NASAL DRUG DELIVERY SYSTEM

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Nasal Drug delivery system :

Nasal Drug delivery system

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Nasal & pulmonary drug delivery system PRESENTED BY : GANDHI SONAM MUKESHCHANDRA M.Pharm I year Industrial Pharmacy

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Contents: introduction Factors influencing nasal absorption Formulation aspects Types of nasal drug delivery system Evaluation studies Merits & demerits Applications

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Introduction: I t is also a type of mucoadhesive drug delivery system In this ,drugs are administered through nasal cavity by different dosage forms like solutions , emulsions , gels etc. 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 It become alkaline in conditions such as acute rhinitis, acute sinusitis. Lysosome in the nasal secretion helps as antibacterial &its activity is diminished in alkaline pH.

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Mechanism of drug absorption: drug passes through the mucous membrane of the nasal cavity. Mainly 2 mechanisms are involved The first mechanism – it involues an aqueous route of transport.(paracellular route) Second mechanism – it involues transport of drugs through lipoidal route (transcellular process) it is mainly responsible for transport of lipophilic drugs that show rate dependency on there lipophilicity. e.g.:- chitosan opens tight junctions between epithelial cells & hence facilitate drug transport.

Factors affecting nasal absorption: :

Factors affecting nasal absorption: The various factors affecting nasal absorption are Effect of molecular size Effect of solution pH Effect of drug lipophilicity Effect of drug concentration Effect of particle size

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Effect of particle size (aerodynamic size distribution) - Access to distal airways is a function of particle size - Large particles (> 7 microns) will be lost in the gastrointestinal tract - Small particles (< 3 microns) will be lost in exhaled breathe - Intermediate particles (3 to 7 microns) reach the actual site of action

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2 . Effect of molecular size - Higher the molecular size, lower the nasal absorption - A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used

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3. Effect of solution pH - Nasal absorption is pH dependent - Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule - Absorption is lower as the pH increases beyond the dissociation constant. The pH of the nasal formulation is important for following reasons To avoid nasal irritation To allow drug to be available in unionized form for absorption To prevent the growth of pathogenic bacteria in the nasal passage To maintain functionality of excipients such as preservatives etc.

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4. Effect of drug lipophilicity - Polar (water soluble) drugs tend to remain on the tissues of the upper airway - Non-polar (lipid soluble) drugs are more likely to reach distal airways - Lipid soluble drugs are absorbed more rapidly than water soluble drugs

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- 5. Effect of drug concentration - Absorption depends on the initial concentration of the drug The absorption follows first-order kinetics.

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General formulation: Drug Viscosifying sgents Solubilizers Preservatives Antioxidants

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Formulation of nasal drug delivery system : Drugs: commonly used are β2-adrenergic agonist: terbutaline sulphate. Corticosteroids : budesonide. Ant cholinergic: ipratropium bromide Mast cell stabilizer : sodium chromogylate.

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Gelling / viscosifying agents: or gel –forming agents: these agents increase the viscosity of the solution prolonging the therapeutic activity of preparation. e.g.: hydroxypropyl cellulose. Solubilizers: aqueous solubility of drug always a limitation for nasal drug delivery. e.g.: glycol, alcohol, labrasol, transcutol. In such cases surfactants or cyclodextrines (HP- β -cyclodextrine) are used , these serve as a biocompatible solubilizer& stabilizer in combination with lipophilic absorption enhancers.

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Preservatives: these are used to prevent the growth of micro organisms. e.g.: parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA etc. Antioxidants : These are used to prevent drug oxidation. E.g.: sodium meta bisulphite , sodium bisulfite, butylated hydroxy toluene& tocopherol etc.

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Types of nasal drug delivery system: nasal drops Nasal sprays Nasal gels Nasal powders nasal drops:- nasal drops are one of the most convenient & simple systems for nasal delivery. These are instilled into the nose by dropper. Aqueous or oily solutions, since the latter inhibit the movement of cilia in the nasal mucosa . if used for longer periods , may reach the lungs &cause lipoid pneumonia. nasal drops should be isotonic having neutral pH & viscosity similar to nasal secretions by using methyl cellulose. E.g.:- ephedrine nasal drops B.P.C, otrivine nasal drops.

