A Review On Buccal Drug Delivery System

Mohammad Tauheed*, Imran kalam, Patel M. siddik, Mohammed Anas

 JIIU’s Ali Allana College of Pharmacy Akkalkuwa, Dist-Nandurbar -425415, Maharashtra, India

 

*Correspondence: 0tauheed@gmil.com; Tel.: (+917972601449)

Article Information		Abstract
Review Article Received: 18/10/2024 Accepted: 20/10/2024 Published:08/11/2024   Keywords Buccal drug delivery system, Bio-adhesion, oral mucosa, buccal patch, factor affecting bio-adhesion, theories of bio-adhesion		The buccal drug administration has direct access to the jugular vein and circumvents first-pass metabolism and gut enzyme degradation, it presents a viable non-invasive option for the systemic distribution of ineffective medications when taken orally. It offers a practical pathway for both systemic and local effects, making it easy to administer medications. This article aims to provide a brief overview of the buccal drug delivery system, adhesion mechanism, theory, adhesion-influencing variables, and buccal mucosa anatomy. The composition, methodologies, production processes, and assessment criteria of the buccal patch are also included in this paper, which will help with future research and formulation design methods.

 

INTRODUCTION

            Drug delivery can occur through various routes in the medical field, but oral administration is the one that patients and clinicians prefer mostly. Unfortunately, there are certain drawbacks to the oral route of administration for some drug classes, particularly peptides and proteins. Because of this, alternative absorptive sites such as mucosae are thought to be possible locations for drug administration.¹ Scientists and researchers working in the drug development industries have been concentrating on alternative routes of administration over time to address the shortcomings of the oral route or to increase the potential for the administration of approved drug products.² The pharmaceutical aspects of bio-adhesion have attracted a lot of attention recently because they offer an alternative to the oral drug delivery route, which is the potential for drug destruction by the gastrointestinal tract or hepatic first-pass metabolism.³

           In 1947, gum tragacanth and dental adhesive powder were combined to apply penicillin to the oral mucosa, introducing the first bio-adhesive drug delivery formulation. The bioadhesive drug delivery system has gained significant interest in recent years for the delivery of therapeutic agents. Due to low bioavailability, GI intolerance, irregular and unpredictable absorption, or pre-systemic elimination of alternative possible routes of administration, some medications are ineffective.⁴ Buccal delivery is the process of giving the intended medication through the oral cavity's buccal mucosal membrane. In contrast to oral drug delivery, which causes the hepatic first-pass effect and acid hydrolysis to make drugs hostile, particularly proteins and polypeptides, the mucosal lining of buccal tissues offers a much milder environment for drug absorption. ⁵

    On the oral mucosa, buccal drug administration seeks to produce a site-specific release of the drug; in contrast, systemic circulation is reached using drug absorption via the buccal mucosa barrier resulting from buccal drug administration. Numerous macromolecules that are good candidates for administration via the buccal route include unstable proteins, hydrophilic drugs, oligonucleotides, and polysaccharides. These molecules are also potential therapeutic agents with incomplete and variable oral absorption.⁶ The buccal route of drug administration avoids the hepatic first-pass metabolism and gives direct access to the systemic circulation through the jugular vein, resulting in excellent bioavailability.⁷ Approximately 50 cm² of the oral cavity's total surface area, which includes the buccal membrane, it is made up of non-keratinized tissues. This leaves 170 cm² of the surface area accessible for drug absorption.^8. Saliva secretion (0.5–2 l/day) is continual and causes the medicine to be diluted later.⁵ However, the benefits and recent advancements in the distribution of a range of compounds make the drawbacks of this approach less substantial, and buccal adhesive drug delivery systems are a viable alternative for further investigation.⁹

IDEAL CHARACTERISTICS OF BUCCAL DRUG DELIVERY SYSTEM: ¹⁰

•                     Must not irritate or cause discomfort to the patient;

•                     Must remain at the place of attachment for a few hours

•                     Should speed up the pace of medication absorption

•                     Medicine should be released in a regulated manner and should only be released in one direction that is towards the mucosa.

MERITS OF BUCCAL DRUG DELIVERY: ¹¹

1.      It is easy to discontinue treatment.

2.      It is simple to use.

3.      Permits a medication to remain localized in the oral cavity throughout time.

4.      It is simple to give to unconscious people.

5.      Offers an effective path for the systemic distribution of medications with a quick first-pass metabolism, increasing their bioavailability.

