Nasal drug delivery system

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NASAL DRUG DELIVERY SYSTEM

Prepared By… Chinchole Pravin Sonu

[IIst sem M. Pharm.]Department of Pharmaceutics

R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur

A SEMINAR ON

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Nasal Drug Delivery System CONTENT

1. INTRODUCTION2. ANATOMY & PHYSIOLOGY OF NOSE3. MERIT & LIMITATION4. MACHANISM OF ABSORPSION5. BARRIARS OF NASAL ABSORPSION6. FACTOR AFFECTIONING NASAL ABSORPSION7. MUCOCILLARY CLEARANCE8. DRUG DISTRUBUTION9. STRATERGIES TO IMPROVE NASAL ABSORPSION10. PENETRATION ENHANCERS11. FORMULATION12. DELIVERY SYSTEM13. EVALUATION14. APPLICATION15. CONCLUSION16. REFERENCE

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Nasal Drug Delivery System

In ancient times the Indian Ayurvedic system of medicines used nasal route for administration of drug and the process is called as “Nasya-karma”

It has been used for local effects extensively in decongestant and local activity.

In recent times intranasal drug delivery is being considered as a preferred route of drug delivery for systemic bioavailability

INTRODUCTION

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ANATOMY & PHYSIOLOGY OF NOSE

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The nasal cavity is run from the nasal vestibule to the nasopharynx which has

depth of approximately 12-14cm.

The nasal vestibule, the respiratory region and the olfactory region are the three

main regions of the nasal cavity.

The submucosal zone of the nasal mucosa directly connects to the systemic

circulation, thus avoids first pass metabolism.

The lateral walls of the nasal cavity includes a folded structure which enlarges

the surface area in the nose to about 150cm2 .

This folded structure includes three turbinates: the superior, the median and the

inferior.

These turbinates increases the area of absorption.

Nasal cavity is about 60mm in length.

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Nasal Drug Delivery System The nasal cavity is covered with a mucous membrane which can be divided

into nonolfactory and olfactory epithelium areas. The nonolfactory area

includes the nasal vestibule and respiratory region.

Nasal blood flow external & internal carotid arteries.

Nasal secretions (1500-2000ml/day):- Goblet cell, nasal glands, lacrimal

glands

Composition:- 95% water, 1-2% salt, 2-3% mucin. in trace amount Na, K,

Ca, Albumin also present.

Nasal enzymes:- Monooxygenase, lactate dehydrogenase, oxidoreductase,

phosphates , hydrolases, esterases, etc.

Nasal pH:- 5.5-6.5(adults)

5.0-6.7(infants & child)

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MERITS Drug degradation is absent.

Hepatic first – pass metabolism is absent.

Rapid drug absorption.

Quick onset of action.

The bioavailability of larger drug molecules can be improved by means of

absorption enhancer or other approach.

Better nasal bioavailability for smaller drug molecules.

Drugs which can not be absorbed orally may be delivered to the systemic

circulation through nasal drug delivery system.

Convenient route when Compared with parenteral route for long term

therapy.

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LIMITATIONS

The absorption enhancers used to improve nasal drug delivery

system may have histological toxicity which is not yet clearly established.

Absorption surface area is less when compared to GIT.

Once the drug administered can not be removed.

Nasal irritation.

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Nasal Drug Delivery SystemMECHANISM OF ABSORPTION

Majority of Drugs are absorbed by passive diffusion.

Some may be by active transport, such as amino acids.

Literature shows that upto 1000dalton drug get easily absorbed without help of

penetration enhancers.

Two mechanisms are found:

Transcellular process: Transport of lipophillic drugs through cell membrane

by active transport or transport through opening of tight junction.

Example: Levodopa,Carbidopa

Paracellular process: It involves aqueous route of transport. it is slow and

passive.Water soluble drugs which have moleculer weight greater than 1000

daltons shows poor bioavailability.

Example: Insulin,MSH,ACTH

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PATHWAY OF ABSORPTION

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Nasal Drug Delivery System BARRIERS TO NASAL ABSORPTION

Low Bioavailability: It is due to Low membrane permeability (limiting factor for high

mol.weight polar drugs like protein and peptides )

Low Membrane Transport: Rapid clearance of administered formulation due to MCC.

Ex: Liquid and powder formulation shows rapid clearance

Enzymatic Degradation: Degradation of protein and peptides by Exopeptidase and Endopeptidase.

