A Review Article on Labia Mucosa: A Significant Area to Design and Deliver of Drugs

Translabial drug delivery system defines a system in which the absorption of drug moiety occurs via lips or mucosal membrane. Oral cavity is a better site and ease for the delivery of drugs.  Hence, there are many benefits of the system over the other route of drug delivery such as oral route in which there are certain dilemmas i.e., first- pass metabolism and GI degradation, which ultimately reduce the bioavailability of some drugs. Whereas due to the ideal characteristics of labial mucosa, it has become an attractive fact towards the drug delivery system which includes many advantages such as duration of action can be increased and prevent from digestive enzymes and rapid action of suitable drugs. As lips are those parts of the body of human being which are the most delicate and made up of thin layer. These are mainly composed of muscles, skin and mucosa, but there is no any bone and infrastructure in its composition. Mucoadhesive agents play key role in the development of the translabial formulation. Due to the natural origin of mucoadhesive agents, it is biodegradable and biocompatible. Hence, it avoids patient non-compliance in chronic patients. It is also getting more important because multiple modification can be done easily. By this both local and systemic action of drugs can be achieved and also bypasses first pass metabolism reducing dose and side effect.

Translabial Drug Delivery System ^{[3,4,5,6,7,8]}

It is commonly known that lips make the external part of the mouth of living organisms as well as form the entrance of oral route for in-taking the food and other substance along with the production of voice. Due to the rich blood supply, lips appear to be red which consist then tissues below and also have less number of melanocytes than the individuals who have more melanocytes. Lips have dual properties, these provide both local and systematic effect when drug is applied on lips. After seeing ideal characteristics of lips, it has been found that lips have an important role in the formulation of translabial drug delivery system. Therefore, this system has distinct pros which include natural origin of mucoadhesive agents which are biodegradable and biocompatible. Hence, it avoids patient non-compliance in chronic patients. It is also getting more important because multiple modification can be done easily. By this both local and systemic action of drugs can be achieved and also bypasses first pass metabolism reducing dose and side effect. It is considered that in near days, this system will soon flourish in drug’s development.

Anatomy And Physiology

Generally, lips contain 3-5 layers. Lips are two full fleshy fold which surrounds orifice of the mouth. Skin, muscles and mucosa accounts for the composition of lips. Mouth is lined by stratified squamous epithelium leads to the arrangement of cells in layers. This also provide the promising chromosomal studies by taking oral smears.  Starting from its unique feature, it is devoid of hair, sebaceous gland and bone which makes lips more flexible in nature. Mucosal tissue is translucent in nature and supplied by a number of blood capillaries it red. Typically, in medical terms upper lips and lowers lip are termed as labia superiors and labia inferiors respectively. The surface of two lips can be differentiated by skin, mucous membrane lining or simply lining. The Junction where the lips meet the surrounding skin of mouth area is known as vermilion border. Typically color of vermilion border is reddish The comparative figure between regular/normal skin and lip skin are shown below in figure no 1

Fig: 1

Lips skin is comprised of epidermis, sub cutaneous, orbicularis oris muscle and mucosa. Vermilion of lips is composed of non-keratinised squamous epithelium that covers a number of capillaries. Inner surface of lips is composed of non-keratinised and consist of stratified squamous epithelium whereas outer surface facing towards external environment composed of squamous keratinised epithelial cells.

Blood Supply ^[12]

facial artery of external non-terminal branches provide the blood supply to the stem of lips, labia superiors and labia inferiors. Later on labia superiors and labia inferiors bifurcate and anastomase with their companion artery from the other side. The blood supply are showmn in figure 2

Nerve supply ^[4]

The maxillary and mandibular branches of fifth cranial nerves provide the sensory stimulation to the lips. The sensory innervation are provided by the branches of mandibular nerve via a mental nerve branch to the lower lip innervation of lip. Whereas the sensory stimulation to the upper lip is received by the branches of maxillary nerve through infra- orbital nerve. The nerve supply are shown in figure 3.