6.      A considerable dosage decrease that reduces the number of dose-related adverse effects is achievable. Drugs that are unstable in an acidic environment and are destroyed by the intestine's alkaline or enzymatic environment can be administered via this route.

7.      It may be more convenient to administer medications with limited oral bioavailability.

8.      Saliva ensures a relatively large amount of water for drug decomposition, in contrast to the rectal and transdermal channels.

9.      The medicine is readily absorbed by the body using this buccal drug delivery method.

10.  This method can be used to deliver medications that are unstable in an acidic environment and are eliminated by the intestine's alkaline or enzymatic environment.

11.  The buccal mucosa is more permeable and has more blood vessels than the skin.

DEMERITS OF BUCCAL DRUG DELIVERY: ¹²

1.                  Ionic medications cannot be delivered using this method.

2.                  The quantity of medications that may be administered in this way is restricted by the low skin permeability.

3.                  As people age, the function of the skin's barrier varies from one location to another and between individuals.

4.                   Its surface area is also smaller.

5.                   The permeability of the buccal membrane is lower than that of the sublingual membrane.

6.                   It is not possible to provide medications that are unstable at buccal pH.

7.                   This method cannot be used to provide medications that irritate the mucosa or have an unpleasant or bitter taste.

8.                   Only a small dose of a medication can be given.

9.                  Only those drugs that are absorbed by passive diffusion can be administered by this route.

10.              There is a restriction on eating and drinking.

11.              The flushing action of saliva or the ingestion of foodstuffs may lead to the requirement for frequent dosing.

OVERVIEW OF ORAL MUCOSA:

ANATOMY: ¹³

Depending on the location of the oral cavity, light microscopy may identify many unique patterns of maturation in the human oral mucosa epithelium. The epithelium, basement membrane, and connective tissues are the three unique layers that make up the oral mucosa. The basement membrane provides support beneath the epithelium that lines the mouth cavity.

EPITHELIUM: ¹³

The epithelium serves as a barrier layer to protect the tissues underneath and is classified as follows:

 (a) non-keratinized surface in the vestibule, lips, cheeks, floor of the mouth, ventral surface of the tongue, and mucosal lining of the soft palate.

(b) Keratinised epithelium, which is present in the oral cavity's non-flexible areas and hard palate.

 

Fig1: Anatomy of oral cavity¹¹

BASEMENT MEMBRANE: ¹⁴

The connective tissue and the epithelium elementary layer encircle the basement membrane. The terms "lamina Lucida" (upper amorphous layer), "lamina dense," and "sub-layer of fibrous material" describe their trilaminar structure. The lamina dense contains collagen, which gives the structure strength. Their surface area is greater than that of the epithelium. Because of this, it alters the diffusional path length, preventing drug permeation or transport. They also serve several other crucial roles, such as providing mechanical strength to the epithelium, facilitating adherences between the epithelium and the underlying connective tissue, and limiting the passage of various macromolecules and cells.

CONNECTIVE TISSUE: ¹⁵

The connective tissues are the lamina propria and submucosa, which are found beneath the basement membrane. The oral mucosa receives blood vessels and nerve fibers from a continuous ring of connective tissue called the lamina propria. Primary lingual, frontal, and retromandibular veins are responsible for vascular drainage from the oral mucosa. These veins do not undergo first-pass metabolism as they open into the internal jugular vein.

Figure 2: Schematic illustration of the layers¹¹

THE MUCUS: ¹³

A transparent, viscous secretion called mucus sticks to the mucosal epithelial surface to form a thin, continuous gel blanket. In humans, this layer's average thickness ranges from 50 to 450 μm. It is secreted by the goblet cells that border the epithelia or certain exocrine glands with acini, or mucus cells. The specific composition of the mucus layer varies considerably depending on the species, anatomical location, and pathophysiological condition. The following is its general composition: though: 1. 95 percent water 2. 0.5 to 5% of lipids and glycoproteins 3. 0.5% to 1% of mineral salts 4. Free Proteins: 1% to 0.5 percent.

VASCULAR SYSTEM OF THE ORAL MUCOSA: ¹⁶

The external carotid artery is the main blood vessel that supplies blood to the mouth. The two minor branches are the lingual and facial arteries, and the major branch is the maxillary artery. Blood flows to the tongue, gingiva, and floor of the mouth through the lingual artery and its branch, the sublingual artery. The maxillary artery gives blood to the major cheek, hard palate, mandibular, and maxillary gingiva and the facial artery supplies blood to the lips and soft palate. The three primary veins that drain the mouth are the deep lingual, maxillary, and facial veins. Most of the blood that comes from the mouth and pharynx eventually ends up in the internal jugular vein.

