Mucosal Drug Delivery System.

 

Introduction.

• Recent years, drug delivery via mucosal drug delivery systems has become highly popular. 

• Certain drugs have a lack of efficacy due to decreased bioavailability, gastrointestinal intolerance, unpredictable and erratic absorption, or pre-systemic elimination by other potential routes of administration. 

• Various routes for mucosal drug delivery include oral, buccal, ocular, nasal, and pulmonary routes, etc.

Classification:

1. Non-attached mucosal drug delivery systems:

1. These systems are being formulated to be absorbed through the mucosa within the oral cavity. Examples: sublingual tablets, fast-dissolving tablets (melt-in-mouth or orally disintegrating tablets), etc.

2. Attached or immobilized mucosal drug delivery systems:

1. These systems are being formulated to be attached to the mucosal surface by their adhesive properties. 

2. These systems are also known as mucoadhesive systems. Examples: buccal drug delivery systems, rectal drug delivery systems, vaginal drug delivery systems, nasal drug delivery systems, etc.

strategies for controlled drug delivery systems.

1. Prolonging solely the duration of absorption process.

2. Developing unidirectional delivery systems

3. Preparing user-friendly mucosal delivery systems

Bioadhesion:

• The term ‘bioadhesive’ describes materials that bind or adhere to the biological substrates. 

• ‘Bioadhesive’ can be defined as a material that is capable of interacting with biological material and being retained on them or holding them together for an extended period of time. 

• ‘Bioadhesion’ may occur via 3 ways:

• Bioadhesion in-between biological layers without the involvement of artificial materials. 

• Cell adhesion into the culture dishes or adhesion to a variety of substances, such as woods, metals, and other synthetic substances. 

• Adhesion of artificial substances to the biological substrates like the adhesion of hydrophilic polymers to skin or other soft tissues.

Mucoadhesive drug delivery systems:

• Mucoadhesive drug delivery systems utilizes the property of mucoadhesion/bioadhesion of certain polymers, which become adhesive on hydration and hence, can be used for targeting a drug to the particular region of the body for extended periods of time. 

• The ability to maintain a delivery system at a particular location for an extended period of time has great appeal for both local as well as systemic drug bioavailability.

• Mucoadhesive drug delivery systems facilitate the possibility of avoiding either destruction by gastrointestinal contents or hepatic first-pass inactivation of drugs.

• Various mucoadhesive polymers are being used to formulate mucoadhesive drug delivery systems. 

• These can be broadly categorized as:

1. Synthetic polymers: 

1. Cellulose derivatives: 

• Methylcellulose (MC), 

• Hydroxyethylcellulose (HEC), 

• Hydroxypropyl cellulose (HPC), 

• Hydroxypropyl methylcellulose (HPMC), 

2. Sodium carboxymethylcellulose (NaCMC), etc.

1. Poly (Acrylic acid) polymers: 

2. Carbomers, 

3. Polycarbophil. 

3. Polyvinyl alcohol (PVA).

2. Natural polymers: 

• Chitosan, 

• gum tragacanth, 

• sodium alginate, 

• xanthan gum, 

• Locust

• bean gum, 

• gellan gum, etc

Principles of bioadhesion /mucoadhesion:

1. Wetting theory: 

1. Ability of bioadhesive/mucoadhesive polymers to spread and develop 

2. Immediate attachment with the mucous membranes 

3. Electronic theory: 

1. Attractive electrostatic forces in-between glycoprotein mucin network and the bioadhesive/mucoadhesive polymers.

4. Adsorption theory: 

1. Surface forces (covalent bonds, ionic bonds, hydrogen bonds, and van der Waals forces) resulting in chemical bonding.

5. Diffusion Theory: 

1. Physical entanglement of mucin strands and the flexible polymeric  chain.

6. Fracture theory: 

1. Analyzes the maximum tensile stress developed during detachment of mucoadhesive/bioadhesive drug delivery systems from the mucosal surfaces. 