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Nasal Drug Delivery System FACTORS AFFECTING ABSORPTION

Chemical form:

The form of a drug can be important in determining absorption.

Example : Nasal absorption of carboxylic acid esters of L-Tyrosine significantly

greater than that of L-Tyrosine.

Polymorphism:

Polymorphism is known to affect the dissolution rate, solubility of drug and thus

their absorption through biological membranes.

Molecular Weight:

A linear correlation has been reported between the absorption of drugs and

molecular Weight up to 300 Daltons.

Absorptions decreases significantly if the molecular weight is greater than

1000 Daltons (except with the use of absorption enhancers).

http://www.pharmainfo.net/tablet-evaluation-tests/dissolution

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Nasal Drug Delivery System Particle Size:

It has been reported that particle sizes 10 -20 μm are deposited in the nasal

cavity. Particles Which are less than 2 μm can be retained in the lungs, and particles

of greater than 20 um size exhaled with air.

Solubility and Dissolution Rate:

Drug solubility and dissolution rates are important factors in determining nasal

absorption from powders and suspensions. The particles deposited in the nasal

cavity need to be dissolved prior to absorption.

Nasal pH:

5.5-6.5(adult)

5.0-6.7(infants)

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Nasal Drug Delivery SystemMUCOCILIARY CLEARANCE

It is a preventive function.

Prevents the entry of hazardous particles

When the drugs adhere to the nasal mucosa, they eventually goes into nasopharynx

and lead towards GIT.

This clearance of mucus & the adsorbed/dissolved substances into GIT called as

Mucocilliary clearance.

A-Ciliated cellsB-Nonciliated cells C-Goblet cellsD-Mucus layerE-Sol layerF-Basal cellsG-Basement membrane

Fig- Cell types of the nasal epithelium

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Strategies To Improve Nasal Absorption1.Nasal Enzymes Inhibitors:

eg- peptidases, proteases, tripsin, aprotinin, borovaline, amas-tatin, bestatin and boroleucin

inhibitors.

2.Formulation Design:

3. Modifying drug structure:

eg- chemical modification of salmon calcitonin to ecatonin (C-N bond replaces the S-S

bond) showed better bioavailability than salmon calcitonin.

4.Prodrug approach:

eg- peptides like angiotensin II, bradykinin, caulein, carnosine, enkepha-lin, vasopressin

and calcitonin.

5.Particulate drug delivery:

6.Absorption Enhancers:

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Nasal Drug Delivery System Mechanism of Penetration Enhancers:

Inhibit enzymetic activity

Reduce mucus viscosity

Reduce MCC

Open tight junctions

Solubilize the drug

Ideal Properties:

1.It should increase in the absorption of the drug

2. It should not cause permanent damage or alteration to the tissue

3. It should be non irritant and nontoxic.

4. It should be effective in small quantity.

5. The enhancing effect should occur when absorption is required .

6. The effect should be temporary and reversible .

7. It should be compatible with other excipients.

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Nasal Drug Delivery System Classification of penetration enhancer

Type Examples

Surfactants Sodium dodecyl sulphate,Polyoxyethylene-9-lauryl ether, Saponin

Complexing and chelating agents EDTA, Salicylates

Cyclodextrins and derivatives α-, β-, γ-cyclodextrin, DMβ-cyclodextrin, HPβ-cyclodextrin

Bile salts Sodium taurocholate Sodium glycocholateSodium deoxycholatFusidic acid derivatives

Fatty acid salts Oleic acid, Caprylate (C8), Caprate (C10), Laurate (C12)

Dry microspheres Degradable starch microsphereDextran microsphere

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Nasal Drug Delivery SystemFORMULATION CONSIDERATION

pH of the formulation It is important as.. To avoid irritation of nasal mucosa. To allow drug to be available in unionised form for absorption. To prevent growth of the bacteria in nasal passage. To sustain normal physiological ciliary moments.

