Mucosal drug delivery system

Mucosal drug delivery system

Learning Objectives

By the end of this session, students will be able to:

• Outline the concepts involved in adhesive systems

• State the advantages of mucoadhesive delivery systems

• Explain the various theories to explain mucoadhesion

• Discuss the factors affecting mucoadhesion

• Classify mucoadhesive polymers with relevant examples

• Discuss   the   mechanism   of   drug   permeation   across   the mucosal barrier

• Outline the role of permeation enhancers in mucoadhesive dosage form

Introduction to Mucosal Drug Delivery Systems

Oral route -------------> Preferred route of administration

Drawback of oral route

Hepatic metabolism

or

Extensive pre- systemic elimination by GIT

↓

Low systemic bio-availability of the drug

↓

Short duration of therapeutic activity

Mucoadhesion Concept

• The molecular force of attraction among two unlike bodies, which holds them together is called ‘adhesion’

• ‘Bioadhesion’ can be defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymers, which allows the polymer to adhere to the biological surface for an extended period of time

• The term ‘mucoadhesion’ is used when the biological surface is a mucosal surface

Mucoadhesion - History

• Various biopolymers show the bioadhesive properties and have been utilized for various therapeutic purposes in medicine

• 1947- Penicillin drug delivery system – penicillin delivery to the oral mucosa - gum tragacanth and dental adhesive powders

• Formulation developed – using   finely   ground   sodium carboxymethylcellulose, pectin, and gelatin as mucoadhesive polymers – Marketed as Orahesive®

• Orabase®- a blend of polymethylene/ mineral oil base

• Various other polymers have been found to exhibit mucoadhesive properties - e.g. sodium alginate, sodium carboxymethylcellulose, guar gum, hydroxyethylcellulose, karya gum, methylcellulose, polyethylene glycol (PEG), retene and tragacanth

• 1980s - Poly (acrylic acid), hydroxypropylcellulose, and sodium CMC were widely explored

• Various other polymers have been found to exhibit mucoadhesive properties - e.g. sodium alginate, sodium carboxymethylcellulose, guar gum, hydroxyethylcellulose, karya gum, methylcellulose, polyethylene glycol (PEG), retene and tragacanth

Mucoadhesive Delivery Systems – Advantages

• Bypass hepatic metabolism, increased bioavailability

• Prevents degradation in GIT

• Rapid absorption, rapid onset of action

• Controlled release and prolonged action

• Improved therapeutic performance

• Localized and targeted action

• Prolonged residence time of the dosage form, permit once or twice a day administration

• Rapid absorption due to good blood flow rate at the absorption site

• Reduction in fluctuations in steady state plasma levels

• Improved patient compliance

Advantage of Transmucosal Drug Delivery

Mucoadhesive Delivery Systems - Disadvantages

• Gastric motility

• Mucous turnover rate

• Irritating drugs cannot be administered

• Lack of a good model for in vitro screening

• Occurrence of local ulcerous effects due to prolonged contact of the drug

• Patient acceptability in terms to taste, irritancy and mouth feel

Mucosal Layer

• Mucus is the viscous slippery gel that covers most of the mucosal surfaces throughout the GIT

• Mucus membranes (mucosae) line the walls of various body cavities such as the gastrointestinal and respiratory tracts

• Consist of a connective tissue layer (the lamina propria)

• Above which is an epithelial layer

• Surface epithelium is made moist usually by the presence of a mucus layer

Single layered epithelia

• e.g. the stomach, small and large intestines and bronchi

• Contains goblet cells which secrete mucus directly onto the epithelial surfaces

Multilayered/stratified epithelia

• e.g. in the esophagus, vagina and cornea

• The multilayerd epithelium contain, or are adjacent to tissues containing, specialized glands such as salivary glands that secrete mucus onto the epithelial surface

Mucus

 • Mucus is present either as a gel layer adherent to the mucosal surface or as a luminal soluble or suspended form

• The major components of all mucus gels are

– Mucin glycoproteins

– Lipids

– Inorganic salts

– Water

• Water accounts for more than 95% of their weight, making them a highly hydrated system.

• The major functions of mucus - protection and lubrication.

Structure of Mucus Membrane

Mucoadhesion Theories

• The process of bioadhesion can be broadly classified into two categories, chemical and physical methods

 Chemical

• Electronic theory

• Adsorption theory

Physical

• Wetting theory

• Diffusion theory

• Cohesive theory

• Mechanical theory

Wetting theory

The contact angle should be equal or close to zero to provide adequate spreadability

•  The  wetting  theory  postulates  that  if  the  contact  angle  of liquids  on  the  substrate  surface  is  lower,  then  there  is  a greater affinity for the liquid to the substrate surface

• If two such substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive amongst the substrate surfaces.