Advantages and disadvantages:

1. Advantages:

1. These systems allow the developing of contact in-between the dosage forms and the mucosa (mucoadhesion/bioadhesion)

2. High drug concentration can be maintained at the absorptive surface for a prolonged period.

3. Dosage forms can be immobilized specifically at any part of the oral mucosa, buccal mucosa, sublingual or gingival mucosa, etc.

2. Disadvantages:

1. Small mucosal surface for contact

2. Lack of flexibility of dosage forms

3. .Difficult to achieve high drug release rates required for some drugs.

4. Extent and frequency and frequency of attachment may cause local irritation

Transmucosal permeability:

• The mucosal lining of the oral cavity is referred to as the oral mucosa. 

• The oral mucosa comprises the buccal, sublingual, gingival, palatal and labial mucosa. 

• The unique environment of the transmucosal route offers its potential as an effective route for the delivery of a variety of drugs. 

• Due to rich blood supply, higher bioavailability, lymphatic drainage and direct access to systemic circulation, the transmucosal route is suitable for drugs, that are generally susceptible to acid-hydrolysis in the gastrointestinal tract or extensively metabolized in the liver.

• In addition, oral mucosa facilitates an advantage of retaining drug delivery systems in contact with the absorptive mucosal surface for a longer period (i.e., mucoadhesion) and thus, optimizing the drug concentration gradient across the mucosal membrane with the reduction of differential Pathways.

• Thus, the delivery of drugs through the transmucosal route has attracted particular attention due to its potential for high patient compliance and unique physiological features. 

• The drugs to be administered through the transmucosal route need to be released from the dosage forms to the effective delivery site (e.g., buccal or sublingual area) and pass through the mucosal layers to enter the systemic circulation. 

• Certain physiological features of the transmucosal route play significant roles in this process,

• including pH, 

• enzyme activity,

• fluid volume 

• permeability of oral mucosa.

• The secretion of saliva is also an important determinant for the performance of transmucosal drug delivery.

• The main mechanisms responsible for the penetration of various molecules include:

• Simple diffusion (paracellular or transcellular)

• carrier-mediated diffusion, 

• active transport, 

• pinocytosis or endocytosis.

• Drug delivery across the oral mucosal membranes is termed transmucosal drug delivery. 

• It can be divided into three main categories of transmucosal drug delivery based on the characteristics of the oral cavity:

• Sublingual delivery: 

• Administration of drugs via the sublingual mucosa (the membrane of the ventral surface of the tongue and the floor of the mouth) to the systemic circulation.

• Buccal delivery:

• Administration of drugs via the buccal mucosa (the lining of the  cheek) to the systemic circulation.

• Local delivery

• For the treatment of conditions of the oral cavity, principally ulcers, fungal conditions and periodontal disease, gingival disease, bacterial and fungal infections, dental stomatitis, etc.

Formulation considerations of buccal delivery systems

• Transmucosal administration of drugs across the buccal lining is defined as buccal drug delivery. 

• The mucosa of the buccal area has a large, smooth and relatively immobile surface, which provides a large contact surface. 

• The large contact surface of the buccal mucosa contributes to rapid and extensive drug absorption. 

• Buccal drug delivery was first introduced by Orabase in 1947, when gum tragacanth was mixed with dental adhesive powder to supply penicillin to the oral mucosa. 

• Recent years, buccal drug delivery has proven particularly useful and offers several advantages over other drug delivery systems, including: 

• 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; 

• administration of drugs in unconscious or incapacitated patients; 

• convenience of administration as compared to injections or oral medications; sustained drug delivery; 

• increased ease of drug administration; and ready termination of delivery by detaching the dosage form.

Schematic Diagram of Buccal Mucosa

• The novel type buccal dosage forms include:

• Buccal mucoadhesive tablets, 

• Buccal patches and films, 

• Semisolids (ointments and gels) and powders

1. Buccal mucoadhesive tablets: 

• Buccal mucoadhesive tablets are dry dosage forms that have to be moistened prior to being placed in contact with buccal mucosa.

