Intranasal drug delivery systems second semester m Pharm

Molecular pharmaceutics

1. 1 MOLECULAR PHARMACEUTICS INTRANASAL DRUG DELIVERY SYSTEM FACULTY IN-CHARGE DR PRASANTH M S ASSOCIATE PROFESSOR PHARMACEUTICS SUBMITTED BY, ABHIJITH P S SECOND SEM M PHARM PHARMACEUTICS

2. 2 CONTENTS INTRODUCTION ADVANTAGES AND DISADVANTAGES MECHANISM FACTORS AFFECTING NASAL ABSORPTION IDEAL CHARACTERISTICS OF DRUG FOR NASAL DELIVERY TYPES OF NASAL DRUG DELIVERY SYSTEM PREVIOUS YEAR QUESTIONS REFERENCES

3. 3 INTRODUCTION Administration of drug through nasal route is referred as nasal drug delivery system. Nasal mucosa has been considered as a potential administration route to achieve faster and higher level of drug absorption because it is permeable to more compounds than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, pH of the nasal mucosa and less dilution by gastrointestinal contents. Nasal therapy, has been recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called “NASYA KARMA”.

4. 4 ADVANTAGES Absorption of drug is rapid via highly vascularized mucosa. Availability of large nasal mucosal surface area helps in greater absorption. Onset of action is rapid. Degradation of drug observed in GIT is avoided. Hepatic first pass metabolism is absent. Bioavailability of large drug molecules can be increased by means of absorption enhancers.

5. 5 Alternate to parenteral route especially for proteins and peptides. Direct transport into systemic circulation and CNS is Possible. Polar compounds exhibiting poor absorption may be particularly suited for this route of delivery. Intranasal drug delivery is a useful delivery method for drugs that are active in low doses and show no minimal oral bioavailability such as proteins and peptides.

6. 6 DISADVANTAGES Delivery volume in nasal cavity is restricted to 25–150 μL . High molecular weight compounds cannot be delivered through this route. Adversely affected by pathological conditions. Normal defense mechanisms like mucociliary Clearance affects the permeability of drug. Limited understanding of mechanisms and less developed models at this stage. Systemic toxicity occurring due to absorption enhancers is yet not established. Possibility of nasal irritation hence inconvenient compared with oral route. Enzymatic barrier to permeability of drug

7. 7 The nasal passage - nasal vestibule to the nasopharynx, depth approximately 12-14 cm . The human nasal cavity has a total volume about - 16 - 19ml. Total surface area - about 180 cm 2 . Nasal cavity is covered with mucous membrane which contains - goblet cells, basal cell & non ciliated & ciliated columnar cell. Nasal pH : 5.5-6.5 (Adults) 5.0-6.7 (Infants) NASAL ANATOMY AND PHYSIOLOGY

8. 8 Nasal enzymes- Cytochrome P-450, Carboxyl esterase and Glutathione S- tranferase , lactate dehydrogenase, oxido reductase, phosphates , hydrolases.

9. 9 3 regions: 1) Vestibular region 2) Respiratory region 3) Olfactory region 1)Vestibular Region: Located at the opening of nasal passage. Responsible for filtering out the air borne particles. 2)Respiratory Region: It having the highest degree of vascularity. Mainly responsible for systemic drug absorption. 3)Olfactory Region: Located roof of the nasal cavity. It is the portion of the cerebral cortex concerned with the sense of smell. It is important for transporting drugs to the brain and cerebrospinal fluid (CSF).

10. 10 MECHANISM OF NASAL ABSORPTION OF DRUG First mechanism- It involves an aqueous route of transport, which is also known as the Para cellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. The drugs having molecular weight greater than 1000 Daltons shows poor bioavailability.

11. 11 Second mechanism- It involves transport through a lipoidal route and it is also known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity . Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions.

