Didar sir-Nasal drug delivery systems.pptx

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1. Chapter- Nasal drug delivery systems The Anatomy of the Nasal Cavity The nasal cavity consists of all the bones, tissues, blood vessels and nerves that make up the interior portion of the nose. The most important functions of the nasal cavity include warming and humidifying the air as you breathe and acting as a barrier for the immune system to keep harmful microbes from entering the body. The inside of the nose, including the bones, cartilage and other tissue, blood vessels and nerves, all the way back posteriorly to the nasopharynx, is called the nasal cavity. It is considered part of the upper respiratory tract due to its involvement in both inspiration and exhalation.

2. The Vestibule The most anterior portion of the nasal cavity is called the vestibule. The exterior nostrils lead into this portion of the nasal cavity which is essentially just a short passageway lined with hair that leads into the respiratory region of the nasal cavity. The Olfactory Region The apex (uppermost pyramidal area) of the nasal cavity contains all of the receptors and cells necessary for olfaction, or your sense of smell. The Nasal Septum The nasal septum is the wall in the middle of the nasal respiratory cavity. It is made up of the septal cartilage, the  vomer bone , and the perpendicular plate of the  ethmoid bone .

3. The Respiratory Region The respiratory region makes up the largest portion of the nasal cavity. The specialized tissue in this area functions to aid in the respiratory process. This part of the nasal cavity is lined with ciliated pseudo-stratified epithelium and mucus-secreting goblet cells. Bones There are 12 bones that contribute to the structure of the nasal cavity. They are the nasal bone, maxilla, sphenoid, vomer, palatine, lacrimal, and ethmoid bones. The first four bones listed are paired (two on each side) The ethmoid bone makes up the largest portion of the nasal cavity. The Turbinates Inside the nasal cavity are three curved shelves of bone called turbinates or nasal conchae. They project from the lateral walls of the cavity and are called the superior, middle and inferior turbinates . The space between the turbinates is called the meatus. Nerves There are many nerves that are involved in the function of the nasal cavity. Some of the most notable include the olfactory nerve, nasopalatine nerve, trigeminal nerve, and nasociliary nerve.

4. Blood Vessels The nasal cavity has a vast and complicated blood supply. Most of the vessels that supply the nasal cavity branch off from the carotid artery and include the anterior ethmoidal artery, posterior ethmoidal artery, sphenopalatine artery, greater palatine artery, superior labial artery, and lateral nasal arteries. These arteries form connections with each other called anastomoses. The blood vessels in the nasal cavity are essential to the function of warming and humidification of the air you breathe.

5. Local drug delivery Introduction to local drug delivery:- The concept of controlled release local delivery of therapeutic agents in the periodontal pocket was pioneered by Dr. Max Goodson who made the initial drug delivery device made up of hollow fibers of cellulose acetate filled with tetracycline. Systemic drug delivery is associated with various drawbacks due to which the concept of local drug delivery (LDD) is becoming more and more popular. In the following paragraphs, we shall discuss in detail the concept of LDD and various chemotherapeutic agents which are presently used for this purpose.

6. Terminologies There are various terminologies which have been used to denote the prolonged release of drug in the past. These terms include sustained-release, controlled-release, prolonged-release, timed release, slow-release, sustained-action, prolonged-action, or extended-action . However, the most commonly used terminologies are sustained release and controlled release

7. Rationale for using local drug delivery The primary rationale for LDD is to place an antibiotic or antiseptic in direct contact with the pathogenic microorganism that are not accessible to mechanical removal by hand or power-driven instruments, can be reduced or eliminated. By using this method of drug delivery, a high concentration (many folds more than the minimum inhibitory concentration) can be attained at a site for a sufficient duration of time.

8. Ideal requirements of a local drug delivery system 1. The drug delivery system must deliver the drug to the base of the pocket. 2. The delivery system must deliver the drug at a desired concentration, which is effective in killing micro-organisms. 3. The delivery system must sustain the concentration of the drug in the pocket for a sufficient duration of time. 4. It should be easily placed and manipulable. 5. It must be retained in place after initial placement. 6. It should be biodegradable 7. It should not give rise to bacterial resistance. 8. It should be safe to use with minimal side effects. 9. It should be effective against periodontal1 pathogens only and not on commensal microflora.