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2.NASAL SPRAYS:- These are aqueous or alcoholic preparations. Applied to the mucous membrane of nose by atomizer. Only fine droplets are required so they may reach the lungs. By using metered pumps & actuators a nasal spray can deliver an exact 25-200µm. e.g.:- adrenaline & atropine spray B.P.C. 3. Nasal gels:- these are high viscosity thickened solutions or suspensions. Nasal gels include the reduction of post –nasal drip due to high viscosity , reduction of taste impact due to reduced swallowing, reduction of anterior leakage of formulation, reduction of irritation by using soothing /emollient excipients & target to mucosa for better absorption.

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E.g :- Sinex Nasal Spray

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E.g for Nasal gels

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4.Nasal powder:- This dosage form may be developed if solution & suspension dosage forms cannot be developed e.g due to lack of drug stability . The powder formulation is dependent on the solubility , particle size , aerodynamic properties &nasal irritancy of the active drug & or expients . E .g:- sinu air nasal powder

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Evaluation of nasal formulations:- In vitro permeation studies: various approaches used to determine the drug through mucosa from the formulation . The 2 important methodologies to study the diffusion of drug. 1.In vitro diffusion studies: The nasal diffusion cell is fabricated in glass. The water jacketed recipient chamber has total capacity of 60 ml & a flanged top of about 3mm. the lid has 3 openings, each for sampling, thermometer, and a donor tube has internal diameter of 1.13 cm.

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The nasal mucosa of sheep was separated from sub layer bony tissues & stoned in distilled water containing few drops at gentamycin injection. After the complete removal of blood from mucosal surface ,is attached to donor chamber tube. The donor tube is placed such a way that it just touches the diffusion medium in recipient chamber at predetermined intervals, samples(0.5ml) from recipient withdraw & transferred to amber colored ampoules . The samples withdrawn is suitably replaced. The samples are estimated for drug content by suitable analytical technique, throughout the experiment temp is maintained at 37 c.

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(B) In vivo nasal absorption studies:- animal models for nasal absorption studies : these models are 2 types. Whole animal or in vivo model. Isolated organ perfusion or ex vivo model. (a) in vivo model: 1)e.g. Rat model:- The rat is anesthetized by intraperitoneal injection of sodium pentobarbital. An incision is made in the neck & trachea is cannulated with a polyethylene tube. Another tube is inserted for through the oesophagus towards the posterior region of the nasal cavity .

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The passage of the nasopalatine track is sealed so that the the drug solution is not drained from nasal cavity through the mouth. The drug solution is delivered to the nasal cavity through the nostril or through the cannulating tubing. The blood samples are collected from the only femoral vein. As all the probable outlets are blocked, the drug can be only absorbed and transported into the systemic circulation by penetration or diffusion. 2) e.g.: rabbit model. 3)e.g.: dog model. 4)e.g.: monkey model.

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Ex vivo nasal perfusion models:- Surgical preparation is same that of in vivo rat model During perfusion studies a funnel is placed between the nose & reservoir to minimize the loss of drug solution. The drug solution is placed in reservoir maintained at 37c & is circulated through the nasal cavity of the rat with a peristaltic pump the perfusion solution passes out from nostrils &runs again into the reservoir, stirred continuously. Amount of drug is absorbed is estimated by measuring the residual drug concentration in the per fusing solution. the drug activity due to stability problem may lost during the experiment. This is especially for peptides & protein drugs that may undergo proteolysis & aggregation .

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MERITS: Ease and convenience of intra nasal drug administration which is user-friendly, painless, non-invasive, needle-free administration mode. Rapid drug absorptionis possible. Avoidance first pass metabolism or gut wall metabolism. The rate and extent of absorption and the plasma concentration versus time profiles are relatively comparable with intravenous administration. Useful for both local & systemic drug delivery

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For CNS drugs, better site for rapid onset of action Ex: Inhalation anesthesia, Morphine etc. Studies indicate that nasal route can be preferred alternative route to parenteral route especially for protein and peptide based drugs . DEMERITS : Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability. Low bio-availability for proteins and peptides and polar drugs. Once administered, rapid removal of the therapeutic agent from the site of absorption is difficult.

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The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established. Relatively inconvenient to patients when compare to oral drug delivery systems since there is a possibility of nasal irritation Rapid mucociliary clearance will occurs. Chances of immunologic reactions.