HUMECTANTS To prevent dehydration adequate intranasal moisture is required and therefore

humectants are added. Prevent nasal irritation. The commonly used humectants are - Glycerine - Sorbitol - Manitol

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Nasal Drug Delivery System OSMOTIC AGENT The osmolarity of the dosage form affect the nasal absorption of the drug. The higher concentration of drug not only causes increased bioavailability but also

leads to the toxicity to the nasal epithelium. The commonly used osmotic agents are Sodium Chloride Sodium sulfite Sodium acid phosphate

SOLUBILISERS Aqueous solubility of drug is always a limitation for nasal drug delivery of dosage form. Commonly used solubilisers are Glycols Small quantities of alcohol Transcutol(diethylene glycol monoethyl ether) Medium chain glycerides Labrasol(saturated polyglycolysed C8-C10 glycerides)

Surfactant Cyclodextrin (B-cyclodextrin)

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Nasal Drug Delivery System GELLING/VISCOSIFYING AGENTS/GEL FORMING CARRIER Increasing solution viscosity may provide means of prolonging the therapeutic effect

of nasal preparations. Highly viscous formulations interfere with the normal functions like ciliary beating or

mucociliary clearance and thus alter the permeability of drug. Commonly used gelling agents are… Carbopol, Cellulose agents, Starch, Dextran, Chitosan, etc.

ABSORPTION ENHANCERS Unlike the most small drug molecules, some drugs and peptides do no cross the nasal

membrane efficiently. The nasal mucosa is almost impermeable to molecular size greater than 1000 Dalton. The low nasal membrane permeability is due to Molecular Size Lack Of Lipophilicity Enzymatic Degradation

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Nasal Drug Delivery System ANTIOXIDANT Usually antioxidants do not affect drug absorption or cause nasal irritation. Chemical / Physical interaction of antioxidant with drug and excipients should be

considered during formulation development. Commonly used antioxidants are - Sodium Metabisulfite - Sodium Bisulfite - Butylated Hydroxytoluene - Tocopherol.

PRESERVATTVE Commonly Used Preservatives Parabens Benzolkonium Choride Phenyl Ethyl Alcohol Benzoyl alcohol Mercury containing preservatives are not used.

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DELIVERY SYSTEM

Nasal Drops Nasal drops are one of the most simple and

convenient systems developed for nasal

delivery.

Nasal drops delivered the drug to a larger area

back in the nasal cavity.

The main disadvantage of this system is the

lack of the dose precision.

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Nasal spray Both solution and suspension formulations

can be formulated into nasal sprays.

Due to the availability of metered dose

pumps and actuators, a nasal spray can

deliver an exact dose from 25 to 200 μm.

Choice of pumps and actuators:-

The particles size and morphology of the

drug

viscosity of the formulation .

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Nasal Gels Nasal gels are high-viscosity thickened

solutions or suspension .

Advantages :

• The reduction of post-nasal drip due to

high viscosity .

• Reduction of taste impact due to reduced

swallowing.

• Reduction of leakage of the formulation.

• Reduction of irritation by using emollient.

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Nasal Powder This dosage form may be developed if

solution and suspension dosage forms

can not be developed , such as lack of

drug stability.

Advantages:

Absence of preservatives

Local application of drug

stability of formulation

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Nasal Aerosols

FORMULATION• Active Drug• Surfactant• Co-solvent• Propellant

Eg:-BUDESONIDE NASAL AEROSOL INHALER.

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Nasal Drug Delivery SystemEVALUATION

IN VITRO NASAL PERMEATION STUDIES

USSING CHAMBER :- (Hans Ussing)

Chamber consist of U-shaped tubing system, usually made of glass, filled with experimental solution.

Barrier used are excised nasal mucosa from rats or rabbits.

Drug solution is introduced into the mucosal side of the chamber and samples were collected from receiver chamber.

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Nasal Drug Delivery SystemEX VIVO NASAL PERFUSION MODEL

Fig- Experimental setup for ex-vivo nasal perfusion studies

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Nasal Drug Delivery System IN VIVO NASAL ABSORPTION STUDIES

1. RAT MODEL The rat is anaesthetized by

intraperitoneal injection of sodium pentobarbital.

An incision is made in the neck and the trachea is cannulated with a polyethylene tube.

The passage of the nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth.

The blood samples are collected from the femoral vein.

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2. RABBIT MODEL

Rabbits anaesthetized by intramuscular injection of a combination of ketamine and xylazine.

The rabbit's head is held in an upright position and the drug solution is administered by nasal spray into each nostril.

The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.

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3. DOG MODEL

The dog is anaesthetized by intravenous injection of sodium thiopental and the anesthesia is maintained with sodium Phenobarbital.

A positive pressure pump through a cuffed endotracheal tube gives the ventilation.

The blood sampling is carried out from the jugular vein.

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Nasal Drug Delivery System4. SHEEP MODEL Practical and suitable for

investigating nasal delivery formulations.

Male in-house bred sheep are employed since they are free from nasal infections.