• The spreadability coefficient, S can be determined as follows,

S_AB = γ_B + γ_A – γ_AB

γ_B is Surface tension of the bioadhesive polymer

γ_A is Surface tension of the substrate

γ_AB is Interfacial tension between the polymer and substrate

Diffusion Theory

• The diffusion theory assumes the diffusion of the polymer chains, present on the substrate surfaces, across the adhesive interface thereby forming a networked structure

• Interpenetration of both polymer and mucin chains to a sufficient depth to create a semipermanent adhesive bond

Cohesive Theory

• The cohesive theory proposes that the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like-molecule

Mechanical Theory

• Mechanical theory explains the diffusion of the liquid adhesives into the micro-cracks and irregularities present on the substrate surface thereby forming an interlocked structure which gives rise to adhesion

The Electronic Theory

• The electronic theory proposes transfer of electrons amongst the surfaces resulting in the formation of an electrical double layer thereby giving rise to attractive forces

The Adsorption Theory

Primary bonds

• Chemical absorptions

• Ionic, covalent, metallic bonding

• Permanent bonds

• Undesirable

Secondary bonds

• Van der Waals forces, hydrophobic Interactions, hydrogen bonding

• require less energy to “break”

• Most prominent

• Semipermanent bonds

• Desirable

• The adsorption theory proposes the presence of intermolecular forces, viz. hydrogen bonding and Van der Waal’s forces, for the adhesive interaction amongst the substrate surfaces

Mechanisms of Mucoadhesion

The process of adhesion may be divided into two stages.

1. Contact stage: wetting of mucoadhesive polymer and mucous membrane occurs

2. Consolidation stage: physico-chemical interactions prevail

Contact stage

• Characterized by the contact between the mucoadhesive and the mucus membrane

• Spreading and swelling of the formulation

• Initiating its deep contact with the mucus layer

Consolidation stage

• The mucoadhesive materials are activated by the presence of moisture

• Moisture plasticizes the system, allowing the mucoadhesive molecules to break free and to link up by weak van der Waals and hydrogen bonds.

• Mucoadhesive device should have features favouring both chemical and mechanical interactions

• Molecules with

– Hydrogen bond building groups (–OH, –COOH),

– An anionic surface charge

– High molecular weight

– Flexible chains

– Surface active properties

Interaction between mucoadhesive molecules and the glycoproteins of the mucus

Interpenetration of their chains and the building of secondary bonds

Factors Affecting Mucoadhesion

1.   Molecular weight

➢ Mucoadhesive strength of a polymer increases with molecular weights above 100,000

2.   Flexibility

➢ The polymer chains should contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus

➢ Higher flexibility of a polymer causes greater diffusion into the mucus network

3.   Crosslinking density

➢ With increasing density of crosslinking, diffusion of water into the polymer network occurs at a lower rate

➢ Causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin

4.   Hydrogen bonding capacity

➢ Polymers must have functional groups that are able to form hydrogen bonds

5.   Hydration

➢ Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucus network

➢ critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and mucoadhesion occurs

6.   Charge

➢ Strong anionic charge on the polymer is one of the required characteristics for mucoadhesion

7.   Concentration

➢ When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small and the interaction between polymer and mucus is unstable

➢ The more concentrated polymer would result in a longer penetrating chain length and better adhesion

➢ For each polymer, there is a critical concentration, above which the polymer produces an “unperturbed” state due to a significantly coiled structure

Physiological variables

Mucin turnover

• Limits the residence time of the mucodhesives on the mucus layer

• Mucin turnover results in substantial amounts of soluble mucin molecules.

• These molecules interact with mucoadhesives before they interact with the mucus layer

Disease state

Changes the physiochemical properties of the mucus

Examples: Common cold, gastric ulcers, ulcerative colitis, cystic fibrosis, bacterial and fungal infections of the reproductive tract

Sites for Mucoadhesive Drug Delivery Systems

1. Oral

– Buccal

– Sublingual

• The buccal cavity has a very limited surface area of around 50 cm2

• Easily accessable

• For systemic delivery and local treatment of oral lesions

• Sublingual mucosa is relatively more permeable than the buccal mucosa

2. Nasal

• Surface area of around 150–200 cm2

• Residence time of a particulate matter in the nasal mucosa varies between 15 and 30 min