FUNCTIONS OF ORAL MUCOSA:¹⁷

The oral environment is continuously subjected to mechanical stress from activities like eating, drinking, and talking. The mouth needs to be able to adapt quickly because it is exposed to sudden changes in pH and temperature. The mouth is the only organ in the body where taste is sensed. The specific physiological features of the oral mucosa require it to carry out several tasks. One of the most important roles of the oral mucosa is to shield the underlying tissues from toxins, bacteria, and mechanical pressures. The keratinized masticatory mucosa is tightly bound to the gingivae and the hard palate. It comprises 25% of the oral mucosa. It resists the loading forces of mastication, protecting the underlying tissues.

ROLE OF SALIVA: ¹⁸

• A protective fluid for the mouth cavity's tissues.

• Constant mineralization of the enamel of teeth.

• To hydrate dosage formulations for oral mucosa.

ROLE OF MUCUS: ¹⁸

·         It consists of both carbs and proteins.

·         Adhesion between cells

·         Lubrication.

·         Bucco sticky drug delivery system's adhesion

WHY BUCCAL MUCOSA? ¹⁹

The buccal mucosa has a high blood flow rate of 20–30 mL/min per 100 g of tissue, indicating a highly perfused oral mucosa. Both the lymphatic drainage system and the blood vessels are highly developed, and they are near the surface. Consequently, the drug can be brought to therapeutic concentrations quickly. In general, the oral mucosa is an intermediate layer of slightly leaky epithelia between the intestinal and epidermis mucosa. The buccal mucosa's permeability is thought to be 4–4000 times higher than the skin's. When compared to normal, hydrated skin, the buccal and oral mucosa consistently have higher permeability coefficients for the majority of compounds. The oral mucosa has two permeation pathways for passive drug transport: transcellular and paracellular.

PERMEABILITY OF DRUGS THROUGH BUCCAL MUCOSA:¹⁸

Drug absorption via the oral mucosa's squamous stratified epithelium can occur in two ways:

i. Transcellular (intracellular, passing through the cell).

ii. Paracellular (intercellular, passing around the cell).

According to reports, the paracellular pathway—which involves the intercellular lipids generated by membrane-coating granules—is the primary means of penetration through the buccal mucosa.

Figure3: Drug transport across the mucosa can be transcellular or paracellular ¹³

BIO-ADHESION:

"Bio adhesion" is the capacity of synthetic or natural polymers to adhere to biological surfaces for extended periods because of molecular attractive forces that are interposed between their surfaces.

Three categories exist for bio adhesion:

• The bio adhesion between biological layers in the absence of synthetic materials. Cell aggregation and diffusion, for example

• The adhesion of cells to metals, wood, and other synthetic materials, as well as to culture dishes, are two examples of bio adhesion in action.

• The adherence of synthetic materials to biological substrates, like the adherence of polymers to skin or soft tissues. ^18,20

THEORIES OF MUCOADHESION:

Since mucoadhesion is a complicated process, several hypotheses have been put out to explain the workings. The mechanical interlocking, electrostatic, adsorption, diffusion–interpenetration, and fracture processes hypotheses are among them. The two most well-recognized theories are interpenetration/diffusion and surface energy thermodynamics.²¹

DIFFUSION THEORY:

This theory's basic premise is that chains of the adhesive and the substrate interpenetrate sufficiently deeply to create a semi-permanent adhesive bond; the diffusion coefficient of the two interacting polymers determines the penetration rate, which is known to be dependent on molecular weight and cross-linking density; other crucial factors that must be taken into account are segment mobility, the bioadhesive polymer's flexibility, mucus glycoprotein, and the expanded nature of both networks.²²

WETTING THEORY:

According to the idea, liquid systems exhibit surface attraction and disperse over it. A technique to gauge affinity is by the contact angle. The contact angle generally decreases as affinity increases. Enough spreadability requires a contact angle that is zero or almost zero. By deducting the surface energy γB from the interfacial energy γA, one can calculate the spreadability coefficient.²³

ADSORPTION THEORY:

