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NASAL DRUG DELIVERY SYSTEM

PRESENTED BYNeha singhM.pharm 1 yr.

GUIDED BYV.B pokharkarHod Pharmaceutics

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Novel drug delivery is one of the

fastest growing healthcare

sectors, with sales of drugs

incorporating novel drug delivery

systems increasing @ an annual

rate of 15%

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Oral Inject-able Mucosal

Trans-derma

lOcular

Vaginal/Anal

Needle

Needle-less

Nasal

Buccal

Pulmo-nary

Active

Passive

Topical

DRUG DELIVERY STSTEM

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GLOBAL DRUG DELIVERY MARKET BY

ADMINISTRATION MODE

Oral 53%

Inhation 32%

Transdermal 8%

Injectable/Implant 3%

Ocular 2%Nasal 2%

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Nasal Drug Delivery

New Chemical Entity

$50 mio

$300-600 mio

DRUG DEVELOPMENT COST

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New Chemical Entity

Nasal drug Delivery2 – 5 years

10 – 14 years

DRUG DEVELOPMENT TIME

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It is also a type of muco-adhesive drug delivery system.

Intranasal Medication administration offers a truly

“Needleless” solution to drug delivery.

Therapy through intranasal administration has been an

accepted as form of treatment in the Ayurvedic system

of Indian medicine

INTRODUCTION

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NASAL ENZYMES:• Cytochrome p-450 dependent oxygenase , lactate

dehydrogenase , oxydoreductase , acid hydrolases, esterases, lactic dehydrogenases, malic enzymes, lysosomal proteinases, steroid hydroxylases etc.

NASAL PH:

• Adult nasal secretion pH: 5.5-6.5• Infants & children : 5-6.7.• Lysosome in the nasal secretion helps as antibacterial &

its activity is diminished in alkaline pH.

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ADVANTAGES OF NASAL DRUG DELIVERY SYSTEM

1 A noninvasive route.

2. Hepatic first – pass metabolism is absent.

3. Rapid drug absorption.

4. Quick onset of action.

5. The bioavailability of larger drug molecules can be improved by

means of absorption enhancer or other approach.

6. Better nasal bioavailability for smaller drug molecules.

7. Drugs which can not be absorbed orally may be delivered to the

systemic circulation through nasal drug delivery system.

8. Convenient route when compared with parenteral route for long

term therapy.

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LIMITATIONS

1. The absorption enhancers used to improve nasal drug delivery

system may have histological toxicity which is not yet

clearly established

2. Absorption surface area is less when compared to GIT.

3. Once the drug administered can not be removed.

4. Nasal irritation.

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ANATOMY OF NOSE

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Site of drug

spray &

absorption

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 brain.

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

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Olfactory mucosa

Highly vascular nasal mucosa

BrainCSF

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MECHANISM OF DRUG ABSORPTION

Paracellular transport

• Aq route of transport.• Slow and passive.

Transcellular transport

• Transport through lipoidal membrane

• Active transport via carrier mediated means.

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FORMULATION DEVELOPMENT

Dosage form

Formulation considerations

Factors affecting drug absorption

Physiological

Pharmaceutical

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DOSAGE FORMS

Liquid drop

Liquid spray/nebulizers

Suspension spray/nebulizers

Gel

Sustained release

Aerosol

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FACTORS AFFECTING DRUG ABSORPTION

Drug concentration

Mucosal contact time

pH of the absorption site

Size of the drug particle

Relative lipid solubility

Molecular weight of the drug

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PHYSIOCHEMICAL PROPERTIES OF DRUGS

1. Effect of perfusion rate

2. Effect of perfusate volume

3. Effect of solution pH

4. Effect of drug lipophilicity

5. Effect of initial drug concentration.

6. Chemical form

7. Polymorphism

8. Partition coefficient

9. Solubility and dissolution

10. Partical size

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PHYSIOLOGICAL FACTORS

1. Blood flow

2. Enzymatic degradation

3. Volume of administration

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METHODS TO ENHANCE NASAL ABSORPTION

OF DRUGS

Structural modification

Formulation design

Salt or ester formation

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Strategies for improving drug availability in nasal administration:

1.Improve nasal residence time

• Apply drug anteriorly• Formulation with polymers• Use of biodegradable microspheres

2.Enhance nasal absorption

• Increase the rate at which drug passes through nasal absorption.

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FORMULATION EXCIPIENTS

Buffer capacity-citrate buffer

Osmolarity-sodium acid phosphate

Viscosifying agent-carbapol,cellulose

Solublizer-labrasol,surfactants

Preservatives-benzalkonium cl,parabens

Antioxidants-tocopherols,sodium metabisulphide

Humectants-glycerine,sorbitol

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Zero order transdermal permeation kinetic=

Plasma concentration=

First order transnasal permeation kinetic=

Plasma concentration=

PHARMACOKINETICS OF NASAL ABSORBTION

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APPLICATIONS

Delivery of non-peptide pharmaceuticals

Delivery of diagnostic drugs

Delivery of peptide-based

pharmaceuticals

Cns delivery through nasal route

Nasal vaccination

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Drugs with extensive pre-systemic metabolism, such as

- progesterone

- estradiol

- propranolol

- nitroglycerin

- sodium chromoglyate

can be rapidly absorbed through the nasal mucosa with a systemic

bioavailability of approximately 100%

1.Delivery of non-peptide pharmaceuticals:

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Peptides & proteins - low oral bioavailability because of

their physico-chemical instability and susceptibility to hepato

gastrointestinal first-pass elimination

Eg. Insulin, Calcitonin, Pituitary hormones etc.

