Oral Transmucosal Drug Delivery Systems

BY:HARDIK DHIMANM PHARMA (ceutics)CHITKARA COLLAGE OF PHARMACY

INTRODUCTION Bioadhesive drug delivery formulations were

introduced in1947 when gum tragacanth was mixed with dental adhesive powder to apply penicillin to the oral mucosa.

Mucoadhesive drug delivery systems (buccal) are delivery systems, which utilized the property of bioadhesion of certain polymers, which become adhesive on hydration and hence can be used for targeting a drug to particular region of the body for extended period of time.

The lack of efficacy of certain drugs due to decreased bioavailability, unpredictable, and erratic absorption, GI intolerance or pre systemic elimination has prompted the examination of other potential route of administration.

Advantages Relatively large surface area Accessibility Rich blood Supply Low metabolic activity Robust Prolonged retention Intestinal alternative Zero-order controlled release Ease of use and Low variability.

Limitations Drugs with large dose are difficult to be

administered. Eating and drinking may be restricted. Possibility of the patient to swallow the

tablet. This route cannot administer drugs, which

are unstable at buccal pH. This route cannot administer drugs, which

irritate the mucosa or have a bitter or unpleasant taste or an obnoxious odor.

Small surface area is available for absorption.

DisadvantagesLimited absorption area- the total

surface area available for drug absorption is 170cm2 of which ~50cm2 represents non-keratinized tissues, including buccal membrane.

The barriers such as saliva, mucus, membrane coating granules, basement membrane etc. retard the rate and extent of drug absorption through the mucosa.

DisadvantagesContinuous secretion of the saliva (0.5-

2 L/day)leads to subsequent dilution of the drug.

The hazard of choking by involuntarily swallowing the delivery system is a concern.

Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and ultimately the involuntary removal of the dosage form.

Oral mucosal sites for drug deliverySublingual delivery- administration

of the drug via the sublingual mucosa to the systemic circulation.

Buccal delivery- is the administration of drug via the buccal mucosa to the systemic circulation.

Local delivery- for the treatment of conditions of the oral cavity, principally ulcers, fungal conditions and periodontal disease.

Oral MucosaMouth as a structural organ.Act as a site for drug absorption.Nitroglycerine –first noted drug in

case of absorption via mucosal membrane.

Highly perfused with blood vessels.

High blood flow of 20-30 mL/min/100gm of tissue.

Less prone to irreversible irritation.

APHE Of Oral MucosaORAL

MUCOSA

Outer vestibule

Bounded on the outside by

lips and cheeks.

On the inside by upper and lower dental

arches.

Oral cavity

Situated within the

dental arches

Oral mucosa structure

Consist of :Outermost stratified epithelium

with a basement membrane.Lamina propria.Submucosa as the innermost

layer.

Structure

Role of SalivaProtective fluid for all tissues of

the oral cavity.Continious mineralization of the

tooth enamel.To hydrate oral mucosal dosage

forms.Converts the dosage form into

solution form leading to drug absorption.

Structure and Design of Buccal Dosage

1. Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive, and additives mixed together.

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

Permeability of Drugs through Buccal MucosaThere are two possible routes of

drug absorption through the squamous stratified epithelium of the oral mucosa

Transcellular(intracellular, passinthrough the cell).

Paracellular (intercellular, passing around the cell).

MECHANISM OF MUCOADHESION

Mucoadhesion is a complex process involving wetting, adsorption and interpenetration of polymer chains. Mucoadhesion is established in the following stages:

Contact stage: Intimate physical contact between a bioadhesive/Mucoadhesive material and a membrane (wetting or swelling phenomenon).

Consolidation stage: Penetration of the bioadhesive/Mucoadhesive into underlying the tissue or into the surface of the mucous membrane (interpenetration).

Theories of Mucoadhesion

Wetting Theory applies to liquid systems which present

affinity to the surface in order to spread over it.

This affinity can be found by using measuring techniques such as the contact angle.

general rule = lower the contact angle, the greater is the affinity.

explains the importance of contact angle and reduction of surface and interfacial energies to achieve good amount of mucoadhesion.

S AB = γ B – γ A – γ AB

WhereS AB = spreadability coefficient,Gamma B and Gamma A = surface

energiesGamma AB = interfacial energy

Diffusion theorydescribes the interpenetration of both

polymer and mucin chains to a sufficient depth to create a semi-permanent adhesive bond.

adhesion force increases with the degree of penetration of the polymer chains.

penetration rate depends on the diffusion coefficient, flexibility and nature of the mucoadhesive chains, mobility and contact time.

The interpenetration depth of polymer and mucin chains can be estimated by the following equation:

l = (tD b )½Wheret is the contact time.D b is the diffusion coefficient of

the mucoadhesive material in the mucus.

Fracture theory

This is perhaps the most used theory in studies on the mechanical measurement of mucoadhesion. It analyzes the force required to separate two surfaces after adhesion is established.