According to this theory, secondary chemical interactions such as hydrogen bonds, van der Waals interactions, and electrostatic attraction are what cause the buccal material to adhere to the mucus. For instance, the interfacial forces that are most common are hydrogen forces because the polymer contains carboxyl groups.²³

ELECTRONIC THEORY:

According to this theory, an electrical double layer forms at the contact between an adhesive polymer and the mucus glycoprotein network as a result of their different electrical structures. This electronic transfer occurs when contact adhesion is induced by attractive forces across the double layer.²⁴

THE FRACTURE THEORY:

This theory examines the forces needed to break the adhesion between two surfaces. One may calculate the greatest tensile stress generated during separation by dividing the total surface area engaged in the adhesive contact by the highest force of detachment. Measuring polymer chain entanglement, diffusion, or interpenetration is not necessary.¹⁶

MECHANISM OF ADHESION: ²

The bioadhesive must be put on the substrate to create tight contact and then improve surface contact to facilitate the dispersion of its chains inside the mucus. There are forces of attraction and repulsion, and

the attraction forces need to be stronger for a buccal to succeed. The type of dose form and method of administration can help with each phase.

 

THE MECHANISM OF BIO-ADHESION IS GENERALLY DIVIDED INTO TWO STEPS: ¹⁰

THE CONTACT STAGE:

The mucous membrane and the buccal bioadhesive come into close contact (wetting) due to the bioadhesive material’s swelling or a moderate wetting of the membrane.

CONSOLIDATION STAGE:

Several physicochemical processes, including dispersion forces, hydrogen bonding, and hydrophobic interactions, combine to strengthen and stabilize the adhesive junction and promote long-term adhesion.

Fig 4: The two steps of the mucoadhesion process²

FACTORS AFFECTING BIO-ADHESION:

POLYMER-RELATED FACTORS:²⁵

Polymer molecular weight:

Depending on the kind of polymer, there is an ideal molecular weight for maximal bio-adhesion. As the molecular weight of the bioadhesive polymer increases, so do the bioadhesive forces.

Molecular flexibility:

It is crucial for expansion and interpenetration. The mobility of a single polymer chain reduces as water-soluble polymers cross-link. The effective length of the chain that can pass through the mucus layer and the bio-adhesion strength both decrease as the cross-linking density rises.

The concentration of active polymer:

The ideal bio-adhesion is associated with a certain polymer concentration. A system with a high concentration causes a considerable loss in adhesive strength.

Polymer chain length:

The polymer molecule must have an adequate length.

ENVIRONMENT RELATED FACTORS:²⁰

pH:

pH has an impact on the charge on the polymer and mucus surfaces. Mucus will vary in charge density according to pH. Because the dissociation of functional groups on the amino acid chains and carbohydrate moiety of the polypeptide backbone has changed.

STRENGTH:

 It is necessary to apply a defined strength for placing a bioadhesive system.

INITIAL CONTACT TIME:

 Once the buccal strength increases, the initial contact time is also increased.

SELECTION OF THE MODEL SUBSTRATE SURFACE:

 It is important to verify the feasibility of the biological substrate by looking at its permeability and histology's electrophysiology.

SWELLING:

The concentration of the polymers and the presence of water both affect swelling. Overly large swelling results in a reduction in bio-adhesion.

5. APPRAOCHES OF BUCCAL DRUG DELIVERY SYSTEM: ^2,13

 Types of buccal drug delivery systems based on their geometry there are three distinct groups.

Type - l (Multidirectional):- The drug is released in several directions from a single-layer interface. Swallowing causes a substantial loss of medication.

Type - 2 (Bi-layered):- Preventing medication ingestion by covering the top with an impermeable backing layer.

Type - 3 (Unidirectional)

This unidirectional release technology achieves minimum drug loss by covering all surfaces except the contact face.

Figure 5: design of buccal dosage forms¹³

 

 

TYPES OF BUCCAL DRUG DELIVERY DOSAGE FORMS: ^26,20

1) Buccal bioadhesive tablets

2) Buccal bioadhesive semisolid dosage forms

3) Buccal patches and films

4) Buccal Powders

BUCCAL BIOADHESIVE TABLETS

When applying buccal bioadhesive tablets to the buccal mucosa, they should first be moistened. Using bioadhesive polymers and excipients, double and multilayered tablets are currently created.

Marketed system: - Bucastem Suscard buccal.