Muscle supply ^[12]

Lips with acting muscles are the part of facial muscles and these muscles are emerged from the mesoderm of the second pharyngeal arch. Therefore, it is supplied by the 7^th cranial nerve of the second pharyngeal arch. The facial muscles are innervated with specialized members of panniculus carnosus that have attachment with dermis and hence, overlying skin is wrinkle or dimple.

Different muscle acting on lips

• Essential oral sphincter of the oral orifice

• Buccinator
• Orbicularis orris

• Muscles act as anchor points for other several other muscle

• Modiolus

• Muscles that elevate the lips

• Levator labii superioris
• Levator labii superioris alaeque nasi
• Levator anguli oris
• Zygomaticus minor
• Zygomaticus major muscle

• Muscles depressing the lips

• Risorious
• Depressor anguli oris
• Depressor labia inferioris
• Mentalis muscles

Lymphatic drainage ^[9,10]

There is an unilateral lymphatic drainage in the upper lip which attaches and makes 5 primary trunks that pass to the ipsilateral submandibular nodes along with other drainage that also lead to the perparotid lymph nodes. The lymphatics which are attached to lower lip form 5 primary trunks that further lead to bilateral submental nodes via central lip and unilateral submandibular lymph nodes through the lateral lip. Lips have first echelon nodes which are the submental, submandibular and parotid lymph nodes.

Properties And Function of Lips ^[9,12,13]

• Lips play key role in exhibiting the facial expression and emotion of individuals
• Devoid of sebaceous gland
• Devoid of hair follicle
• Absent of skin pigment which leads to visible of blood vessels appearing red in color.
• It  is very elastic and pliable in nature due to absent of bones.
• Lips are very sensitive to touch, warm and cold due to number of nerve supply.
• With greater permeability therapeutic concentration can be achieved quickly as it contains non-keratinized squamous epithelium.

Advantages Of Labia Mucosal Drug Delivery System ^[9]

• Ease of application and termination of medication
• Allow localized and systemic action of drug formulation
• Avoid patient non- compliance for chronic patients.
• It can also be administered to unconscious patient
• Biocompatibility and biodegradability are key feature of labial delivery.
• Reduction in dose and decrease dose dependent side effect
• It has a great patient compliance due to its non-invasive, painless and simple application in comparison to parenteral route.
• It avoids hepatic degradation of drugs which offers an excellent result for systemic effect. Therefore, it has a high rate of bioavailability.

Limitations Of Labia Mucosal Drug Delivery System ^{[1,4,14,15,16]}

• Unsuitable for local irritants
• Drug, adhesives, or other excipients providing local arrythmia, erythemia or itching cannot be used.
• Small area featuring in dose limitations
• Peptide delivery is not feasible due to presence of peptidase.
• Drugs with half life having 2-8 hrs only used for translabial purpose.
• Drugs having unpleasant odor, taste cannot be given by this route rather it need to be masked.

Probable Drug Permeation Mechanism Through Lip Skin:

There are two pathways for the penetration of drug through lip skin:

1. Transcellular/intracellular transport

It is defined as the passage of drug’s molecules across the lip skin epithelium.

2. Paracellular/intercellular transport

It is defined as the transport of drug molecules through junctions between epithelial cell of lip skin.

The permeation of drug through sweat ducts, hair follicles and sebaceous glands which collectively known as shunt route, is not possible due to the absence of hair follicles and sweat ducts in vermillion zone of labial mucosa.

Labial Secretions ^[1,17,18]

The submucosal layer consists of salivary glands which secrete mucous.

Composition of mucous

Labial Mucoadhesion or Bioadhesion ^[1,17,18]

The term bioadhesion represents the bond between any two biological surface or a bond between biological and synthetic surface. But, in the case of adhesive drug delivery, bioadhesion describes the adhesion between the polymer either synthetic or natural and soft tissues or gastrointestinal mucosa. When the bond is formed with mucus, the term mucoadhesion can be used synonymously adhesion. Mucoadhesion is used as a term to define a state in which two components, one is if biological origins held together for a long period of time with the help interfacial forces. Generally, bioadhesion is a term which widely includes adhesive interactions to any biologically derived substance and mucoadhesion can be defined as the formation of bond with mucosal surface.

