nasal drug delivery

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What is “NASAL” Drug Delivery system?

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NASAL DRUG DELIVERY INTRODUCTION: Nasal drug delivery is receiving much attention from the pharmaceutical industry. About 2% of the overall drug delivery is administered via the nasal route. Topical decongestants or anti-inflammatory drugs used to treat a rhinitis or allergy related indications are well-known drug products. The nasal route is an attractive alternative to invasive administrations, and provides a direct access to the systemic circulation.

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MERITS OF 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 administration Rapid absorption, peaking generally within 15–30 minutes Apparent permeability to some peptides Ease of self-administration/good patient compliance lower doses and less side effects quicker onset of pharmacological activity . Rate of absorption comparable to IV medication. User-friendly, painless, non-invasive, needle-free administration mode. Useful for both local & systemic drug delivery. For CNS drugs, better site for rapid onset of action Ex. Inhalation anesthesia, Morphine etc. 13. The nose is a very easy access point for medication delivery - even easier to access than IM or IV sites.

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DEMERITS OF NASAL DRUG DELIVERY SYSTEM: Environmental conditions, infection, and inter-subject variability can lead to inconsistent absorption. Short time span is available for absorption due to rapid clearance. Local metabolism in the nose and instability of compound (especially for peptide drugs) occur. Once administered, removal of the therapeutic agent from the site of absorption is difficult. The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established. Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation. Nasal cavity provides smaller absorption surface area when compared to GIT. There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form. Certain surfactants used as chemical enhancers may disrupt and even dissolve membrane in high concentration. There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration.

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TRADITIONAL NASAL DISPENSING SYSTEMS Traditional application systems consist of Nasal drops, Pipettes, Squeeze bottles, Sprays Nasal drops may be suitable for infants only. In adults, drops into the nasal cavity mostly lead to a rapid clearance of the drug along the floor of the nasal cavity toward the throat. Studies demonstrate a longer duration of sprayed products on the nasal mucosa than formulations administered as drops.

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Compared to drops, sprays results in: Larger surface area of coverage. Smaller liquid particle size allowing thin layer to cover mucosa. Less run-off out the nasal cavity. SPRAY PUMP DEVICES - Unidose - Multidose - Bidose

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VARIOUS MULTIDOSE CONTAINERS THE UNIT-DOSE SYSTEM AND THE BI-DOSE SYSTEM Nasal spray products contain therapeutically active ingredients (drug substances) dissolved or suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, and buffering agents). These agents can be for local therapy (e.g., established treatments such as corticosteroids for rhinitis) or for systemic therapy [e.g., migraine therapies such as Imigran. Absorption of drugs from the nasal mucosa is also influenced by the contact time between drug and epithelial tissue.

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(MAD) Mucosal Atomization Device Atomization results in higher bioavailability than either spray or drops. MAD - Mucosal Atomization device: 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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NASAL ANATOMY AND PHYSIOLOGY The nose actively contributes to two major functions of the human system. The first function is the sense of smell (olfaction) The second is respiration or breathing. The nasal septum divides the nasal cavity into left and right halves. The nasal septum is never a straight vertical separation of the two cavities.

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The respiratory tract, which includes the nasal mucosa hypopharynx large airways & small airways provides a relatively large mucosal surface area for drug absorption. The most efficient area for drug administration is the lateral walls of the nasal cavity, which consist of highly vascularized tissue, the mucosa.

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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

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Site of drug spray & absorption

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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

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Lipophilicity “Lipid Loving” Cellular membranes are composed of layers of lipid material. Drugs that are lipophilic are easily and rapidly absorbed across the mucous membranes. Blood stream Cell Membrane Non-lipophilic molecules Lipophilic molecules

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 Absorption through the supporting cells & the surrounding capillary bed - venous drainage

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Cytochrome P 450 dependent onooxygenases, Lactate dehydrogenase, Oxidoreductase, Hydrolases, Esterase, lactic dehydogenase, malic enzymes, lysosomal proteinases, steroid hydroxylases., etc., Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics, nasal decongestants, nocotine, cocaine, phenacetin, nitrosamine progesterone etc., Insulin zinc free was hydrolysed slowly by leusine aminopeptidase, PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats Nasal enzymes

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Nasal secretion of adult : 5.5-6.5 Infants and children: 5-6.7 It becomes alkaline in conditions such as acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH Nasal pH

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Formulation Development

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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 Vehicle of drug delivery Mucosal contact time pH of the absorption site Size of the drug molecule Relative lipid solubility Degree of drug’s ionization

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Physiological effects - Drug metabolism in the respiratory tract & reduction of systemic effect - Mucociliary transport causing increased or decreased drug residence time - Protein binding - Local or systemic effects of propellants, preservatives, or carriers - Local toxic effects of the drug Ex., edema, cell injury, or altered tissue defenses

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1. Effect of particle size 2. Effect of molecular size 3. Effect of solution pH 5. Effect of drug concentration 4. Effect of drug lipophilicity

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Effect of particle size - Large particles (> 7 microns) will be lost in the gastrointestinal tract - Intermediate particles (3 to 7 microns) reach the actual site of action - Small particles (< 3 microns) will be lost in exhaled breathe 2. Effect of molecular size - A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used - Higher the molecular size, lower the nasal absorption

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3. Effect of solution pH - Nasal absorption is pH dependent - Absorption is lower as the pH increases beyond the dissociation constant - Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule 4. Effect of drug lipophilicity - Polar (water soluble) drugs tend to remain on the tissues of the upper airway - Lipid soluble drugs are absorbed more rapidly than water soluble drugs - Non-polar (lipid soluble) drugs are more likely to reach distal airways 5. Effect of drug concentration - The absorption follows first-order kinetics - Absorption depends on the initial concentration of the drug

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For an effective administration of therapeutic drugs through the nasal mucosa, the following must be taken into consideration: The method and technique of administration. The site of drug deposition Droplet size Spray characteristics The rate of clearance through the ciliary cavity The pathological condition of the nose The speed of mucus flow The presence of infection and atmospheric conditions [e.g., relative humidity (RH)] will affect the efficacy of nasal absorption.