2. Buccal patches and films: 

• Buccal patches and films consist of two laminates, with an aqueous  solution of the adhesive polymer being cast onto an impermeable backing sheet, which is then cut into the required round or oval shape. 

3. Semisolids (ointments and gels): 

1. Bioadhesive gels or ointments have less patient acceptability than solid bioadhesive dosage forms, and most of the dosage forms are used only for localized drug therapy within the oral cavity.

Structure and design of buccal patches:

• Buccal patches are of two types on the basis of their release pattern: 

• Unidirectional buccal patches and 

• Bidirectional buccal patches

• Unidirectional patches release the drug only into the mucosa, while bidirectional patches release drugs in both the mucosa and the mouth.

• Buccal patches are structurally of two types:

• Matrix type.

• The buccal patch is designed in a matrix configuration and contains drug, adhesive, and additives mixed together.

• Reservoir type:

• 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; and reduce patch deformation and disintegration while in the mouth; and to prevent drug loss. 

composition of buccal patches:

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

• The drugs having biological half-life between 2-8 h 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 pre-systemic drug elimination.

• The drug absorption should be passive when given orally.

• Buccal adhesive drug delivery systems with the size 1–3 cm and a daily dose of 25 mg or less are preferable.

Polymers in mucoadhesive Drug Delivery SYstems.

• Bioadhesive polymers play a major role in the design of buccal patches. 

• Bioadhesive polymers are from the most diverse class.

Ideal properties for polymers for mucoadhesive Drug Delivery SYstems.

1. The polymer should be inert and compatible with the buccal environment.

2. It should allow easy incorporation of drugs into the formulation.

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

4. It should adhere quickly to moist tissue surface and should possess the site specificity.

5. It should form a strong non covalent bond with the mucin or epithelial surface and possess sufficient mechanical strength.

6. The polymer must not decompose in storage or during the shelf life of the dosage form.

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

8. The polymer should have good spreadability, wetting, swelling and solubility and biodegradability properties.

9. The pH of the polymer should be biocompatible and should possess good viscoelastic properties.

10. It should demonstrate local enzyme inhibition and penetration enhancement properties.

11. Should have a good shelf life.

Backing layer:

• Backing layer plays a major role in the attachment of buccal patches 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 buccoadhesive patches prevents the drug loss and offers better patient compliance.

• The commonly used materials in baking membrane include water insoluble polymers such as ethylcellulose, Eudragit RL and RS, etc

Penetration enhancer:

• Substances that facilitate the permeation through buccal mucosa are  referred as permeation enhancers. 

• Selection of the appropriate permeation enhancer and its  efficacy depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other excipients. 

• Permeation enhancers used for designing buccal patches must be non irritant and have a reversible effect. 

• The most common classes of buccal penetration enhancers 

• include fatty acids that act by disrupting intercellular lipid packing, surfactants, bile salts, and alcohols.

Plasticizers:

• They are added to impart appropriate plasticity of the buccal patches, 

• Typically, the plasticizers are used in the concentration of 0-20 % w/w of dry polymer.

• Plasticizer is an important ingredient of the film, which improves the flexibility of the film and reduces the brittleness of the film.

• The selection of plasticizer depends upon the compatibility with the polymer and type of solvent employed in the casting of film.

• Plasticizers should be carefully selected because improper use of the plasticizers affects the mechanical properties of the film. 

• Widely used plasticizers in buccal patches and films are PEG100, 400,  propylene glycol, glycerol, castor oil etc

Taste masking agents:

• Taste masking agents should be used in the formulation if the drugs have bitter taste, as the bitter drugs makes the formulation unpalatable,  especially for pediatric preparations. 

• Thus, before incorporating the drugs in the buccal patches, the taste needs to be masked.