12. 12 FACTORS INFLUENCING THE NASAL DRUG ABSORPTION 1.FACTORS RELATED TO DRUG MOLECULAR WEIGHT CHEMICAL FORM POLYMORPHISM SOLUBILITY AND DISSOLUTION RATE LIPOPHILICITY PARTITION COEFFICIENT AND Pka 2 . FACTORS RELATED TO FORMULATION pH VISCOCITY OSMOLARITY BUFFER CAPACITY DRUG CONCENTRATION, DOSE AND VOLUME

13. 13 3. PHYSIOLOGICAL FACTORS EFFECT OF DEPOSITION ON ABSORPTION. NASAL BLOOD FLOW EFFECT OF ENZYMATIC ACTIVITY. EFFECT OF MUCOCILIARY CLEARANCE EFFECT OF PHYSICAL CONDITION

14. 14 1.FACTORS RELATED TO DRUG MOLECULAR WEIGHT The permeation of drug less than 300 Dalton is not significantly influenced by the physicochemical properties of the drug. CHEMICAL FORM Important parameter in drug absorption because conversion of the drug into a salt or ester form may alter its absorption. POLYMORPHISM Polymorphism affects the dissolution rate and solubility of drugs and their absorption through biological membranes. Therefore, polymorphic stability and purity of drugs for nasal powders or suspension should studied.

15. 15 SOLUBILITY AND DISSOLUTION RATE For better absorption drug should get dissolved. If particles are present, it is difficult for absorption. LIPOPHILICITY Increased lipophilicity, increased permeation through the nasal mucosa. Lipophilic compounds readily cross biological membrane via transcellular route, since they are able to partition into the lipid bilayer of the cell membrane and diffuse into the cell cytoplasm.

16. 16 2. FACTORS RELATED TO FORMULATION pH The pH of the formulation as well as the nasal surface can affect a drugs permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5 -6.5. VISCOSITY As viscosity increases, the contact time between the drug and the nasal mucosa thereby increases. OSMOLARITY Optimum osmolarity should be maintained, as it causes shrinkage of the nasal epithelial mucosa and alter the permeation of drugs.

17. 17 BUFFER CAPACITY. Nasal formulations are generally administered in small volume. Hence, nasal secretions will alter the pH of the administered dose. This can affect the concentration of unionized drug available for absorption. Therefore an adequate formulation buffer capacity may be required to maintain the pH. DRUG CONCENTRATION, DOSE AND DOSE VOLUME. These three are inter related parameters that impact the performance of nasal delivery. Nasal absorption of L- Thyrosine was shown to increase with drug concentration in nasal perfusion experiments.

18. 18 3.PHYSIOLOGICAL FACTORS EFFECT OF DEPOSITION ON ABSORPTION. Deposition of the formulation in the anterior of the nose provides a longer nasal residence time. The anterior portion of the nose is an area of low permeability while posterior portion of the nose where the drug permeability is generally higher, provides shorter residence time. NASAL BLOOD FLOW Nasal mucosal membrane is very rich in blood flow and plays a vital role in the thermal regulation and humidification of the inhaled air. Therefore the drug absorption will depend upon the vasoconstriction and vasodilation of the blood vessels.

19. 19 EFFECT OF MUCOCILIARY CLEARANCE The absorption of drug is influenced by the residence time between the drug and the epithelial tissue. The mucociliary clearance is inversely related to the residence time and therefore inversely proportional to the absorption of drug administered .

20. 20 EFFECT OF PHYSICAL CONDITION Intranasal pathologies may affect the nasal mucociliary transport process and or capacity for nasal absorption. There are times when the mucosa is crushing, bleeding or dry. One may be suffering from rhinorrhea, sinusitis or nasal or nasal infection. In people suffering from severe nasal allergies, an excessive nasal secretion can wash away the formulation before the drug has a chance of getting absorbed through the mucosa or before acting locally.

21. 21 IDEAL CHARACTERISTICS OF DRUG FOR NASAL DELIVERY Appropriate aqueous solubility to provide the desired dose in a 25–150 ml volume of formulation administration per nostril. Appropriate nasal absorption properties. No nasal irritation from the drug. A suitable clinical rationale for nasal dosage forms, e.g. rapid onset of action. Low dose. Generally, below 25 mg per dose. No toxic nasal metabolites. No offensive odors/aroma associated with the drug. Suitable stability characteristics.

