The Project Presentation is submitted to BCDA COLLEGE OF PHARMACY AND TECHNOLOGY

Under the guidance of

Mr. Seemanchala Rath, Assistant ProfessorM. Pharm. (Utkal Univ.)

By

Nilanjan Bhattacharya B. Pharm. 7th Sem.University Roll No : 20101911022

&

Prosenjit Chakraborty B. Pharm. 7th Sem.University Roll No : 20101911026

• The use of nasal cavity as a route of administration ofdrugs, specifically systemically acting drugs that pose adelivery challenge, have become an area of greatinterest.

• In situ forming polymeric formulations are drugdelivery systems that are in sol form beforeadministration in the nasal cavity, but onceadministered, undergo gelation in situ, to form a gel.

• This presentation will gives us an overview of howmucoadhesive in situ gels as a promising approach fornasal drug delivery system.

Fig:2 Cell types of the nasal epitheliumshowing ciliated cell (A), non-ciliated cell(B),goblet cells(C), gel mucus layer (D), sol layer(E), basal cell (F) and basement membrane(G)

Fig:1 Parts of nasal cavity consists of nasalvestibule, inferior turbinate, middleturbinate, superior turbinate & Olfactory

neurons.

• Results in higher bioavailability thus use lower doses ofdrug.

• Results in rapid absorption and onset of action.

• Easily accessible, non-invasive route.

• Avoids degradation of drug in GIT resulting from acidic orenzymatic degradation.

• High molecular weight compounds cannot bedelivered through this route.

• Volume that can be delivered into nasal cavity isrestricted to 25 –200 µl.

• It involves an aqueous route oftransportation.

• The absorption here is slow.

• It is also known as theparacellular route.

FirstMechanism

• It involves a lipoidal route oftransportation.

• Drug cross cell membranes by anactive transport route via carrier-mediated means or transport throughthe opening of tight junctions.

• It is also known as the transcellularprocess.

SecondMechanism

• The mucoadhesives spread overthe substrate to initiate closecontact & increase surfacecontact, promoting the diffusionof its chains within the mucus.

• Attraction and repulsion forcesarises for a mucoadhesive to besuccessful.

• Mechanism of mucoadhesion areof two steps :

Contact stage

Consolidation stage

Mucoadhesion is a state in which two materials, one of which isbiological in nature, are maintained together for a prolonged timeperiod by means of interfacial forces.

Mucoadhesive Carrier

Hydration & Swelling of Polymers

Hydrophilic Macromolecular Drug

Internal Absorption

Interaction with Mucus

Drug Release

Ciliary Clearance Enzymatic Metabolism

Gels

• Gel is the state which exists between solid and liquidphase.

• The solid component comprises a three dimensionalnetwork of inter-linked molecules.

In-Situ Gel Delivery System

• It is a process of gel formation at the site of actionafter the formulation has been applied at the site.

• The phenomenon based upon liquid solution ofdrug formulation and converted into semi-solidmucoadhesive key depot.

• Increased residence time of drug in nasal cavity.

• Low dose required.

• Results in rapid absorption and onset of effect.

• The nasal in-situ gel follows phase transitionmechanism and to stand with the shear forces in thenasal cavity wall.

• Nasal in-situ gel should have long residence time.

• It should be of low viscosity.

They can be classified under:

IN SITU FORMING

HYDROGELS

In situ gel formation based on physiological

stimuli

Thermally triggered

pH triggered

In situ gel formation based

on chemical reactions

Ionic cross linking

Photo-polymerization

A. Thermally triggered

• Three main strategies exist for thermally triggered system :

• Negatively thermo-sensitive have lower critical solutiontemperature (LCST).

• positively thermo-sensitive have upper critical solutiontemperature (UCST).

• Thermo-reversible gels are made from Pluronics.

• All the pH-sensitive formations contain acidic or basicgroups that either accept or release protons which istriggered by the change in environmental pH.

A. Ionic Cross-linking

• Polymers may undergo phase transition in presence ofvarious ions

• k-carrageenan forms rigid, brittle gels in replacement ofsmall amount of K+ while i-carrageenan forms elastic gelsmainly in the presence of Ca2+ ion.

• Alginic acid undergoes gelation in presence of divalent/polyvalent cations.

• A solution of monomers or reactive macromers andinitiator can be injected into a tissue site and anelectromagnetic radiation used to form gel.

• Acrylate or similar functional groups undergo photo-polymerization in the presence of suitable photo initiator.

1. Measurement of gelation temperature and gel

melting.