5. MONKEY MODEL • The monkey is tranquillized by

intramuscular injection of ketamine hydrochloride or anaesthetized by intravenous injection of sodium Phenobarbital.

• The head of the monkey is held in an upright position and the drug solution is administered into each nostril.

• The blood samples are collected through an indwelling catheter in the vein.

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Nasal Drug Delivery SystemAPPLICATION OF NASAL DRUG DELIVERY

SYSTEMS

1. Delivery of non-peptide pharmaceuticals

EX.. Progesterone, estradiol, propranolol, nitroglycerin, sodium chromoglyate, etc.

2. Delivery of peptide-based pharmaceuticals

Eg. Insulin, Calcitonin, Pituitary hormones etc.

3. Delivery of Diagnostic Drugs Phenolsulfonphthaline-For diagnosis of kidney functions

Secretin-For diagnosis of pancreatic disorders

Pentagastrin-For diagnosis of secretory functions of gastric acid.

Cerulin-For diagnosis of Gallbladder function

Vital dyes-Trypan blue and Evans blue (it can not enter in cranium because they

can not pass through sheath)

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Nasal Drug Delivery System4. Delivery of drugs to Brain: For Treatment of Parkinson’sdisease,Alzheimer disease.

For Delivery of MSH,ACTH,Insulin to brain

5. Delivery of Vaccines : Nasal mucosa is the first site of contacts with inhaled pathogens Nasal passages are rich in lymphoid tissue Creation of both mucosal and systemic immune responses Non injectableExamples: Nasal Vaccines are Prepared for Measels,pertussis,meningitis and Influenza

virus because these pathogens enter into the body through nasal mucosa.

Nasal delivery of vaccines produces both local and systemic immune response.

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Drug Brands Delivery Action Indications Azelastine Astelin

(Meda)Duonase(Cipla)

Nasal spray Local Allergic rhinitis

Beclometasone

Beconase(Glaxo)

Nasal spray Local Hay fever

Ciclesonide Zetonna(Sunovion pharma)

Nasal aerosol

Local Allergies

Xylomethazoline

Otrivin(novartis)

Nasal sprayNasal gel

Local Congestion , Sinusitis

Oxytocin Syntocinon(novartis)

Nasal spray Systemic Labor pain

Cynocobalamine

Nascobal(par. pharma)

Nasal gelNasal spray

Systemic Pernicious Anaemia (B12 def)

Marketed Preparations

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Nasal Drug Delivery SystemCONCLUSION

Nasal route is attractive for the delivery of the many drugs and vaccines. Studies are going on improving the efficiency of the nasal route. Outcome of these studies is that we can utilise it for treatment of diabetes,

osteoporosis, infertility.

Nasal drug delivery offers such benefits as

- Rapid onset of action with lower dose & minimal side effects

It has an advantage of site-specific delivery with improved therapeutic effects.

Allowing systemic administration without significant degradation.

Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray

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Nasal Drug Delivery SystemREFERENCES

Y.W.Chein, K.S.E. Su and S.F.Chang. “Nasal systemic drug delivery” Dekker, 1989, 27-34,89,199.

Anya M.Hillery, Andrew W.Lloyd, James Swarbrick. “Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists” published by Taylor & Francis, 2001, 215-243.

M.E. Aulton “ Pharmaceutics – The science of dosage form design” Churchill Livingston., 2002, 494.

Y.W.Chein, “ Novel drug delivery systems”, Marcel Dekker Inc.50 (2), 1982, 229- 260. Latika Nasare* , Kamlesh Niranjane, Anuradha Nagdevte, Sumedh Mohril “Nasal drug

delivery system : An Emerging Approach For Brain Targeting’’ Review Article of WJPPS.

M.Alagusundaram*, B.Chengaiah, K.Gnanaprakash, S.Ramkanth, C.Madhusudhana Chetty, D.Dhachinamoorthi “Nasal drug delivery system - an overview” Review Article of IJIPRS.

RAHISUDDIN*, PRAMOD K SHARMA, GARIMA GARG, AND MOHD SALIM “REVIEW ON NASAL DRUG DELIVERY SYSTEM WITH RECENT ADVANCEMNT” Review Article of IJPPS.

Shivam Upadhyay, Ankit Parikh, Pratik Joshi, U M Upadhyay and N P Chotai “Intranasal drug delivery system- A glimpse to become maestro” Review Article of JAPS.

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Date post:	15-Apr-2017
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