This theory helps in the determination of fracture strength (σ) following the separation of two surfaces via its relationship to the Young’s modulus of elasticity (E), the fracture energy (ε) and the critical crack length (L)

Electronic theory

The electronic theory depends on the assumption that the bioadhesive material and the target biological material have different electronic surface characteristics. Based on this, when two surfaces come in contact with each other, electron transfer occurs in an attempt to balance the Fermi levels, resulting in the formation of a double layer of electrical charge at the interface of the bioadhesive and the biologic surface. The bioadhesive force is believed to be present due to the attractive forces across this double layer.

Adsorption theory

This theory states that the bioadhesive bond formed between an adhesive substrate and the tissue is due to the weak Van der Waals forces and hydrogen bond formation. It is one of the most widely accepted theories of bioadhesion. Table indicates types of bond formed…..

Regions where the mucoadhesive bond rupture can occur.

Factor Affecting Mucoadhesion

MUCOADHESIVE POLYMERSwater-soluble and water insoluble

polymers, which are swellable networks, joined by cross-linking agents.

polymers possess optimal polarity to make sure that they permit sufficient wetting by the mucus and optimal fluidity that permits the mutual adsorption and interpenetration of polymer and mucus to take place.

Mucoadhesive polymers Two classes- hydrophilic polymer and hydrogels. hydrophilic polymers containing carboxylic group

exhibit the best mucoadhesive properties, poly vinyl pyrrolidone (PVP), Methyl cellulose (MC), Sodium carboxymethylcellulose (SCMC) Hydroxypropyl cellulose (HPC) and other cellulose derivative.

Hydrogels are the class of polymeric biomaterial that exhibit the basic characteristics of hydrogel to swell by absorbing water interacting by means of adhesion with the mucus that covers epithelia.

Mucoadhesive Polymers examples

Buccal FormulationsThe size of the delivery system

varies with the type of formulation. buccal tablet may be approximately

5-8mm in diameter, whereas a flexible buccal patch may be as large as 10 -15cm2 in area.

Mucoadhesive buccal patches with a surface area of 1–3 cm2 are most acceptable.

Buccal mucoadhesive tablets -Buccal mucoadhesive tablets are dry dosage forms that have to be moistened prior to placing in contact with buccal mucosa.

Example: a double layer tablet.

Patches and Films- Buccal patches consists of two laminates. A novel mucosal adhesive film called “Zilactin” – consisting of an alcoholic solution of hydroxyl Propyl cellulose and three organic acids.

Semisolid Preparations (Ointments and Gels)- 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.

Powders- Hydroxypropyl cellulose and beclomethasone in powder form is used on rats for experimental studies.

beclomethasone is retained on buccal mucosa for over 4 hours.

EVALUATION STUDIES In vitro/ex vivo testsMethods determining tensile

strength Methods determining shear stress Adhesion weight method Fluorescent probe method Flow channel method Mechanical spectroscopic method Falling liquid film method

In vitro/ex vivo tests

Colloidal gold staining method.Viscometer method.Thumb method. Adhesion number.Palatability test. Swelling properties. In vitro drug release studies. Muco retentability studies.

In vivo methods Use of radioisotopes .Use of gamma scintigraphy .Use of pharmacoscintigraphy .Use of electron paramagnetic

resonance (EPR) oximetry .X - ray studies.Isolated loop technique.

The tensile strength and elongation at break values was calculated using the formula:

Tensile strength (kg. mm–2) = Force at break(kg) Initial cross sectional area (mm2)

Elongation at break (%.mm–2) = Increase in length (mm) × 100 Original length Cross sec tionalarea (mm2)

Surface pH = acidic or alkaline pH may cause irritation to the buccal mucosa, it was determined to keep the surface pH as close to neutral as possible.

In vitro drug release = The United States Pharmacopoeia (USP) XXIII rotating paddle method used to study the drug release from the bilayered and multilayered tablets.

Fluorescent probe method In this method the membrane lipid bilayer and

membrane proteins are labeled with pyrene and fluorescein isothiocyanate, respectively. The cells are mixed with the mucoadhesive agents and changes in fluorescence spectra were monitored. This gives an indication of polymer binding and its influence on polymer adhesion.

Flow Channel method The method was conducted in an attempt to

understand structural requirements for bioadhesion in order to design improved bioadhesives polymers for oral use.

Palatability testPalatability study is conducted on the

basis of taste, after bitterness and physical appearance.

All the batches are rated A, B and C grades as per the criteria.

When the formulation scores at least one A grade, formulation is considered as average.

scores two A grade then considered as good and the one with all three A grade cosidered good formulation.

Swelling index The extent of swelling can be

measured in terms of % weight gain by the dosage form. The swelling index is calculated using following formula.

S.I= Wt – Wo Woo Where, S.I = Swelling index Wt = Weight of tablet at time t Wo = Weight of tablet before placing

in the beaker

In vivo methods Gamma Scintigraphy TechniqueDistribution and retention time of the

mucoadhesive tablets can be studied using the gamma scintigraphy technique.

GI Transit using Radio-Opaque Tablets It is a simple procedure involving the use of

radio-opaque markers, e.g. barium sulfate, encapsulated in mucoadhesive tablets to determine the effects of mucoadhesive polymers on GI transit time

Reference