9. Classification The local drug delivery systems can be classified as follows, Based on the application: Personally applied (in patient home self-care) A. Non-sustained subgingival drug delivery, Home oral irrigation Home oral irrigation jet tips Traditional jet tips Oral irrigation (water pick) Soft cone rubber tips (pickpocket) B. Sustained subgingival drug delivery Professionally applied (in dental office) A. Nonsustained subgingival drug delivery Professional pocket irrigation B. Sustained subgingival drug delivery Controlled release devices Hollow fibers Dialysis tubing Strips Films

10. Advantages of drug delivery system Advantages: 1. A high concentration (up to 100 fold higher as compared to systemic therapy) of the drug can be achieved at a localized site that can be maintained there, long enough for the desired effect to be accomplished without causing any side effect. 2. The concentration of the drug in periodontal pocket is not affected by the fluctuation in plasma levels. 3. The technique is suitable for agents which cannot be given systemically, such as chlorhexidine. 4. Superinfection and drug resistance are rare. 5. Reduction in total drug usage when compared with systemic therapy. 6. Reduction in drug accumulation with chronic therapy. 7. Reduction in frequency of drug administration 8. Improved patient compliance as the agent is placed by a dental professional

11. Systemic delivery The rationale for the use of the nasal cavity for systemic delivery includes- Its accessibility Avoidance of pre-systemic metabolism Potential to provide a rapid onset of action Types of drugs administered with examples The nasal cavity for systemic delivery is used in the case of some peptides that  have- Wide therapeutic windows which exceed the minimum therapeutic level in the bloodstream A large variability in the final attained plasma level can be tolerated, without systemic toxicity becoming manifest. Some peptides which have a very low percentage of absorption  (i.e. low bioavailability), the attained plasma levels are sufficient for therapeutic efficacy.

12. Types of drugs administered with examples Any potential localized toxicity can be minimized in chronic administration by alternating nostrils when daily dosing. Intranasal delivery can also be useful in emergency situations, such as in the treatment of  opioid overdose (using naloxone) or in the treatment of intractable childhood seizures (using benzodiazepines). Drug delivery via this route is also well-suited to drugs that, when administered orally, cause emesis e.g. galantamine used to treat dementia. Advantages 1.Large surface area or absorption (approximately160 cm2) 2.Good blood supply and lymphatic system 3.Avoids hepatic first-pass metabolism 4.Epithelium is permeable to small, lipophilic drug molecules; rapid absorption and onset of action 5.Non-invasive, so minimal infection risk during application and low risk for disease transmission (unlike parenteral route) 6.Easy to self-administer and adjust dose

13. Disadvantages 1 .Limited to small delivery volumes (25–200 μL ) therefore require potent drugs 2.Mucociliary clearance, mucus barrier 3.Enzymatic activity (pseudo first-pass effect) 4. Low epithelial permeability for hydrophilic drugs 5. Require absorption enhancers and large doses Vaccine Delivery (Examples of vaccines administered or has a potential for administration, advantages The mucosal surfaces represent the major site of entry of many pathogens, and major challenges in vaccine development include safety and stability in a suitable dosage form. Micro- and nanocarrier-based delivery systems as nasal vaccines induce humoral, cellular, and mucosal immunity. The nasal route of vaccination could also offer immunity at several distant mucosal sites (oral, rectal, vaginal, and pulmonary), which is considered a simplified and cost-effective mode of vaccination with enhanced patient compliance.

14. Vaccine Delivery Most of the nasal vaccine delivery systems in the form of microparticulates, nanoparticulates, and liposomes are currently under development and prove to offer immunity in animal models. The importance and potential of the nasal route of administration for vaccines is unexplored, and this chapter outlines the opportunities, challenges, and potential delivery solutions to facilitate the development of improved nasal vaccines for infectious diseases. Importance of Nasal Vaccine Delivery The mucosal route of vaccine delivery is one of the better alternatives to conventional multiple injection vaccines, which employ traumatic procedures and may also lead to the spread of infectious agents via contaminated syringes. Nasal administrations of vaccines have been shown to achieve a better systemic bioavailability and protection from gastric enzymes compared with parenteral and oral administration Nasal delivery of vaccines acts as a “first entry block,” that is, blocks the pathogen entry, while invading to the mucosal surface by inducing local microbial-specific immune responses, thus increasing the general efficacy of the vaccine.

