.

 

Although passive diffusion is the main mechanism of drug absorption, specialized transport mechanisms have been reported to exist in other oral mucosa (that of the tongue) for a few drugs and nutrients; glucose and cefadroxil were shown to be absorbed in this way.

 

The buccal mucosa is a potential site for the controlled delivery of hydrophilic macromolecular therapeutic agents (biopharmaceuticals) such as peptides, oligonucleotides and polysaccharides.

 

However, these high molecular weight drugs usually have low permeability leading to a low bioavailability, and absorption enhancers may be required to overcome this. 

The buccal mucosa also contains proteases that may degrade peptide salivary enzymes may also reduce stability. 

 

Factors affecting drug delivery via buccal route ^10,11 

The rate of absorption of hydrophilic compounds is a function of the molecular size. Smaller molecules (75100 Da) generally exhibit rapid transport across the mucosa, with permeability decreasing as molecular size increases. For hydrophilic macromolecules such as peptides, absorption enhancers have been used to successfully alter the permeability of the buccal epithelium, causing this route to be more suitable the delivery of larger molecules.

 

The partition coefficient is a useful tool to determine the absorption potential of a drug. In general, increasing a drug’s polarity by ionization or the hydroxyl, carboxyl, or amino groups, will increase the water solubility of any particular drug and cause a decrease in the lipid-water partition coefficient. Conversely, decreasing the polarity of a drug (e.g. adding methyl or methylene groups) results in an increased partition coefficient and decreased water solubility.

 

The partition coefficient is also affected by pH at the site of drug absorption. With increasing pH, the partition coefficient of acidic drugs decreases, while that of basic drugs increases. The partition coefficient is also an important indicator of drug storage in fat deposits. Obese individuals can store large amounts of lipid soluble drug in fat stores. The ionization of a drug is directly related to both its pKa and pH at the mucosal surface. Only the nonionized form of many weak acids and weak bases exhibit appreciable lipid solubility, and thus the ability to cross lipoidal membranes. As a result, maximal absorption of these compounds has been shown to occur at the pH at which they are unionized, with absorbability diminishing as ionization increases.

 

Structure and design of buccal dosage form ^4,8

Buccal Dosage form can be of 1.Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive and additives mixed together.

 

 

Figure 3: buccal patch designed for bidirectional drug release

 

Transmucosal drug delivery systems can be bidirectional or unidirectional. Bi-directional (Figure 3) patches release drug in both the mucosa and the mouth.

2. Reservoir type:

 

Figure 4: buccal patch designed for unidirectional drug release

 

The buccal patch designed in a reservoir system contains a cavity for the drug and additives separate from the adhesive. An impermeable backing is applied to control the direction of drug delivery; to reduce patch deformation and disintegration while in the mouth; and to prevent drug loss.  Additionally, the patch can be constructed to undergo minimal degradation in the mouth, or can be designed to dissolve almost immediately.  Unidirectional (Figure 4) patches release the drug only into the mucosa.

 

Basic components of buccal drug delivery system;

The basic components of buccal drug delivery system are

1) Drug substance

2) Bioadhesive polymers

3) Backing membrane

4) Permeation enhancers

 

1. Drug substance:

Before formulating buccoadhesive drug delivery systems, one has to decide whether the intended, action is for rapid release/prolonged release and for local/systemic effect. The selection of suitable drug for the design of buccoadhesive drug delivery systems should be based on pharmacokinetic properties.  The drug should have following characteristics. ¹²

·        The conventional single dose of the drug should be small.

·        The drugs having biological half-life between 2-8 hours are good candidates for controlled drug delivery. Tmax of the drug shows wider-fluctuations or higher values when given orally. Through oral route drug may exhibit first pass effect or presystemic drug elimination.

·        The drug absorption should be passive when given orally.

2. Bioadhesive polymer:

The first step in the development of buccoadhesive dosage forms is the selection and characterization of appropriate bioadhesive polymers in the formulation. Bioadhesive polymers play a major role in buccoadhesive drug delivery systems of drugs.

 

Polymers are also used in matrix devices in which the drug is embedded in the polymer matrix, which controls the duration of release of drugs¹⁵. Bioadhesive polymers are from the most diverse class and they have considerable benefits upon patient health care and treatment¹⁶.

 

The drug is released into the mucous membrane by means of rate controlling layer or core layer. Bioadhesive polymers which adhere to the mucin/ epithelial surface are effective and lead to significant improvement in the oral drug delivery¹⁴.

 

An ideal polymer for buccoadhesive drug delivery systems should have following Characteristics.^{12, 13}

·        It should be inert and compatible with the environment

·        The polymer and its degradation products should be non-toxic absorbable from the mucous layer.

·        It should adhere quickly to moist tissue surface and should possess some site specificity.

·        The polymer must not decompose on storage or during the shelf life of the dosage form.

·        The polymer should be easily available in the market and economical.

·        It should allow easy incorporation of drug in to the formulation

 

Criteria followed in polymer selection

•        It should form a strong non covalent bond with the mucin/epithelial surface 

•        It must have high molecular weight and narrow distribution.