Nasal route is proving to be the best route for such

biotechnological products

2.Delivery of peptide-based pharmaceuticals:

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Diagnostic agents such as

Phenolsulfonphthalein – kidney function

Secretin – pancreatic disorders

Pentagastrin – secretory function of gastric acid

3. Delivery of diagnostic drugs

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4.CNS delivery through nasal route :

The delivery of drugs to the CNS from the nasal route may

occur via olfactory neuroepithelium

Drug delivery through nasal route into CNS has been

reported for

i. Alzheimer’s disease

ii. brain tumours

iii. epilepsy

iv. pain and sleep disorders.

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5.Systemic delivery:

Fast and extended drug absorption

Ex.- analgesics (morphine),

i. cardiovascular drugs(propranolol)

ii. hormones (levonorgestrel, progesterone)

iii. antiviral drugs

Marketed formulation- zolmitriptan and sumatriptan

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6.Nasal vaccines

Nasal mucosa is the first site of contact with inhaled antigens and therefore, its use for vaccination, especially against respiratory infections, has been extensively evaluated.

Ex. Human efficacy of intranasal vaccines include those against influenza A and B virus, proteosoma‐influenza, adenovirus‐vectored influenza, group B meningococcal native, attenuated respiratory syncytial virus and parainfluenza 3 virus.

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SPRAY PUMP DEVICES

- Unidose

- Bidose

- Multidose

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DOSAGE FORMS

Liquid drop

Liquid spray/nebulizers

Suspension spray/nebulizers

Gel

Sustained release

Aerosol

Nasal drops

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Most simple and convenient systems developed for nasal delivery. It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal sprays. Disadvantage-lack of the dose precision .

Nasal sprays

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Both solution and suspension formulations can be formulated into nasal sprays.

Deliver an exact dose from 25 to 200 μm.

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Lincoln Pharma wins patent for a novel nasal drug delivery system

Presently in India anti-vomiting treatments are available in the conventional form of tablet and injection which take longer time to bring relief.

LPL becomes the first company in India to introduce an anti-vomiting treatment in the form of a Nasal spray pump.

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Nasal Gels Nasal gels are high-viscosity thickened solutions or suspensions. Advantages of a nasal gelReduction of post-nasal drip due to high viscosity,Reduction of taste impact due to reduced swallowing,Reduction of anterior leakage of the formulation,Reduction of irritation by using soothing/emollient excipients and target to mucosa for better absorption.

Mucosal Atomization Device (MAD)

Device designed to allow emergency personnel to delivery nasal medications as an atomized spray.

Broad 30-micron spray ensure excellent mucosal coverage.

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Stem Cell Nasal Spray For Parkinson Disease Significantly Improves Motor Function

Successful intranasal delivery of stem cells to the brains of rats with Parkinson disease yielded significant improvement in motor function and reversed the dopamine deficiency characteristic of the disease.

This was reported as a Rejuvenation Research in journal published by Mary Ann Liebert.

Nasal vaccines

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Nasal mucosa is first site of contact with inhaled antigens and, therefore, its use for vaccination, especially against respiratory infections

Promising alternative to the classic parenteral route, because it is able to enhance the systemic levels of specific immunoglobulin G and nasal secretary immunoglobulin A.

Examples of human efficacy of intranasal vaccines include those against influenza A and B virus, proteosoma influenzaIntra nasal H1N1 vaccine Nasovac by Serum Institute

Therapeutic class of drugs for nasal

route

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1. 2 adrenergic agonists

2. Corticosteroids

3. Antiviral

4. Antibiotics

6. More recently, vaccines

5. Antifungal

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CONCLISION

An accessible alternative route for drug administration.

Provides future potential for several drugs through the development

of safe and efficacious formulations for simple, painless and long‐term

therapy.

Drugs can be directly target to the brain in order to attain a good

therapeutic effect in CNS with reduced systemic side effects.

Much has been investigated and much more are to be investigated for

the recent advancement of nasal drug delivery system.

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CASE STUDY

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MATERIAL AND METHOD:

Zolmitriptan was a gift sample from Natco Labs, Hyderabad, India.

Pluronic F-127 and pluronic F-68 by BASF Corporation, Mumbai, India.

Sodium alginate, sodium carboxy methyl cellulose and polyvinyl pyrrolidone (K-25) of extra pure grade were supplied by Emcure Research Center, Pune, India.

Benzalkonium chloride was procured from Loba Chemicals, Mumbai, India. All other chemicals were of research grade.

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METHOD:

Preparation of nasal gel formulations

Slow addition of polymer, drug and other additive in cold water with continuous agitation. The formed mixtures were stored overnight at 4oC.

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RESULT AND DISCUSSION:

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CONCLUSION

Study revealed that the temperature sensitive gelling system can be formulated using optimum concentration of PF-127 and PF-68 that can gel at the body temperature. Addition of bioadhesive polymers can prolong the release of zolmitriptan that may be helpful for migraine treatment.

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REFERENCES

.Chien, Y.W., Nasal drug delivery. In: chien, W. (Ed.) Novel Drug Delivery System, 2nd ed. Marcel Dekker, 1985, 189-195.

Pisal S.S., Paradkar A.R., Mahadik K.R., Kadam S.S., Pluronic gels for nasal delivery of vitamin B12 Part I: Preformulation study, Int. J. Pharm., 2004, 270, 37-45.

Devi S.G., Udupa N., Niosomal sumatriptan succinate for nasal administration, Ind. J.Pharm. Sci., 2000, Nov – Dec., 479 – 481.

Alexandridis, P., Holzwarth J.F., Hatton, T.A., Macromolecules, 1994,27,2414.

Alexandridis, P. & Hatton T.A., Colloids surface A., 1995, 96.

Singhare D.S., Khan S., Yeole P.G., Poloxamers: Promosing block co-polymers in Drug delivery, Ind. J.Pharm. Sci. 2005, sept – oct., 523 – 531.