3. Ocular

• Conventional dosage forms are rapidly cleared from site of application

• This can be minimized by delivering the drugs using ocular insert or patches

4. Vaginal and the rectal lumen

• Bypass the hepatic first-pass metabolism

• Helps in reducing the migration within the vaginal/rectal lumen

5. GIT

• Modulation of the transit time of the delivery systems in a particular location of the gastrointestinal system

• Has a drawback of acid instability and first-pass effects

Mucoadhesive Polymers

• Polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate

• Attach to mucous or the cell membrane by various interaction such as hydrogen bonding and hydrophobic or electrostatic interactions

• Cause polymer to swell in water and thus expose the maximum number of adhesive sites

Ideal characteristics of mucoadhesive polymers

• Should adhere to the site of attachment for a few hours

• Should release the drug in a controlled fashion

• Should provide a unidirectional drug release – towards the mucosa

• Should facilitate the rate and extent of drug absorption

• Should not cause any irritation or inconvenience

• Should not interfere with normal functions like talking, eating, etc

Classification of Mucoadhesive Polymers

Based on origin

Synthetic - Cellulose derivatives, Polyacrylate, Polymethacrylate, PVP, Carbopol

Natural – Tragacanth, Sod. Alginate, Karaya gum, Xanthan, Guar gum, Lectins, Pectin gelatin, chitosan

Based on nature

Hydrophillic – Poloxamer, Methyl cellulose, HEC, Sod. CMC, Carbopol, Chitosan, PVA, PAA

Hydrogels – Carageenan, Sod. Alginate, Guar gum

Based on charge

Anionic – PAA, Polycarbophil, carbopol

Cationic - Chitosan

Non-ionic-

Second generation polymers

thiomers

Lectin

• The anionic and cationic polymers exhibit stronger mucoadhesion

• Anionic polymers are the most widely employed mucoadhesive polymers within pharmaceutical formulations due to

– Their high mucoadhesive functionality

– Low toxicity

• Examples: PAA and its derivatives, Sodium CMC

• Such polymers are characterised by the presence of carboxyl and sulphate functional groups that give rise to a net overall negative charge at pH values exceeding the pKa of the polymer

• Among cationic polymers, chitosan is the most extensively investigated

• Chitosan is a cationic polysaccharide, produced by the deacetylation of chitin

• Biocompatible, biodegradable and has favourable toxicological properties

• Chitosan binds via ionic interactions between primary amino functional groups and the sialic acid and sulphonic acid substructures of mucus

Second-generation polymers

• Less susceptible to mucus turnover rates

• Some bind directly to mucosal surfaces

• More accurately termed “cytoadhesives”

• Furthermore as surface carbohydrate and protein composition at potential target sites vary regionally, more accurate drug delivery may be achievable

Examples: lectins and thiomers

• Lectins are naturally occurring proteins

• After initial mucosal cell-binding, lectins can either remain on the cell surface or in the case of receptor-mediated adhesion possibly become internalised via endocytosis

• Lectins offer significant advantages in relation to site targeting

• Many are toxic or immunogenic

• Thiolated polymers (thiomers) are derived from hydrophilic polymers such as polyacrylates, chitosan or deacetylated gellan gum

• Thiol groups allows the formation of covalent bonds with cysteine rich  sub  domains  of  the  mucus  gel  layer  leading  to  increased residence time and improved bioavailability

Transmucosal permeation

Passive diffusion

1.       Paracellular             

2.       Transcellular

Facilitated diffusion

1.       Carrier mediated transport

Passive diffusion

• Transport of drugs across the epithelium occurs by passive mechanisms

• Governed by laws of diffusion

• Two route for simple diffusion of materials across the epithelium

– Transcellular route

– Paracellular route

Transcellular route

• Transport into and across the cells

• Seen with highly lipid soluble molecules

Paracellular route

• Transport of molecules through intercellular spaces

• Water soluble substances and ions

Transmucosal Permeability

Facilitated diffusion

• Nutrients from mouth are shown to be absorbed by carrier systems

• Exhibits stereospecificity

• Competitive inhibition can be seen in cases of a common carrier system

Permeation Enhancers

• They help in enhanced transmucosal absorption of medicament.

• Effective in delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal absorption rates.