15. Why Nasal Vaccine Delivery Effective We found that local mucosal immunity that's established by intranasal vaccination elicits a much more robust and cross reactive, cross protective immunity than a conventional vaccine that uses intramuscular injection. Administration: Administering a vaccine via the nose is painless, non-invasive and easier to perform than using a needle, which has risks of needle stick injuries and issues relating to safe disposal. Benefits and challenges of vaccines delivery The nasal route is considered an attractive route for vaccine administration with the following advantages Better patient compliance Numerous microvilli present in the nasal epithelium provide a better absorption surface. Mucosal and systemic immune response can be induced • Easy immunization of large population groups
• Nasal immunization does not require needles and syringes

16. Benefits and challenges of vaccines delivery Major challenges vaccines delivery are given below: A relatively large dose of vaccine is required, and it is difficult to administer through the nasal route and also difficult to monitor the actual dose that crosses the mucosa.
• Costly innovative vaccination strategy.
• Efficacy of nasal vaccines may be limited due to the including mucociliary clearance and the inefficient uptake of soluble antigens by nasal epithelial cells in the nasal cavity.
• Nasal delivery may require adjuvants to enhance their immunogenicity and delivery to the mucosal tissues. Several enzymes that are present in the nasal mucosa might affect the stability of drugs. For example, proteins and peptides are subjected to degradation by proteases and amino-peptidase at the mucosal membrane. Low antigen entrapment efficiency mode. Normal defense mechanisms like mucociliary clearance and ciliary beating affect the permeability of the drug.

17. Direct nose to brain delivery The blood-brain barrier (BBB) restricts the entry of potentially harmful substances into the brain but also limits the access of potentially useful drugs. The endothelial cells in the brain exhibit low rates of pinocytosis and are joined by tight junctions which limit the paracellular diffusion of hydrophilic solutes from the blood into the brain. In addition, BBB expresses a high number of efflux transporters, such as P-glycoprotein (P- gp ), which further reduce access to the brain for molecules that might be predicted to be well-absorbed from their size and lipophilicity. So, Drugs delivered intranasally that enter the systemic circulation would have to cross the BBB to enter the CNS. Potential routes Nose to brain pathway is the potential route for the transport of therapeutic modalities/ nanocarriers directly into the brain by non-invasive route by passing the BBB. The transport mechanism involves three different ways such as Olfactory pathway, Trigeminal nerve pathway, and Systemic pathway

18. Potential routes Olfactory pathway Therapeutic modalities once administered via nose, it travels to the olfactory mucosa ( also known as olfactory epithelium ) that contains olfactory receptor neurons. Molecules reach the olfactory receptor neurons by paracellular or transcellular mechanism. The neuronal pathway considered to be determining step of the nose to brain route. Drug moieties travels along axon and via nerve bundle cross the cribriform plate and reach the olfactory bulb. From the olfactory nerves, the therapeutic moiety can enter the cerebrospinal fluid (CSF) .The drug can be distributed from the CSF to brain by mixing with interstitial fluid in the brain. After a nasal administration of drug, it takes only few minutes to reach brain via olfactory transport.

19. Potential routes Trigeminal pathway Drug transported through nose via trigeminal nerve pathway by intracellular transport (axonal transport) or by endocytosis . The trigeminal nerve composed of three branches such as ophthalmic, maxillary and mandibular . Branches from the ophthalmic part of the trigeminal nerve innervate to the dorsal part of the nasal mucosa and the anterior nose but maxillary branch innervate to the turbinates of the nasal mucosa. Once the compounds diffuse through the mucosa of the nasal cavity, it reaches the branches of trigeminal nerves in olfactory and respiratory regions, and via brain stem transported to the axonal route. A part of the trigeminal nerve that passes through the cribriform plate that may also involved in the delivery of therapeutics from nasal cavity to the forebrain. Example : After an intranasal administration of insulin-like growth factor-I(IGF-I) rapidly reached brain via trigeminal neuronal pathway.