22. 22 TYPES OF NASAL DRUG DELIVERY SYSTEM NASAL DROPS NASAL GELS NASAL POWDERS NASAL SPRAYS INSUFFLATORS MICROEMULSION NANO PARTICLES MICROSPHERES NASAL IN - SITU GEL

23. FORMULATION OF NASAL DRUG DELIVERY SYSTEMS Drugs Humectants Viscosifying agents Osmotic agent Solubilizers Surfactants Bio-adhesive polymers Preservatives Antioxidants Penetration Enhancers 23

24. Drugs :commonly used in nasal drug delivery are: • β2- adrenergic agonist: Terbutaline sulphate • Corticosteroids: Budesonide • Anti-cholinergic: Ipratropium bromide • Mast cell stabilizer: sodium chromogylate Humectants To prevent dehydration, adequate intranasal moisture is required and therefore humectants are added. The commonly used humectants are- Glycerine,Sorbitol , Mannitol 24

25. Viscosifying agents These agents increase the viscosity of the solution, there by prolonging the residence time of preparation. e.g.: hydroxypropyl cellulose. Osmotic agent The osmolarity of the dosage form affect the nasal absorption of the drug. The commonly used osmotic agents are: Sodium Chloride, Sodium sulfite, Sodium acid phosphate 25

26. Solubilizers Aqueous solubility of drug always a limitation for nasal drug delivery. E.g.: glycol, alcohol, labrasol etc. Surfactants Modify the permeability of nasal mucosa & facilitate the nasal absorption of drugs. E.g. Poly acrylic acid, sodium glycol- cholate . 26

27. Bio-adhesive polymers Increases the residence time of drug in nasal cavity and a higher local drug concentration in the mucus lining on the nasal mucosal surface E.g.: Methylcellulose, Carboxymethylcellulose , Hydroxyl propyl cellulose preservatives These are used to prevent the growth of micro organisms. e.g. parabens , benzalkonium chloride, phenyl ethyl alcohol, EDTA etc. 27

28. Antioxidants These are used to prevent drug oxidation. E.g.: sodium meta bisulphite , sodium bisulfite , butylated hydroxy toluene& tocopherol etc. Penetration Enhancers Mechanism: Inhibit enzymatic activity Reduce mucus viscosity Open tight junctions Solubilize the drug E.g. Sodiumdodecyl Sulphate , EDTA, salicylates , oleic acid 28

29. NASAL DROPS Nasal drops are generally formulated to resemble nasal secretion. Hence nasal drops should be isotonic and slightly buffered to maintain pH 5.5 to 7.5 . The viscosity of nasal drops should be similar to the viscosity of the nasal secretions. Therefore viscosity of the nasal drop is adjusted with the help of thickening agents like methyl cellulose, hydroxyl propyl methyl cellulose. 29

30. Examples of nasal drops Ephedrine hydrochloride nasal drops Phenylephrine nasal drops Oxymetazoline nasal drops Betamethasone nasal drops 30

31. Nasal drops- ingredients Ingredients type Example Vehicle Purified water For tonicity adjustment Sodium chloride, dextrose Buffer Phosphate buffer (pH- 6.5) Preservatives Chlorobutanol (0.5%) Benzalkonium chloride (0.01-0.05) Aromatic alcohols (0.5-0.9%) 31

32. Methods of preparation Simple solution method is employed for the preparation of nasal drops, because most of the drugs and additives used are water soluble. Eg . Ephedrine hydrochloride nasal drops Rx Ephedrine hydrochloride 0.1g Sodium Chloride 0.1g Chlorbutanol (preservative ) 0.01g Water q.s 20 ml 32

33. Procedure Accurately weigh the Chlorobutanol and powder it. Select a small conical flask with suitable stopper In a conical flask, take 3/4 th quantity of water and heat to 60°C without putting the stopper. Add chlorobutanol to the hot water and quickly insert the stopper, prevent the volatilization of chorobutanol and shake well. Allow the solution to cool and add ephedrine hydrochloride and sodium chloride, dissolve them by stirring and filter the solution. Transfer the filtrate to measuring cylinder and adjust the final volume with water. 33

34. NASAL GELS Nasal gels are high viscosity thickened solutions or suspensions. The adv: reduction of post-nasal drip due to high viscosity, reduction of taste impact due to reduced swallowing. 34