•  Various methods can be used to improve the palatability of the formulation, such as complexation technology, salting out technology, etc

Mechanism of buccal absorption:

• Buccal absorption leads systemic or local action via the buccal mucosa and it occurs by passive diffusion of the non ionized species.

• As mucosa is lipoidal lipophillic drugs gets bettter absorbed.

Factors affecting buccal absorption:

1. Membrane Factors: 

• This involves degree of keratinization, surface area available for absorption, mucus layer of salivary pellicle, intercellular lipids of epithelium, basement membrane and lamina propria. 

• In addition, the absorptive membrane thickness, blood supply/ lymph drainage, cell renewal and enzyme content will all contribute to reducing 

• the rate and amount of drug entering the systemic circulation. 

2. Environmental Factors: 

• Saliva: 

• The thin film of saliva coats throughout the lining of buccal mucosa and is called salivary pellicle or film. The thickness of salivary film is 0.07-0.10 mm. 

• The thickness, composition and movement of this film affect the rate of buccal absorption. 

• Salivary glands: 

• The minor salivary glands are located in the epithelial or deep epithelial region of buccal mucosa. 

• They constantly secrete mucus on the surface of buccal mucosa. 

• Although, mucus helps to retain mucoadhesive dosage forms, it is potential barrier to drug penetration.

Manufacturing methods of buccal patches:

• Manufacturing processes involved in making buccal patches, are,

• solvent casting, 

• hot melt extrusion 

• direct milling.

1. Solvent Casting: 

1. In this method, all patch excipients—including the drug—are co-dispersed in an organic solvent and coated onto a sheet of release liner. 

2. After solvent evaporation, a thin layer of the protective backing material is laminated onto the sheet of coated release liner.  to form a laminate that is die-cut to form patches of the desired size and geometry.

2. Hot melt extrusion: 

1. In hot melt extrusion, a blend of pharmaceutical ingredients is molten  and then forced through an orifice to yield a more homogeneous material in different shapes such as granules, tablets, or films. 

2. Hot melt extrusion has been used for the manufacture of controlled release matrix tablets, pellets, and granules, as well as oral  disintegrating films. 

3. Direct milling: 

1. In this way, patches are manufactured without the use of solvents. 

2. Drug and excipients are mechanically mixed by direct milling or by kneading, usually without the presence of any liquids. 

3. After the mixing process, the resultant material is rolled on a release liner until the desired thickness is achieved. 

4. The backing material is then laminated as previously described. While there are only minor or even no differences in patch performance between patches fabricated by the two processes, the solvent-free process is preferred because there is no possibility of residual solvents and no associated solvent-related health issues.

Advantages of buccal drug delivery systems

1. Sustained drug delivery. 

2. Increased ease of drug administration.

3. Excellent accessibility. 

4. Drug absorption through the passive diffusion.

5. Versatility in designing as multidirectional or unidirectional release systems for local or systemic actions, etc.

6. The drug is protected from degradation due to pH and digestive enzymes of the middle gastrointestinal tract.

7. Improved patient compliance. 

8. 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.

9. Flexibility in physical state, shape, size and surface.

10. Though less permeable than the sublingual area, the buccal mucosa is well vascularized, and drugs from the buccal systems can be rapidly absorbed into the venous system underneath the oral mucosa.

Limitations of buccal drug delivery systems:

1. For local action the rapid elimination of drugs due to the flushing action of saliva or the ingestion of food may lead to the requirement for frequent dosing.

2. The non-uniform distribution of drugs within saliva on release from a solid or semisolid delivery system could mean that some areas of the oral cavity may not receive effective levels.

3. For both local and systemic action, patient acceptability in terms of taste, irritancy and ‘mouth feel’ is an issue

Commonly asked questions.

1. What is a Mucosal drug delivery system, given its advantages and limitations.

2. Explain different manufacturing processes of buccal patches.

3. Discuss different components of Mucosal drug delivery system

4. Give Principles of bioadhesion /mucoadhesion.

5. Write a short note on factors affecting drug absorption by mucosal route.