2. Gel-strength.

3. Viscosity and rheology.

4. Evaluation of the mucoadhesive strength.

5. In vitro drug diffusion.

6. In vitro permeation studies.

1. Lectins

• Lectins are carbohydrate-binding proteins, macromoleculesthat are highly specific forsugar moieties.

• Lectins have the ability to stay onthe cell surface .

• Lectins allow target specificattachment & also act as a meansof delivering the drug through acontrolled process to the cells .

• Thiomers are mucoadhesivepolymers having side chainscarrying thiol which lead toformation of covalent bondsbetween the cystiene groups inthe mucus and the polymer bysimple oxidation process.

• Thiolated polymers display in situgelling properties due to theoxidation of thiol groups atphysiological pH-values resulting inthe formation of intermolecularand intramolecular disulfidebonds.

• This increases theviscosity of theformulation therebyincreasing theresidence time of theproduct tremendously.

2. Thiomers

3. Alginate Poly-Ethylene Glycol Acrylate

• Alginate-PEGA has analginate backbone withacrylated polyethylenglycolgroups attached to it.

• It is known to undergo ionicsol to gel transition(gelation) upon interactionwith multivalent ions such asCa2+, Fe2+.

• Combining these threefunctional moieties ofAlginate Polyethyleneglycol Acrylate leads toan improved novelpolymer which can beused mucoadhesivenasal drug delivery.

4. Poloxamer (Pluronics)

• Poloxamers are made non-ionic difunctional triblockcopolymers containing a centrally located hydrophobicpolypropylene oxide between hydrophilic polyethyleneoxides.

• Poloxamers have thermoreversible property whichconvert from a liquid to a gel at body temperature,thus, causing in situ gelation at the site of interest.

• Poloxamers are also known as Pluronics.

• Pluronics have been chemically combined with poly(acrylic acids) to produce systems with enhancedadhesion and retention in the nasal cavity. E.g.:Poloxamer 407 (Pluronic F127) .

• Mucoadhesive nanoparticlesoffers better encapsulationefficiency, enhancedbiocompatibility control release &has less toxic properties.

• Polymeric mucoadhesive NP withimproved sinus mucuspenetration capability which maylead to the development of newgenerations of nanoparticle basedintranasal drug deliverysystems.

1. Mucoadhesive Nanoparticles

2. Bacterial Adhesion

• The attachment ofsynthetic/natural macromoleculesto mucus or epithelial surface isdefined as bioadhesion.

• Bacteria are capable of adhering tothe epithelium surface with aid offimbriae, which are long, lectin-like proteins found on the surfaceof many bacterial strains.

• The adhesion of bacteria toepithelial surfaces is used as anefficient method for nasal drugdelivery with the intention ofreducing mucociliary clearance.

3. Altered Amino Acid Sequence

• Certain amino acid sequencescan be used to promote bindingof drug molecules to specific cellsurface glycoproteins due to theamino acids havingcomplementary sequencespresent to these glycoproteins.

• In certain disease conditions thesequence of glycoproteins isaltered.

• This altered state can be used asa target by complementaryamino acid sequences byattaching them to a drug deliverydevice.

4. Antibody mechanism

• Antibodies can be a rationalchoice as a polymeric ligand fordesigning site-specificmucoadhesives due to theirhigh specificity.

• Antibodies can be producedagainst selected moleculespresent on mucosal surfaces.

• This approach can be useful fortargeting drugs to tumor tissuesor even normal cells.

There is no question that the nasal route has a greatpotential for systemic drug delivery. . As nose- to- braindelivery makes it possible to by-pass the blood-brainbarrier for certain drugs; administration of drugs viathis route for treatment of neurological diseasespresents exciting opportunities. Several strategies havebeen developed to enable the drug molecules to attachonto the mucus or epithelial layer, thus preventingthem from being cleared from the nasal cavity. Theapplication of lectins, thiomers, alginate poly-ethyleneglycol acrylate and poloxamers have been of great useto overcome the challenges.

• Singh S, Kanupriya and kumar S.L.H, INTRANASALTHERMOREVERSIBLE MUCOADHESIVE GELS: AReview, International Journal of Pharmacy, 2012; vol:2,Issue-3.

• Utkarshini Anand, Tiam Feridooni and Remigius U. Agu,Novel Mucoadhesive Polymers for Nasal DrugDelivery,INTECH. (http://dx.doi.org/10.5772/52560)

• Alagusundaram M*, Chengaiah B, Gnanaprakash K,Ramkanth S, Chetty CM, Dhachinamoorthi D, Nasal drugdelivery system - An overview, International Journal ofResearch in Pharmaceutical Sciences, 2010 Vol-1, Issue-4,454-465.