35. Preparation Mucoadhesive nasal gels were prepared by dissolving venlafaxine HCl in solution 0.65% NaCl , 0.04% KH 2 PO 4 and 0.02% benzalkonium chloride (pH 6) in a constant stirring condition. Required amount of polymers (sodium alginate, carbopol or mixture of Carbopol and sodium alginate ) were added to the solution and stirred on a magnetic stirrer until a uniform solution was obtained which was kept at 4°C overnight to allow complete swelling so that a homogeneous gel was formed. 35

36. Nasal sprays Nasal spray drug product contain therapeutically active ingredients dissolved or suspended in solutions or mixtures of excipients in non-pressurized dispensers that deliver a spray containing a metered dose of the active ingredient. The dose can be metered by the spray pump. 36

37. Preparation β - cyclodrexin , hydroxyl propyl β - cyclodrexin : mucoadhesive polymers PVP, PEG: solubilizer Disodium EDTA, benzalkonium chloride: anti-oxidant Sodium chloride: maintain tonicity Potassium dihydrogen phosphate, disodium hydrogen phosphate: buffer to maintain pH 37 Ingredients

38. Procedure 400 mg of the drug ( Ondransetron Hydrochloride), and 20 mg of EDTA were dissolved in solubilizer (PVP) for period of 30 min and volume of 70 ml was made by using PEG with cyclodexin . Simultaneously 1 % polymeric dispersion contained 0.02% of benzalkonium chloride prepared (pH 6 was adjusted with 0.1 M sodium hydroxide) 38

39. Potassium dihydrogen phosphate in disodium hydrogen phosphate buffer solution was prepared. 70 ml of drug solution was incorporated in a drop wise manner in 30 ml of polymeric dispersion and stirred gently using a magnetic stirrer. Throughout the formulation the temperature was maintained at 50°C ± 5°C. A clear transparent colloidal dispersion was formed. 39

40. 40 Nasal powders Powder dosage forms may be developed if solution and suspension dosage forms cannot be developed, mainly due to lack of drug stability. Advantage - absence of preservative and superior stability of the drug in the formulation. The suitability of the powder formulation is dependent on the solubility, particle size, aerodynamic properties and nasal irritancy of the active drug and/or excipients Example: Glucagon nasal powder.

41. 41 Glucagon nasal powders are used along with emergency medical treatment to treat very low blood sugar in adults and children 4 years of age and older who have diabetes .

42. 42 Metered – dose pump sprays. Most of the pharmaceutical nasal preparations on the market containing solutions, emulsions or suspensions are delivered by metered – dose pumps sprays. Nasal mist or nasal sprays are generally used for allergy symptoms such as nasal congestion . Most nasal sprays function by instilling a fine mist into the nostril by action of hand – operated pump mechanism. Three main type available for local effect are: anti- histamines, corticosteroids and decongestants.

43. 43 Metered dose pump sprays include the container, the pump with the valve and the actuator. The dose accuracy dependent on the surface tension and viscosity of the formulation. For solution with higher viscosity, special pumps and valves combinations are on the market.

44. 44 INSUFFLATORS These are the devices to deliver the drug substance for inhalation. It can be constructed by using a straw or tube which contains the drug substance and sometimes it contains syringe also. The achieved particle size of these systems is often increased compared to the particle size of the powder particles due to insufficient deaggregation of the particles and results in a high coefficient of variations in initial deposition areas.

45. 45 NOVEL INTRA NASAL DRUG DELIVERY SYSTEM TO TARGET CNS MICROEMULSIONS Promising approach for intra nasal delivery. They are clear, stable, isotropic mixture of oil, water and surfactant, frequently in combination with a co- surfactant. They offer advantage of spontaneous formation, ease of manufacturing and scale up, thermodynamic stability and improved drug solubilization and bioavailability.

46. 46 NANO – PARTICLES These are colloidal system with compact structure where the therapeutic agent is either entrapped within colloidal matrix or coated on the particle surface by conjugation or adsorption. It provides sustained and controlled drug release. They are made up of polymer, lipid or combination of both. The correct mechanism of barrier opening by nanoparticles is not exactly known. But the delivered nanoparticle enter into the brain by crossing BBB by various endocytotic mechanisms. The polymeric nanoparticle made by albumin is reported to enter into the brain by their small size by endocytosis. These nanoparticles travel intact and release the drug in brain microenvironment directly which is finally biodegraded due to endocytosis uptake because of very small size by BBB.