20. Potential routes Systemic pathway Drug uptake into the brain from nasal cavity occurs also through blood circulation. Due to the rich vasculature of the respiratory epithelium, fraction of the drug was absorbed into the systemic circulation. The respiratory segment allows the passage of both small and large molecules into the blood circulation subsequently transport across the BBB to the CNS. Small lipophilic molecules easily enter into the blood and cross the BBB compared to the high molecular weight and hydrophilic molecules. The active moiety was distributed throughout the systemic circulation and it enters into the nasal blood vessels and they were rapidly transferred to the carotid arterial blood supply to the brain and spinal cord, this process is called counter current exchange.

21. Nasal products for CNS targeting List of marketed nasal products for CNS targeting Dihydroergotamine mesylate (DHE-45) Desmopressin acetate Nafarelin acetate Butorphanol tartarate Zolmitriptan Nasal spray

22. FACTORS INFLUENCING INTRANASAL SYSTEMIC DELIVERY The different factors that affect the bioavailability of intranasally administered drugs can be categorized as follows:

23. 1. Nasal Anatomical and Physiological Factors Anatomical factors: Structural features Biochemical changes Physiological factors : Mucociliary clearance (MCC) Nasal secretions pH of the nasal cavity Blood flow Pathological conditions Environmental effects

24. Anatomical Factors 1.Structural features: The anatomical features of the nasal cavity affect the drug permeability through the nasal mucosa. The respiratory region is most suitable for drug permeability as it is highly supplied with blood which provides a large surface area. The presence of microvilli on cells also greatly increases the surface area for absorption. 2.Biochemical Changes: In the nasal mucosa various enzymes are present which act as a barrier for the absorption of drugs. These include: Oxidative and conjugative enzymes Peptidases and proteases such as Cytochrome P450 (CYP- 450) dependent monooxygenase Carboxyl esterase and Amino peptidase These enzymes cause degradation of the administered drug. 

25. Physiological Factors  1. Mucociliary clearance (MCC): The nasal mucociliary clearance system transports the mucus by ciliary beating. Its function is to protect the respiratory system from damage by inhaled substances. It filters the foreign particles, which get attached to mucus layer by draining them into the nasophyranx and are cleared by the gastrointestinal tract. It is known as self-defense mechanism of the respiratory tract. MCC alters the residence time of the drugs administered from the nasal cavity thereby altering the drug absorption. In physiological conditions, 5 mm/min is the rate of mucus transportation and 15-20 min is the reported as the transit time in human nasal cavity. Whenever a substance is nasally administered, it is cleared from the nasal cavity in ~21 min by MCC. Thus, if there is decrease in the MCC, there will be increase in the residence time of the therapeutics in nasal mucosa.  

26. Figure : Mucociliary clearance (MCC) MCC alters the residence time of the drugs administered from the nasal cavity thereby altering the drug absorption.

27. Physiological Factors 2. pH of the nasal cavity:

28. Physiological Factors Nasal Secretions:

29. Physiological Factors 4. Blood flow and Neuronal regulation: Nasal mucous membrane is richly supplied with the blood. Nasal absorption of drugs is influenced by the blood flow rate as nasal congestion and relaxation regulate the rise and fall in amounts of the drug permeated, respectively. Thus, it may be concluded that parasympathetic stimulation results in increased permeability. 5. Pathological Conditions: Any factor that can influence the efficacy and pace of mucociliary clearance, nasal secretions and irritation of the nasal mucosa may modify the drug absorption profile. The pathological condition that alter drug absorption including: Common cold Rhinitis Atrophic rhinitis Nasal polyposis

30. Physiological Factors 6. Environmental Effects: The environmental pH and temperature affects the nasal drug absorption. The drug absorption is greater at the pH values where the drug is in the non-ionized form. This means that the non-ionized lipophilic form crosses the nasal epithelial barrier via transcellular route whereas the more lipophilic ionized form passes through the paracellular route.  Physicochemical properties of drugs

31. Physicochemical properties of drugs (Contd.) i) Molecular weight, lipophilicity and pKa : Lipophilic drugs such as propranolol, progesterone and fentanyl are well absorbed from the nasal cavity, exihibiting pharmacokinetic profiles similar to those obtained after intravenous administration. These drugs are absorbed quickly and efficiently across the nasal membrane via transcellular mechanisms. This observation is true for lipophilic compounds having molecular weight lower than 1 kDa . The extend of nasal absorption of lipophilic drugs bigger than 1 kDa is significantly reduced. On the other hand, the rate and degree of nasal absorption of polar drugs is low and highly dependent of the molecular weight.