• These may act by a number of mechanisms, such as:

1.    Increasing the fluidity of the cell membrane

2.    Extracting inters/intracellular lipids

3.    Altering cellular proteins

4.    Altering surface mucin

Permeation enhancers may be of the following categories

• Surfactants

• Fatty acids and derivatives

• Vehicles and adjuvants

• Chelators

• Enzyme inhibitors

• Cyclodextrin

• Chitosan

Surfactants

Anionic - Sodium lauryl sulphate, Sodium laurate

Cationic Nonionic - Cetyl pyridinium chloride

Nonionic - Poloxamer

Mechanism of action of surfactants

• Disruption protein domain integrity as well as lipid structures

• Longer the chain length, greater the permeation effect Example: Sucrose palmitate (16 carbon chain) is a better permeation enhancer compared to Sucrose laurate (12 carbon chain)

Fatty acids and derivatives

Effect of fatty acids depends on the presence and the position of double  bonds,  isomer  types  (cis  or  trans),  chain  length  and degree of branching

➢ Sodium laurate and myristate - insulin and calcitonin.

➢ Oleic acid/hydro alcoholic solutions -lidocaine hydrochloride.

Fatty acids and derivatives - Mechanism of action

• Insertion between the alkyl chains of membrane lipids

• Disturbance of the lipid packing order in the deep liquid bilayer and polar head regions

• Increased fluidity of the phospholipids domains.

Vehicles and adjuvants

➢ 10% lauric acid in propylene glycol - insulin

➢ Ethanol (15 to 30%) - peptides

➢ Dimethylsulfoxide (DMSO)

➢ N-methylpyrrolidine (NMP)

Mechanism of action

• Increased drug concentration at the mucosal site

• Increase the solubility of the drug in the epithelial mucosal barrier

• Increasing the partitioning of the drug from the vehicle to the mucosa

Chelators

➢ EDTA,

➢ Salicylates,

➢ Sodium citrate,

➢ Polyacrylates

Mechanism of action of chelators

• Interfere with the calcium efflux of the membrane

• Altering the conformation of peptides and making them less susceptible to enzymatic degradation

Enzyme inhibitors

1.    Peptidase inhibitors.

2.    Protease inhibitors such as aprotinin, bestatin and bile salts

Mechanism of action

Altering the conformation of peptides and making them less susceptible to enzymatic degradation

Cyclodextrins

➢ α-, β-, and γ cyclodextrins

➢ Methylated β- cyclodextrins

Mechanism of action

•    Inclusion of membrane compounds

Eg. Hydroxypropyl cyclodextrin (HPCD) at a concentration of 10 mM increased the flux of buspirone 35 times

Chitosan

• Positively charged biodegradable polymer

• Interact with the negatively charged mucosal surface

• Interaction with the proteoglycan matrix leading to lead to widening of intercellular filaments

• Interference with the extracellular lipid and glycolipid contents

Summary

Mucoadhesive Delivery Systems - Advantages

• Bypass hepatic metabolism, increased bioavailability

• Prevents degradation in GIT

• Rapid absorption, rapid onset of action

• Controlled release and prolonged action

• Improved therapeutic performance

• Localized and targeted action

• Prolonged residence time of the dosage form, permit once or twice a day administration

• Rapid absorption due to good blood flow rate at the absorption site

• Reduction in fluctuations in steady state plasma levels

• Improved patient compliance

Mucoadhesive Delivery Systems Disadvantages

• Gastric motility

• Mucous turnover rate

• Irritating drugs cannot be administered

• Lack of a good model for in vitro screening

• Occurrence of local ulcerous effects due to prolonged contact of the drug

• Patient acceptability in terms to taste, irritancy and mouth feel

Mucoadhesion Theories

• The process of bioadhesion can be broadly classified into two categories, chemical and physical methods

Chemical

• Electronic theory

• Adsorption theory

Physical

• Wetting theory

• Diffusion theory

• Cohesive theory

• Mechanical theory

Mechanisms of Mucoadhesion

The process of adhesion may be divided into two stages.

1. Contact stage: wetting of mucoadhesive polymer and mucous membrane occurs

2. Consolidation stage: physico-chemical interactions prevail

• Factors affecting mucoadhesion – Polymer related and physiological factors

• Polymer related – molecular weight, crosslinking density, hydrophilicity etc

• Physiological – mucin turnover, pathological conditions, etc.

• Mucoadhesive polymers

• ‘Bioadhesion’ can be defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymers

• The term ‘mucoadhesion’ is used when the biological surface is a mucosal surface

• Advantages of mucoadhesive systems – prolonged residence time, controlled drug delivery, increased bioavailability

• Theories of mucoadhesion - Wetting theory, diffusion theory, fracture theory, electronic theory, and adsorption theory

• Mucoadhesive systems – utilize various mucoadhesive polymers

• Methods of transmucosal permeability – passive diffusion, tranfollicular route

• Permeation enhancers used in transmucosal delivery systems – cationic, anionic and non-ionic surfactants

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