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Applications Delivery of non-peptide pharmaceuticals Delivery of diagnostic drugs Delivery of peptide-based pharmaceuticals

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1. Delivery of non-peptide pharmaceuticals 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%

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2. Delivery of peptide-based pharmaceuticals Peptides & proteins have a generally 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

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3. Delivery of diagnostic drugs Diagnostic agents such as  Phenolsulfonphthalein – kidney function  Secretin – pancreatic disorders  Pentagastrin – secretory function of gastric acid

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34 PULMONARY DRUG DELIVERY SYSTEM

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35 Contents : Introduction factors effecting pulmonary drug delivery system Mechanism of absorption Formulations Evaluation of pulmonary drug delivery system Applications

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Introduction: “Pulmonary drug delivery describes various systems, devices, formulations & method of delivery of drugs to the lungs for the treatment of Diseases of the respiratory tract by systemic delivery via the drug.” Pulmonary route is the one of the non-invasive routes for the administration of the variety of drugs . Once the drug is administered they readily pass into the blood stream without the need of any enhancers 36

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The pulmonary drug delivery system depends on the following drug properties : Drugs used in aerosols must be quiet potent but with negligible side effects. Drugs must gain access to target site. Drug must bind to the tissue components there by providing high local concentration for prolonged periods. Better aerosol delivery from nebulizer is needed to enhance the amount of drug in the lungs. thus the absorption from lungs is relatively poor although it overcome with systemic elimination. 37

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HUMAN RESPIRATARY SYSTEM 38

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Mechanism of drug absorption Drug diffusion occurs through alveoli. Absorption through aqueous pores by carrier mediated transport. phagocytosis of insoluble particles allow absorption of compounds with low lipophilicity or high molecular weight. 39

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Inhalables Advanced technology for pulmonary delivery is expanding a category of drugs called Inhalables defined as respiratory & systemic therapies administered simply by inhaling. Advantages It supply drugs into the blood stream directly. It provide a non-invasive method of drugs delivery. It gives very rapid onset of action similar to IV route. 40

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Aerosols These consists of fine liquid droplets or solid particle in a gaseous suspension. atomizer is used for a device that generates an aerosol & may be powdered by electric, pneumatic or mechanical means. Types of aerosols Space sprays aerosols Surface coating aerosols Space sprays disperse the drug as finely divided spray with particles less than 50 µm in size. 41

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Surface coated aerosols generate a coarse & wet spray &are used for coating the surface with a residual film. These are unsuitable for pulmonary use. Limitations of aerosols Poor patient compliance. Irritant activity . Increase bronchoconstriction . High cost of mfg. 42

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43

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Formulations Propellant metered dose inhalers (PMDIs) Dry powder inhalers (DPIs) Nebulizers 44

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Propellant metered dose inhalers(PMDIs) These are sophisticated and safe dosage forms that can deliver accurate doses. Components 1.The base formulation- drug ,propellants, excipients. 2.The container. 3.Metering valve . 4.The actuator (mouth piece). 45

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Formulations are widely used in suspensions state than the solution. Because the latter has got limited solubility and poor chemical stability problems. Hence suspension formulation are made in order to maintain the drug dispersed in a combination of volatile propellants . 46

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Propellants Commonly CFC propellants are used because of their low pulmonary toxicity , high chemical stability and purity and compatibility, Non-inflammable. But now a days the CFC propellants are replaced with Hydrofluoroalkanes(HFAs) as these CFC cause the ozone depletion effect. Examples: trichlorofluromethane dichlorodifluoromethane 1,2-dichlorotetrafluromethane. 47

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Surfactants These are added to maintain the drug in dispersed state & promotes stability of formulation. It is also lubricates the valve. Examples : oleic acid , sorbitol . Containers & valve Usually the container is made up of aluminum or glass. Glass containers are normally plastic coated or laminated to enhances their ability to ensure internal pressures of high magnitude. 48

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49 Metering valves These are designed to release a fixed volume of product during each actuation. Usually valves volumes range from 25 to 100ml although larger volume are available.