•        It should be compatible with the biological membrane.                                                   

 

The polymers that are commonly used as Bioadhesive in pharmaceutical applications are shown in tables.

 

 

 

Table (1): Mucoadhesive polymers used in the oral cavity ¹⁶

Criteria	Categories	Examples
Source	Semi- natural/natural	Agarose, chitosan, gelatin, Hyaluronic acid, Various gums (guar,  xanthan, gellan, carragenan, pectin and sodium alginate)
		Cellulose derivatives [CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, Methyl hydroxyl ethyl cellulose]
	Synthetic	Poly(acrylic acid)-based polymers [CP, PC, PAA, polyacrylates, poly(methylvinylether-co-methacrylic acid), poly(2-hydroxyethyl methacrylate), poly(acrylic acid co ethylhexylacrylate), poly(methacrylate),  poly(alkylcyanoacrylate), Others: polyoxyethylene, PVA, PVP, thiolated polymers
Aqueous Solubility	Water-soluble	CP, HEC, HPC (waterb38 8C), HPMC (cold water), PAA, sodium CMC, sodium alginate
	Water-insoluble	Chitosan (soluble in dilute aqueous acids), EC, PC
Charge	Cationic	Aminodextran, chitosan, (DEAE)-dextran, TMC
	Anionic	Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum
	Non-ionic	Hydroxyethyl starch, HPC, poly(ethylene oxide), PVA PVP, scleroglucan
	Hydrogen bond	Acrylates [hydroxylated methacrylate,poly(methacrylic acid)], CP, PC, PVA Chitosan

 

 

 

 

Table (2): List of investigated bio adhesive polymers ¹

Bioadhesive Polymer(s) Studied	Investigation Objectives
HPC and CP	Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination
	Measured Bioadhesive property using mouse peritoneal membrane bioadhesive strength
CP, HPC, PVP, CMC	Studied inter polymer complexation and its effects on bioadhesive strength
CP and HPMC	Formulation and evaluation of buccoadhesive controlled release delivery systems
HPC and CP	Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base
CP, PIP, and PIB	Used a two roll milling method to prepare a new bioadhesive patch formulation
Xanthum gum and Locust bean gum	Hydrogel formation by combination of natural gums
Chitosan, HPC, CMC, Pectin, Xanthan gum and polycarbophil	Evaluate mucoadhesive properties by routinely measuring the detachment force form pig intestinal mucosa
HPC, HEC, PVP, and PVA	Tested mucosal adhesion on patches with two-ply laminates with an impermeable backing layer and hydrocolloid polymer layer
Hyaluronic acid benzyl esters, Polycarbophil, and HPMC	Evaluate mucoadhesive properties Poly(acrylic acid) Poly(methacrylic acid) Synthesized and evaluated crosslinked polymers differing in charge densities and hydrophobicity,Number of Polymers including HPC, HPMC, CP, CMC.Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion.
Hydroxyethylcellulose	Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis
Polycarbophil	Design of a unidirectional buccal patch for oral mucosal delivery of peptide drugs
Number of Polymers including HPC, HPMC, CP, CMC	Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion
Poly(acrylic acid)	Effects of PAA molecular weight and crosslinkingConcentration on swelling and drug release characteristics
Poly(acrylicacid-methylmethacrylate)	Effects of polymer structural features on mucoadhesion
Poly (acrylicacid-cobutylacrylate)	Relationships between structure and adhesion for mucoadhesive polymers
HEMA copolymerized with Polymeg® (polytetramethylene glycol)	Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine
Cydot® by 3M (bioadhesive polymeric blend of CP and PIB)	Patch system for buccal mucoadhesive drug delivery
Formulation consisting of PVP, CP, and cetylpyridinium chloride (as stabilizer)	Device for oramucosal delivery of LHRH - device containing a fast release and a slow release layer
CMC, Carbopol 974P, Carbopol EX-55, Pectin (low viscosity), Chitosan chloride,	Mucoadhesive gels for intraoral delivery
HPMC and Polycarbophil (PC)	Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC yielding the highest force of adhesion
PVP, Poly(acrylic acid)	Transmucosal controlled delivery of isosorbide dinitrate
Poly(acrylicacid-co-poly ethyleneglycol) copolymer of acrylic acid and poly ethyleneglycol monomethylether monomethacryalte	To enhance the mucoadhesive properties of PAA for buccal mucoadhesive drug delivery
Poly acrylic acid and poly ethylene glycol	To enhance mucoadhesive properties of PAA by interpolymer complexation through template polymerization
Drum dried waxy maize starch (DDWM), Carbopol 974P,	Bioadhesive erodible buccal tablet for progesterone delivery

3. Backing membrane:

Backing membrane plays a major role in the attachment of bioadhesive devices to the mucus membrane. The materials used as backing membrane should be inert, and impermeable to the drug and penetration enhancer. Such impermeable membrane on buccal bioadhesive patches prevents the drug loss and offers better patient compliance. The commonly used materials in backing membrane include carbopol, magnesium stearate, HPMC, HPC, CMC, polycarbophil

etc ¹⁵.