32. Physicochemical properties of drugs (Contd.) ii) Stability: Biological, chemical and physical drug stability studies are a major consideration in all process during the development of new drug formulations. The biological stability of nasally administered drugs may reduce due to the metabolism of drugs by defensive enzymatic mechanisms by nasal cavity. To overcome this difficulty a variety of strategies may be followed, mainly through the use of prodrugs and enzymatic inhibitors.

33. Physicochemical properties of drugs (Contd.) iii) Solubility: For drug absorption, drug dissolution is a pre‐requisite because molecularly disperse form of a drug may cross the biomembranes. Drug allowed enough contact with the nasal mucosa which may show slow absorption. Drugs with poorly soluble in water may require high doses hence can cause problem. The problem can be overcome by enhancing drug solubility using various techniques.

34. Formulation factors A. PHARMACEUTICAL F ORM Nasal drops : Not Hazardous But Problematic lack of dose precision, may result in overdose rapid nasal drainage can occur while using may not be suitable for prescription products i nstead of powder sprays, solution and suspension sprays are preferred.

35. Formulation factors B. VISCOSITY : Formulation with higher viscosity is desired. Due to- better contact time thus increasing absorption enhance the permeability of drugs *Observed during nasal delivery of insulin, acyclovir, metoprolol.

36. Formulation factors C . pH : pH of nasal cavity & pKa of a particular drug need to be considered- t o allow drug availability in unionized form t o prevent growth of bacteria in nasal passage t o maintain functionality of excipients t o sustain normal physiological ciliary movement pH of formulation should be 5-6.5 to prevent sneezing

37. Formulation factors D. PHARMACEUTICAL EXCIPIENTS: L ist of commonly used excipients- S olubilizers (glycols, small quantities of alcohol, l abrasol) B uffer components A ntioxidants (sodium meta bisulfate, sodium bisulfate, tocopherol ) Preservatives (parabens, benzalkonium chloride, EDTA) Humectants (glycerin, sorbitol, mannitol) G elling agents/ Gel forming carriers (hydroxyl propyl cellulose)

38. Patient factors Patient compliance: Good patient compliance is paramount for successful treatment. For systemic treatment, the nasal route is usually chosen when the oral route is not available. Thus, use of the nasal route is generally compared with parenteral delivery or with other transmucosal routes. The nasal route is accessible to the patient using simple dosage forms (sprays and drops) permitting self –medication over extended periods of time. When compared with another transmucosal route, e.g. rectal, the use of intranasal midazolam or the treatment of childhood seizures was   found to be safe and effective.

39. LIMITATIONS OF NASAL ABSORPTION 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.

40. KEY FACTORS LIMITING NASAL ABSORPTION Nasal drug delivery system is considered has a profitable route for the formulation scientist because it has easy and simple formulation strategies. Intra-nasally administered drug products therapeutic efficacy and toxicities are influenced by number of factors. Following factors are the barriers to the absorption of drugs through nasal cavity:   Low bioavailability: Lipophilic drugs are generally well absorbed from the nasal cavity compared to polar drugs. Low membrane transport: Another importance factor is low membrane transport is the general rapid clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism. Enzymatic Degradation: Another contributing (but normally considered less important) factor to the low transport of especially peptides and proteins across the nasal membrane is the possibility of an enzymatic degradation of the molecule either within the lumen of the nasal cavity or during passage across the epithelial barrier.

41. Approaches used to overcome these limitations There are many barriers present in nasal cavity which interfere with absorption of various drugs. There are some methods which have been successfully used for the improvement of nasal drug absorption . Nasal enzymes inhibitors Various kinds of enzyme inhibitors are utilized to minimize metabolism of drug in nasal cavity which minimize activity of enzymes present in nasal cavity includes protease and peptidase, used as inhibitors for the formulation of peptide and protein molecule. Structural modification Modification of drug structure can be done without changing the pharmacological activity for improvement of nasal absorption. Particulate drug delivery Carriers are used for the encapsulation of drug which prevent exposure of a drug to nasal environment and improve the retention capacity in nasal cavity. Some examples of carriers may include microspheres, liposomes, nanoparticles and niosomes . Prodrug approach Inactive chemical moiety is called prodrug which becomes active at the target site. Prodrugs are mainly used to improve taste, odor, solubility and stability.