Mechanism of Mucoadhesion

Mucoadhesion drug delivery system includes various ways of drug delivery systems; they are as follows:

• Buccal delivery system
• Vaginal delivery system
• Rectal delivery system
• Oral delivery system
• Nasal delivery system
• Ocular delivery system

There is not yet a complete understanding available that how and why certain molecules are attached to the mucus surface, few steps are accepted in the process at least for solid system. There are certain theories which are proposed to comprehend the process for fundamental mechanism of adhesion. Firstly, mucoadhesion should have the capability to spread over the substrate in order to initiate the close contact and increase in surface contact promotes the diffusion of its chain within the mucus. Attraction and repulsion forces are a complexity in the mucoadhesion, and for successful adhesion, attractions should be controlled over it. Each step of mucoadhesion can be made easy by the nature of dosage form and how it takes. For instance, a substrate can adsorb by a partially hydrated polymer due to attraction by water surface. It is more likely Mucoadhesion just by one theory, the process of Mucoadhesion cannot be described. There are four different mechanisms of Mucoadhesion to describe in different approaches:

• Dehydrated or partially dosage forms make surface contact with substantial mucus layers (typically particulates administered drugs into the nasal cavity).
• Fully hydrated dosages forms contacting surfaces with substantial mucus layers (typically particulates of many mucoadhesive that have hydrated in the luminal contents on delivery to the lower gastrointestinal tract).
• Dry or partially hydrated dosages forms contacting surface with thin/discontinuous mucus layers (typically tablets or patches in the cavity or vagina).
• Fully hydrated dosage forms contacting surssfaces with thin/discontinuous mucus layers (typically aqueous semisolids or liquids administered into the esophagus or eye)

Theory Of Mucoadhesion ^{[5, 6]}

• Electronic theory- According to this theory, when contact is formed between adhesive polymer and a mucus glycoprotein network, then transfer of electrons takes place due to the difference in their electronic structures. This leads to the formation of double electronic layer at the interface i.e., when a positively charged polymer chitosan and negative mucosal surface interact with each other, it creates adhesion on hydration which provides an intimate contact between dosage form and absorbing tissue.
• Adsorption theory- This theory postulates that when an initial contact is formed between two surfaces, material adheres with each other due to surface force which acting between the two atoms in its surfaces. There are two types of chemical bonds which formed by these forces that can be differentiated as primary chemical bonds that has covalent nature and secondary chemical bonds that have various types of forces of attraction, with electrostatic forces, vander walls force, hydrogen and hydrophobic bonds.
• Diffusion theory- In this theory, when both the polymer chain and mucus mix with each other at a sufficient depth, they create a semi permanent adhesive bond. The depth at which polymer chain penetrates, diffusion coefficient and time of contact of mucus plays a crucial role in this process, in which diffusion coefficient relies upon the value of molecular weight between crosslinking that goes down significantly as its density increases.
• Wetting theory- This theory proposes that if there is a contact angle of liquids which is lower on the substrate surface, it has great affinity towards the liquid to the substrate surface. In the presence of liquid, when two substrate surface bring together in the contact with each other, liquid acts as an adhesive between the substrate surface.

• Cohesive theory- According to this theory, the intermolecular interaction amongst same molecules plays a vital role in the phenomenon of bioadhesion.

• Mechanical theory- This theory proposes that adhesion takes place due to the filling of irregularities on the surface by a mucoadhesive liquid. Additionally, this roughness enhances the interfacial area which considered as the most important phenomena for the process because of interactions which is available with the help of dissipating energy
• Fracture theory- This theory is widely employed in the study for the measurement of mucoadhesion. It determines the force which is required to differentiate two surfaces after adhesion is founded. And this force Sm, is most used to calculate the test of resistance to rupture by the ratio of maximal detachment force Fm, and the total surface area, AO, included in the surface interaction: Sm = Fm/AO

Since this theory is only preferred with the force to distinguish the parts. Hence, this is not concerned for the interpretation or diffusion of polymer chains.

Factors affecting Mucoadhesion ^[9,17]

Mucoadhesive Polymer ^[5,6]

Classification

1. On the basis of source