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2.DRY POWDER INHALERS This device dispenses a powder in a stream of inspired air. These are environmentally friend since they do not require CFC propellants for drug dispersion. Self medication is possible. Types Passive dry powder inhaler Active dry powder inhaler 50

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Advantages Product stability is more. High drug volume delivery possible low susceptibility to microbial growth Applicable to both soluble and insoluble drugs Self medication is possible Disadvantages Hygroscopic powders have chances to particle growth. Accurate dose is not possible . 51

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3.Nebulizer Nebulizers are those that aerosolize aqueous solutions of water-soluble drugs or suspensions & solvent-water based solutions of water- insoluble substances. Nebulizer have been successfully employed for drug delivery to the lung. It is also used for local drug delivery to trachea for local anesthesia 52

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Types Pneumatic Nebulizer :It is operated by an pressurized gas source ex:- jet or hydro dynamic type Electrical Nebulizer : It operated by an electric source ex:-ultra sonic Nebulizer 53

Therapeutic application::

Therapeutic application : For the treatment of asthma Pulmonary infections For chronic obstructive pulmonary disease Cardio vascular diseases Lung cancer Cystic fibrosis 56

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Characterization of pharmaceutical aerosols: ( a)Emitted dose : The therapeutic effect of aerosols is depend up on their drug delivery to the lungs. The first measure of the potential to deliver drug to the lungs is the dose delivered from the device. Two unit dose sampler methods are used for this purpose. (b) Particle size characterization : Inertial impaction is the method to evaluate particle or droplet size delivery from pharmaceutical aerosol systems. stokes law is used to determine aerodynamic diameter of particles. 57

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Stokes law: V t = gd 2 ( ρ p - ρ m ) ÷ 18 µ Terminal velocity ( V t ) acceleration of gravity (g) particle diameter (d) density of particle ( ρ p ) density of medium ( ρ m ) viscosity of medium (μ)

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the collection efficiency of particles at a stage of an impactor is based on curvilinear motion & assumes reynolds numbers for flow greater than 500 but less than 3000. The principle of inertial sampling in which particles with high momentum travel in the initial direction of flow of an airstream impacting on an obstructing surface & those with low momentum adjust to the new direction of flow & pass around the obstruction. The efficiency of this phenomenon can be described as follws d 50 [C(D)] 0.5 = ( 9( Dj (Stk 50 )) ÷ ρ p U ) 0.5 59

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d50 = 50% collection efficiency Dj and u = the jet diameter and linear velocity Stk 50= stokes number for 50 % efficiency. ρ p = particle density. General sizing methods :- A number of alternative sizing methods are available . In this , the inertial samplers , cascade impacters and impingers appear in compendial standards and in regulatory affairs. The other methods like thermal imaging are also under development . 60

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In vivo characterization :- The use of animals to evaluate aerosol performance is conducted by the use of toxicological studies. Instillation and insufflation have been employed to deliver drugs to lungs of various rodent species. Insufflator is suitable for delivery of powders to rats or guinea pigs. Efficacy :- Propellant Metered Dose Inhaler asthma therapy was introduced for the development of new products. 61

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The major therapeutic categories are – β 2 adrenergic agonists. Anticholinergics . Glucocorticosteroids . Anti inflammatory agents. The β 2 adrenergic agonists and anticholinergics act on the para sympathetic and sympathetic nervous system to induce bronchodilator which relieves bronchoconstriction a symptom of asthma. E.g. :- cromolin blocks the production of histamine an inflammatory mediator by stabilizing mast cells . 62

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Applications Delivery of non-peptide pharmaceuticals Delivery of peptide-based pharmaceuticals Delivery of diagnostic drugs

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1. Delivery of non-peptide pharmaceuticals 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%

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2. Delivery of peptide-based pharmaceuticals Peptides & proteins have a generally low oral bioavailability because of their physic-chemical instability and susceptibility to hepatic-gastrointestinal first-pass elimination E.g.. Insulin, Calcitonin, Pituitary hormones etc. Nasal route is proving to be the best route for such biotechnological products

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3. Delivery of diagnostic drugs Diagnostic agents such as  Phenolsulfonphthalein – kidney function  Secreting – pancreatic disorders  Pentagastrin – secretary function of gastric acid

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REFERENCES CONTROLLED DRUG DELIVERY CONCEPTS AND ADVANCES BY-S.P.VYAS & R.P.KHAR MODERNPHARMACEUTICS FOUTH EDITION BY- BANKER & RHODES ADVANCE IN CONTROLLED AND NOVEL DRUG DELIVERY BY-N.K. JAIN WWW.Google.com 67

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68 Thank you

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