42. Approaches used to overcome these limitations (Contd.) Bioadhesive polymer To improve the nasal residence and absorption of the drug bioadhesive polymers are used. They improve the retention time of the drug inside the nasal cavity is increased by making an adhesive force between formulation and nasal mucosa, which leads to minimization of mucociliary clearance of formulation In situ gel These are the formulations which get converted into gel upon instillation into nasal cavity by the influence of stimuli includes temperature, pH and ionic concentration. Consistency of the gel is thick which makes the formulation difficult to drain by the influence of ciliate movement. Mucoadhesive polymers for enhancing nasal delivery: types with examples One way of increasing the time that the formulation is in contact with the absorptive mucosa is by the use of mucoadhesive polymers, such as cellulose derivatives, polyacrylates, starch and chitosan. Mucoadhesive Polymers Type : Cellulose derivatives (soluble) Cellulose derivatives (insoluble) Polyacrylates Starch Chitosan Pectin

43. Mucoadhesive polymers for enhancing nasal delivery: types with examples (Contd.) Cellulose derivatives (soluble) Examples: Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose Dosage forms: Gel, Powder, Liquid 2. Cellulose derivatives (insoluble) Examples: Ethyl cellulose, microcrystalline cellulose Dosage forms: Powder, Spray 3. Polyacrylates Examples: Carbopol 971P, Carbopol 934P, Carbopol 981P Dosage forms: Powder, Liquid, Gel Mechanism: Decrease the rate of mucociliary clearance. By reducing or abolishing ciliary motility the rate of clearance of the drug from the nasal cavity is reduced. 4. Starch: Examples: Drum-dried waxy maize starch, Degradable starch microspheres, Starch nanoparticles, Starch microspheres Dosage forms: Liquid, Powder 5. Chitosan Examples: Chitosan, Chitosan microspheres, Chitosan glutamate Dosage forms: Liquid, Powder 6. Pectin Examples: Low methoxyl (LM) pectin ( PecSys ™) Dosage forms: Liquid turning to gel in situ  

44. MECHANISM OF ACTION   Mucoadhesives can increase absorption by three mechanisms:   Optimum hydration will promote the extension of polymer chains which will interact with the nasal tissue and resist the removal of the formulation by mucociliary clearance, thus increasing its retention time in the nasal cavity Acting as carriers, they can reduce the contact between the drug and the enzymes of the nasal mucosa and protect the drug from any potential degradation S ome polymers can affect the tight junctions between the epithelial cells. As the polymer becomes hydrated it causes dehydration of the epithelial cells which can temporarily open the tight junctions, so increasing permeability of the epithelium to drugs using the paracellular route.

45. FORMULATION APPROACHES   Mucoadhesive formulations can be administered to the nasal cavity in the form of solid powders or particulates, gels or liquids. For good mucoadhesion, the formulation should spread well on the nasal mucosa (solid formulations should flow well and be readily wettable). When the polymers are formulated in solution, the viscosity of the preparation will be greater than that of a simple solution. Whilst an increased formulation viscosity leads to a prolonged residence time, it does not always result in increased absorption To overcome this problem a type of gel has been developed (in-situ gel) that is liquid prior to administration (allowing convenient and accurate dosing) but forms a gel once in contact with the nasal mucosa. Polymers can also be formulated as microparticles/ microspheres and nanoparticles. These systems can protect the drug from enzymatic degradation, improve contact with the absorptive epithelium and enhance uptake.

46. Permeation enhancers for nasal delivery : Ideal characteristics The absorption of both small and large hydrophilic drug molecules is increased by administering them with permeation enhancers which modify the structure of the nasal epithelium. Ideal Characteristics:- The requirements of an ideal permeation enhancer include the following: rapidly-acting with a transient and reversible effect on the nasal epithelium not absorbed systemically non-toxic, non-irritant and non-allergenic does not permit entry of dangerous environmental material compatible with drugs and other excipients in the formulation safe for chronic use (depending on the condition to be treated).