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In Vivo Animal Models Several animal models have been described for studying drug absorption through the nasal mucosa. The most convenient model is the anesthesized rat model developed by Hirai et al. For most non-peptide drugs, the results obtained in rats can accurately reflect the absorption profiles in humans. Some experimental modifications are possible, with a similar surgical operation, and can be chosen for special purposes. DETERMINATION OF NASAL ABSORPTION BY INVIVO METHODS:

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RAT MODEL: It has the following steps Rat is anesthetised by IP injection of sodium pentobarbital. Then an incision is made in the neck, the trachea is cannulated with a poly ethylene tube another tube is inserted through oesophagus towards the posterior part of the nasal cavity. The passage of the nasopalatine tract is sealed surgically to prevent to prevent the drainage of drug solution from the nasal cavity in to the mouth. The drug solution is delivered to the nasal cavity through either nostril or the oesophageal tubing. The blood samples are then collected from the femoral vein and analysed for absorbed drug.

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RABBIT MODEL: It has the following steps A rabbit weighing 3 kg is anaesthetised by an IM injection of a combination of ketamine and xylazine. The drug solution is delivered by nasal spray in to each nostril while the rabbits head is held in an upright position. The rabbit is permitted to breath normally through nostrils and body temperature maintained at 37oC by a heating pad. The blood samples are collected in the marginal ear vein. Ex: Progesterone and its hydroxyl derivatives.

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In vivo–in situ model Following the same surgical operation as in the in vivo model, the drug remaining in the nasal cavity can be recovered at a predetermined time and analyzed in this simple model. This method is useful for evaluating both the absorption and the degradation of peptides. Other than the rat & rabbit model, dogs, monkeys, and sheep are also used for in vivo studies. In such large animals, the formulation can be administered while the animal is under anesthesia—or, in some cases, under conscious conditions—and care should be taken for physical loss of the formulation because of drainage. Interspecies differences in nasal drug absorption

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In Vitro Cell Culture Models Various in vitro systems are currently available, which include the excised nasal epithelium from different animal species, primary cell cultures, and cell lines, of the human nasal epithelium. Excised nasal mucosae from different animal species (rabbits, dogs, sheep, pigs, cattle, and humans) are used for studying nasal transport and metabolism. An experimental set-up using an Ussing chamber is frequently used for evaluating the permeability of a drug through the excised mucosa. Excised nasal mucosae

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EXVIVO NASAL PERFUSION MODEL During perfusion studies, a funnel is provided underneath the nose to lead the drug solution, which is flowing out of nasal cavity in the drug reservoir(37oC) and circulated through the nasal cavity of the rat by means of a peristaltic pump. The perfusion solution passes out from the nostril and through the funnel and flows in to the drug reservoir solution again. Drug solutions of 3–20mL are continuously circulated through the nasal cavity of anesthesized rats. The reservoir is stirred constantly and the amount of drug absorbed is determined by measuring the drug concentration remaining in the solution after a period of perfusion.

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The obtained disappearance kinetics can be used for predicting the in vivo rate of drug absorption. The method is also applicable to the assessment of the damaging effects of absorption enhancers on the nasal mucosa.

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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 1) Adrenal corticosteroids 2) Sex hormones: 17ß-estradiol, progesterone, no- rethindrone , and testosterone. 3) Vitamins: vitamin B 4) Cardiovascular drugs: hydralazine , Angiotensin II antagonist, nitroglycerine , isosobide dinitrate , propanolol , and colifilium tosylate . 5) Autonomic nervous system: a. Sympathomimetics : Ephedrine, epinephrine, phenylephrine , b. Xylometazoline, dopamine and dobutamine. c. Parasympathomimetics : nicotine, metacholine d. Parasympatholytics : scopolamine, atropine, ipatropium e. Prostaglandins 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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Basic concepts for achieving improved nasal peptide and protein delivery.

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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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Delivery of Vaccines through Nasal Route: Nasal delivery of vaccines has been reported to not only produce systemic immune response, but also local immune response in the nasal lining, providing additional barrier of protection Delivering the vaccine to the nasal cavity itself stimulates the production of local secretory IgA antibodies as well as IgG, providing an additional first line of defense, which helps to eliminate the pathogen before it becomes established Recently, for the diseases like anthrax and influenza are treated by using the nasal vaccines prepared by using the recombinant Bacillus anthracis protective antigen (rPA) and chitosan respectively

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Conclusions Multiple drugs can be given IN Rapid Immediate access Can be given to almost anyone Exception = Nasal mucosal abnormalities. “Atomization” is the best method Cheap, easy to use device Disposable/single use (MAD) Appropriate drug concentrations IN is a true “needleless” system! Reduce Level III bloodborne exposures HIV Hepatitis B, C

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REFERENCES: 1. Encyclopedia of pharmaceutical technology. 3 rd Edition . Vol 1. Page :1201 by JAMES SWARBRICK. 2. Text book of Novel Drug Delivery System by Chien, 2 nd Edition. 3. Shaji J and Marathe S.W. NASAL DRUG DELIVERY SYSTEM: OPPORTUNITIES & CHALLENGES INDIAN DRUGS Vol. 45 No. 5 May 2008 Pg no (345 – 353)

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