BUCCAL BIOADHESIVE SEMISOLID DOSAGE FORMS

The ingredients of buccal bioadhesive semisolid dosage forms include finely ground natural or synthetic polymer dissolved in polyethylene or water.

Marketed system: - Arabase.

BUCCAL BIOADHESIVE PATCHES AND FILMS

Buccal bioadhesive patches are composed of multilayered thin films or two-ply laminates with an oval or rounded form. They are mostly made up of a bioadhesive polymeric layer and an impermeable backing layer that allows drugs to pass through the buccal mucosa in a single route. To make buccal bioadhesive films, the medication is combined with an alcohol solution of the bioadhesive polymer.

BUCCAL BIOADHESIVE POWDER DOSAGE FORMS

The drug and bioadhesive polymers are combined to create buccal bioadhesive powder dosage forms, which are sprayed onto the buccal mucosa. Following the administration of Nifedipine as a buccal tablet and buccal film, there is a decrease in diastolic blood pressure.

MICROPARTICLE

Microparticles are more beneficial than tablets. Microspheres' physical properties allow for intimate contact with a large mucosal surface. Moreover, they can be injected into harder-to-reach areas including the gastrointestinal system and nasal cavities. These microspheres are not irritating to the local environment at the Pharmaceutical and Biological Evaluation site of adhesion, but they are not particularly effective there due to their short residence period.

WAFER

A brand-new method of periodontal medication administration is the wafer. This is applied to address microbiological infections.

LOZENGES

Among the drugs used topically to the mouth in lozenges are antibiotics, corticosteroids, local anesthetics, antifungals, and microbiologists. Lozenges require several daily doses due to their strong initial drug release in the oral cavity, which quickly drops to subtherapeutic levels.

 

COMPOSITION OF BUCCAL PATCHES:²⁷

The basic components of a buccal bio-adhesive drug delivery system are:

1. Active Pharmaceutical Ingredient

2. bioadhesive polymers

3. Backing membrane

4. Penetration enhancers

5. Plasticizers

ACTIVE PHARMACEUTICAL INGREDIENT (API):¹³

To achieve the intended therapeutic effect for buccal drug delivery, it is critical to extend and enhance the contact between API and mucosa. The molecular weight, chemical activity, and melting point of a drug are significant factors that affect how easily it diffuses through the patch and the buccal mucosa. When designing a buccal medication delivery system, the following factors should be taken into consideration when choosing a drug:

·         The typical dosage for a medicine should be minimal. Medications with a biological half-life of two to eight hours are suitable candidates for controlled drug administration.

·         The medicine should not have an unpleasant taste, be free of irritation or allergies, and not cause tooth erosion or discoloration.

·         The drug's absorption should be passive when taken orally.

BIOADHESIVE POLYMERS:²⁵

Choosing and analyzing the right bio-adhesive polymers for the formulation is the first stage in producing buccal dosage forms. It is essential to employ bioadhesive polymers in buccal medication delivery devices. Polymers are also utilized in matrix devices, which encapsulate a medicine and regulate its release period using a polymer matrix. The most varied class of polymers, bioadhesive polymers, offers significant advantages for patient care and treatment. The mucous membrane's core layer, also referred to as the rate-controlling layer, allows the medicine to be delivered. Oral drug distribution can be significantly enhanced by an effective bioadhesive polymer that sticks to the mucous membrane and epithelium.

An ideal polymer for Bucco adhesive drug delivery systems should have the following characteristics.¹⁰

Ø  It ought to be environmentally friendly and inert.

Ø  To be absorbed from the mucosal membrane, the polymer and its breakdown products need to be non-toxic, possess site specificity, and stick easily to the surface of wet tissue.

Ø  When the dosage form is on the shelf or in storage, the polymer shouldn't degrade.

Ø  The polymer needs to be affordable and easily available in the market, facilitating the incorporation of the drug into the formulation.

Criteria followed in polymer selection: ²⁸

Ø  It should form a strong non-covalent bond with the mucine/epithelial surface.

Ø  It must have a high molecular weight and narrow distribution.

Ø  It should be compatible with the biological membrane.

BACKING MEMBRANE:¹³

The backing membrane has a major impact on how well bioadhesive devices adhere to the mucous membrane. The components of the backing membrane should be an enhancer of penetration, inert, and impermeable to the medication. Materials such as carbopol, magnesium separate, HPMC, HPC, CMC, and polycarbophil are commonly used to make backing membranes.

PENETRATION ENHANCERS: ²⁹