 

4. Permeation enhancers:

Substances that facilitate the permeation through buccal mucosa are referred as permeation enhancers. Selection of enhancer and its efficacy depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other excipients.

 

Mechanisms of action of permeation:

1) Changing mucus rheology: By reducing the viscosity of the mucus and saliva overcomes this barrier.

2) Increasing the fluidity of lipid bilayer membrane: Disturb the intracellular lipid packing byinteraction with either lipid packing by interaction with either lipid or protein components.

3) Acting on the components at tight junctions: By inhibiting the various peptidases and proteases present within buccal mucosa, there by overcoming the enzymatic barrier. In addition, changes in membrane fluidity also alter the enzymatic activity indirectly.

4) Increasing the thermodynamic activity of drugs: Some enhancers increase the solubility ofdrug there by alters the partition coefficient.

 

Table (3): Examples of permeation enhancers with mechanism ¹

Category	Examples	Mechanism(s)
Surfactants and Bile Salts	Sodium glycodeoxycholate	Acting on the components at tight junctions; Increasing the fluidity of lipid bilayermembrane;
	Sodium dodecyl sulphate
	Sodium lauryl sulphate
	Polysorbate 80
Fatty Acids	Oleic acid	Increasing the fluidity of lipid bilayer membrane
	Cod liver oil
	Capric acid
	Lauric acid
Polymers and Polymer Derivatives	Chitosan	Increasing the fluidity of lipid bilayer membrane; Increased retention of drug at mucosal surface
	Trimethyl chitosan
	Chitosan-4-thiobutylamide
Others	Ethanol	Acting on the components at tight junctions; Increasing the fluidity of lipid bilayer membrane
	Azone®
	Octisalate
	Padimate
	Menthol

 

Abbreviations:

CP = Carbopol 934P

HPC = Hydroxypropyl cellulose

PVP = Poly vinylpyrrolidone

CMC =Sodium carboxymethyl cellulose

HPMC = Hydroxypropyl methyl cellulose

HEC = Hydroxy ethyl cellulos

PVA = Poly vinyl alcohol

PIB = Poly isobutylene

PIP =Polyisoprene

 

REFERENCES:

1.       Shojaei Amir H, Buccal Mucosa As A Route For Systemic Drug Delivery: A Review; J Pharm Pharma.Sci  (www.ualberta.ca/~csps) 1998;1(1):15-30,

2.       Miller N.S., Johnston T. P., The use of mucoadhesive polymers in buccal drug delivery,      Advanced Drug Delivery Reviews., 2005; 57: 1666 – 1691.

3.       Lalla J.K. and Gurnancy R.A., Polymers for mucosal Delivery-Swelling and Mucoadhesive Evaluation, Indian Drugs, 2002; (5):39.

4.       Mitra A. K, Alur H. H.,Johnston, Peptides and Protein- Buccal Absorption, Encyclopedia of Pharmaceutical technology, Marcel Dekker Inc., Edition 2002: 2081-2093.

5.       Sevda Senel, Mary Kremer, Katalin Nagy and Christopher Squier, Delivery of Bioactive Peptides and Proteins Across Oral (Buccal) Mucosa, Current Pharmaceutical Biotechnology, 2001; 2: 175-186.

6.       Ghosh Tapash K., William R. Pfister, Drug Delivery to the Oral Cavity by Taylor & Francis, Preclinical Assessment of Oral Mucosal Drug Delivery Systems, Page no 46.

7.       Marcos Luciano Bruschi and Osvaldo de Freitas, Oral Bioadhesive Drug Delivery Systems, Drug Development and Industrial Pharmacy, 31(3), 2005; 293-310.

8.       Hong Wen, Kinam Park, Oral controlled release formulation design and drug delivery, Theory to practice; 169-183 International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 Available online on www.ijprd.com 173

9.       Birudaraj Raj, Mahalingam Ravichandran, Xiaoling Li, Bhaskara R. Jasti; Advances in Buccal Drug Delivery ; Current Status In Buccal Drug Delivery System; Vol. 5, Issue 2 ,2007;

10.     Harris, D. and Robinson, J.R., Drug delivery via the mucous membranes of the oral cavity, J. Pharm. Sci., 1992; 81:1-10.

11.     Wise Donald L, Handbook of Pharmaceutical controlled release technology: 255-265.

12.     Yajaman S., Bandyopadhyay A.K., Buccal bioadhesive drug delivery- A promising option for orally less efficient drugs, Journal of Controlled Release, 2006;114:15–40.

13.     Jain N.K., Controlled and novel drug delivery; 65- 75; 371-377.

14.     Edgar W.M., Saliva: its secretion, composition and functions, Br. Dent. J, 1992; 172:305-312,

15.     Indian Journal of Pharmaceutical Science, July-Aug. 2004; 66 (4): 371-536:556-562.

16.     www.controlled drugdelivery.com

 

 

 

Accepted on 31.05.2012      © RJPT All right reserved

Research J. Pharm. and Tech. 5(7): July 2012; Page 883-888