Presented by:GOH CHEOW KATHAINORITA HAIRONMOHD.REHANNORSAKILAH MOHD. NORDI

Application of Chitosan as Drug Delivery Material in Pharmaceutical and Industry

INTRODUCTION

What is Chitosan?

Extracted sugar from exoskeleton of crustacean E.g. crab, shrimp, lobster and other shellfish

CHITOSAN

De Andrade et al. (2012) The Use of Exoskeletons of Shrimp (Litopenaeus vanammei) and Crab (Ucides cordatus) for the Extraction of Chitosan and Production of Nanomembrane. Materials Sciences and Applications, 3, 495.

Structure of the polymeric long chain chitosan

APPLICATIONS OF CHITOSAN

Bansal, V., Sharma, P. K., Sharma, N., Pal, O. P., & Malviya, R. (2011). Applications of chitosan and chitosan derivatives in drug delivery. Advances in Biological Research, 5(1), 28-37.

Cosmetic

Ocular, mucosal, topical delivery

Coating materials

INTRANASAL DRUG DELIVERY SYSTEM

CHITOSAN AS INTRANASAL DRUG DELIVERY AGENT

Biodegradability Biocompatibility Bioadhesive Low toxicity

Pires, A., Fortuna, A., Alves, G., & Falcão, A. (2009). Intranasal drug delivery: how, why and what for?

Nasal preparations for chitosan can be found several forms: sprays drops creams ointments Solutions for irrigation

P. Arora, S. Sharma, S. Garg. (2002). Permeability issues in nasal drug delivery. Drug discovery today, 7(18), 967-975.

A. Rapoport, P. Winner. (2006). Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache: The Journal of Head and Face Pain, 46(s4), S192-S201.

CHITOSAN AS INTRANASAL DRUG DELIVERY AGENT

Chitosan + protein kinase C

Opening of tight junction between epithelial cell

Increase paracellular transport of polar drugs Resulted from activation of specific cell

surface receptor Lead to activation of PKC dependent signal

transduction pathway.Pires, A., Fortuna, A., Alves, G., & Falcão, A. (2009). Intranasal drug delivery: how, why and what for?

CHITOSAN AS INTRANASAL DRUG DELIVERY AGENT

Nasal absorptionEpithelial cell carrier

Epithelial cell barrierThere are three main junctional complexes:

1. zona occludens which is nearest to the apical surface (normallyreferred to as the tight junction)2. zona adherence (below zona occludens)3. macula adherence (below zona adherence)

The structural components of the tight junctions and the possible modulating factors are shown in Fig. 1

The tight junction comprises a series of integral membrane proteins that interact with the components of thecytoskeleton through other proteins.

The key components in the extracellular cell to cell contacts between adjacent epithelial cells arethe transmembrane proteins occludin and claudin and the junctionaladhesion molecule, JAM.

The NH2 and COOH termini of the occludinare situated in the cytoplasma of the cell and the COOH interacts (areanchored) to the N-termini of the scaffolding proteins ZO-1, ZO-2and ZO-3 present in the cytoplasm, which again is linked to theF-actin as shown in Fig. 1

Physical and Chemical propertiesdegree of deacetylation (40-98%) molecular weight is (50 kDa-2000

kDa)insoluble in neutral and basic solution forms salts with inorganic or organic

acids such as HCl and glutamic acid that are soluble in water

positively charged at acidic pH and its apparent pKa (6.1-7.3)

The higher the ionic strength the lower the solubility and the more folded the conformation due to shielding of the positive charges.

ability to interact through its positively charged amino groups with the anionic counterpart present in the mucous layers

chitosan derivatives in the form of trimethylated, PEGylated, carboxylated and thiolated chitosans have been produced

Molecular structure

Chitosan chemical structure

Trimethylated chitosan

Molecular grafted structure of chitosan-PEG-FA complex. (1) Chitosan; (2) PEG; (3) folic acid

Carboxylated chitosan

Thiolated chitosan

Nasal Delivery System ;)

NASAL DRUG DELIVERY SYSTEM ?

A rapid onset of action is possible through nasal route, for the administration of systemically acting products. Deposition of an active compound in the nasal cavity results in avoidance of its degradation through the ‘‘first-pass’’ metabolism. Avoids parentral administrationRapid absorption, peaking generally within 15–30 minutesApparent permeability to some peptidesEase of self-administration/good patient compliancelower doses and less side effectsRate of absorption comparable to IV medication.User-friendly, painless, non-invasive, needle-free administration mode.Useful for both local & systemic drug delivery.The nose is a very easy access point for medication delivery.

Anatomy of nasal cavity delivery

1.The anterior one-third of the nasal cavity viewed in cross-section reveals a central septum dividing the two cavities. This region, including the proximal portion of the inferior and middle turbinates, is nonciliated .    

2. In the posterior two-thirds of the nasal cavity, clearance of deposited particles occurs by slow spreading of the mucus layer into the ciliated regions along the inferior and middle meatuses, followed by a more rapid mucociliary clearance into the nasopharynx from where they are swallowed.  

3. Approximately 1 L of mucus is transported from the anterior part to the posterior part of the nose per day. It takes approximately 20–30 min for the whole mucus layer to be renewed. a – nasal vestibule d – middle turbinate b – palate e – superior turbinate (olfactory mucosa) c – inferior turbinate f – nasopharynx

Nose- Brain Pathway Pathways for nasal absorption - Absorption

through the olfactory neurons - transneuronal absorption. Olfactory epithelium is considered as a portal for substances to enter CNS Nose brain pathway

The olfactory mucosa (smelling area in nose) is in direct contact with the brain and CSF.

Medications absorbed across the olfactory mucosa directly enter the CSF.

This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain.

Olfactory mucosa, nerve Highly vascular nasal mucosa Brain CSF

Mechanism of nasal delivery

Optimization of chitosan as excipient for nasal to

brain targeting

For years, the blood-brain barrier is considered to be an obstacle for a large number of drugs.

Blood Brain Barrier- allow a small amount of therapeutics drugs goes into central nervous system

To overcome-chitosan can act as excipient to deliver drugs from the nasal cavity to the central nervous system.

Blood Brain Barrier

Fig. 1. The blood-brain barrier. The

blood-brain barrier has several important functions that include

filtering of large molecules and polar

solutes.

chitosan as excipient have bioadhesion and absorption capability to the formulation intended to deliver the drugs from the nasal cavity to the CNS.

in order for the enhancer systems to increase the transport into the brain, the formulations need to be placed near the targeted tissue

Olfactory regiondecreased plasma level,increasedbrain level

Respiratory areaincreased plasma level, decreasedbrain level

chitosan as nanoparticles this nanoparticles pass epithelial membranes either transcellularly or paracellularly. In paracellular transport, a diameter <20 nm is necessary to pass the epithelial tight junctions and entering the brain

Chitosan microspheresCan be produced by produced by various methods such as spray drying and emulsification.allowed a control release of drug from the microparticles also a significant burst release,which allowed the required rapid onset of the therapeutic effect

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