47. Example of Permeation Enhancer Example of permeation enhancer with mechanism of action is given below:

48. Example of Permeation Enhancer (Contd.)

49. Example of Permeation Enhancer (Contd.)

50. A brief account of different types of nasal dosage forms/delivery systems Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. The selection of dosage form depends upon the drug being used, proposed indication, patient population and last but not least, marketing preferences. Nasally administered medicines can be formulated as ointments or creams but most usually as a liquid (solution, gel or suspension) or as a powdered solid. There are a variety of nasal formulations available in the market.

51. Different types of nasal dosage forms/delivery systems A. Liquid nasal formulations Liquid preparations are the most widely used dosage forms for nasal administration of drugs They are mainly based on aqueous state formulations Their humidifying effect is convenient and useful, since many allergic and chronic diseases are often connected with crusts and drying of mucous membranes. 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 the system is the lack of the dose precision.

52. Different types of nasal dosage forms/delivery systems Squeezed nasal bottle Squeezed nasal bottles are mainly used as delivery device for over-the-counter (OTC) products like topical decongestants. They include a smooth plastic bottle with a simple jet outlet. Squeeze bottles are not recommended for children. 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 200µm. Choice of pumps and actuators:- -The particle size and morphology of the drug -Viscosity of the formulation.

53. Different types of nasal dosage forms/delivery systems B. Powder dosage forms Dry powders are less frequently used in nasal drug delivery Powder dosage form may be developed if solution & suspension dosage form cannot be developed. E.g.: due to lack of drug stability Major advantages of this dosage form are the lack of preservatives and the improved stability of the formulation For example, DirectHaler™ Nasal and OptiNose™ Powder Delivery.

54. Different types of nasal dosage forms/delivery systems Pressurized metered dose inhalers A pressurized metered-dose inhaler (pMDI) is a device that delivers a specific amount of medication to the lungs in the form of a short burst of aerosolized medicine that is inhaled by the patient. A metered-dose inhaler consists of three major components; -the canister which is produced in aluminium or stainless steel by means of deep drawing, where the formulation resides; -the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and - an actuator (or mouthpiece) which allows the patient to operate the device and directs the aerosol into the patient's lungs. The first nasal pMDI using HFA as propellant- deliver beclomethasone dipropionate (BDP) for allergic rhinitis Figure- Nasal pressurized metered-dose inhaler (pMDI)

55. Different types of nasal dosage forms/delivery systems Dry powder inhaler Dry powder inhalers (DPIs) are devices through which a dry powder formulation of an active drug is delivered for local or systemic effect . These are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema. Most DPIs rely on the force of patient inhalation to entrain powder from the device and subsequently break-up the powder into particles that are small enough to reach the lungs. For this reason, insufficient patient inhalation flow rates may lead to reduced dose delivery. Figure-Dry powder inhaler

56. Different types of nasal dosage forms/delivery systems C. Semi-solid dosage form Nasal Gels By its characteristics, it is soft semi solid in nature. The flow properties of the nasal gel depends on vicious concentration and type of polymer. A long time contact of a drug at the absorption site can increase the bioavailability because of slowing the muco-ciliary movement .For example- Sodium chloride nasal gel. Nasal gels include- The reduction of post-nasal drip due to high viscosity. Reduction of taste impact due to the reduced swallowing. Reduction of leakage of the formulation. Reduction of irritation by using emollient. Figure- Nasal gel

57. A brief account on Different types of Nasal Dosage Forms / Delivery systems Drug Delivery system Locally-acting preparations   Azelastine hydrochloride Metered spray Fluticasone propionate, beclometasone dipropionate, betamethasone sodium phosphate and budesonide Nasal drops/Metered spray Ephedrine hydrochloride and xylometazoline hydrochloride Nasal drops

58. A brief account on Different types of Nasal Dosage Forms / Delivery systems (cont’d..) Preparations administered for systemic effects   Desmopressin acetate Metered spray Fentanyl citrate Metered spray Nicotine Metered spray Salmon calcitonin Metered spray Buserelin Metered spray Sumatriptan Unit dose spray Nasal Vaccines   Influenza Pre-filled unit-dose syringe