47. 47 MICROSPHERE One of the specialized systems becoming popular for designing nasal products, as it provides prolonged contact with nasal mucosa and thus enhances absorption and bioavailability. In the presence of microsphere, the nasal mucosa is dehydrated due to the moisture uptake by the microspheres. This results in the shrinkage of the cells, providing a temporary physical separation of the tight junctions that increase the absorption of the drugs. Microspheres have been reported to be present up to 3 to 5 hours in the nasal cavity depending upon the bioadhesive material used in the formulation. The ideal microsphere particle size requirement for nasal delivery should range from 10 – 50 micrometer as smaller particles than this will enter the lungs.

48. Preparation – solvent evaporation technique The microspheres were prepared by dissolving ethyl cellulose in dichloromethane/ethyl acetate(volatile solvents), followed by the addition of drug to the polymeric solution. It was poured as thin stream into 0.5% sodium CMC solution (continuous phase) which was prepared in 0.1 N of HCl, held at 1400 rpm Stirring was continued until solvent was completely evaporated. Microspheres formed were collected by decantation, filtered and dried. 48

49. 49 NASAL IN- SITU GEL These are drug delivery systems that are in solution form before administration in the body, but after administration it undergoes gelation to form gel. This can be achieved by using different polymers suh as Chitosan, PVA, Carbapol .

50. Nasal Drug Delivery Devices A. LIQUID NASAL FORMULATIONS 1. Instillation and rhinyle catheter 2. Squeezed bottle 4. Metered-dose pump sprays B. POWDER DOSAGE FORMS 1. Insufflators 2. Dry powder inhaler 50

51. Instillation and rhinyle catheter Catheters are used to deliver the drops to a specified region of nasal cavity easily. Place the formulation in the tube and kept tube one end was positioned in the nose, and the solution was delivered into the nasal cavity by blowing through the other end by mouth. Dosing of catheters is determined by the filling prior to administration and accuracy of the system. 51

52. Squeezed bottle Squeezed bottles are often used for nasal decongestants and work by spraying a partially atomized jet of liquid into the nasal cavity. They give a better absorption of drug by directing the formulation into the anterior part of the cavity and covering a large part of the nasal mucosa. They include a smooth plastic bottle with a simple jet outlet. 52

53. Metered-dose pump systems This systems offer greater control over dosing than squeezed bottle They can deliver solutions, suspensions or emulsions within predetermined volume between 25 and 200 µl, thus offering deposition over a large area Factors affect deposition are: particle size, volume, device design 53

54. Insuffalators Insufflators are the devices to deliver the drug substance for inhalation; It can be constructed by using a straw or tube which contains the drug substance. The achieved particle size of these systems is often increased compared to the particle size of the powder particles due to insufficient deaggregation of the particles and results in a high coefficient of variation for initial deposition areas. 54

55. EVALUATION OF NASAL FORMULATIONS Particle size analysis Mucoadhesive testing Drug permeation study through nasal mucosa . In-vivo bioavailability studies Pharmacokinetic analysis 55

56. Particle size analysis It was determined by optical microscope About 100 of micro particles were used for the study and the mean particle size was determined. 56

57. Mucoadhesive testing A 1 1 cm 2 piece of goat nasal mucosa was tied onto a glass slide using thread. Microparticles were spread onto the wet rinsed tissue specimen and the prepared glass slide was hung on one of the groves of a USP tablet disintegration test apparatus. The disintegration test apparatus was operated where by tissue specimen was given regular up and down movements in the beaker of the disintegration apparatus containing phosphate buffer pH 6.4. The time required for complete washing of micro particles was noted. This evaluation is preferred for the formulations having mucoadhesion property. 57

58. Drug permeation study through nasal mucosa . Animal models for nasal absorption studies. The animal models employed for nasal absorption studies can be of two types, viz., Whole animal or in vivo model and An isolated organ perfusion or ex vivo model . 58

59. Whole animal models These models are; Rat model Rabbit model Sheep model Monkey model Dog model 59

60. 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. Another tube is inserted through the esophagus towards the posterior region of the nasal cavity. 60

61. The passage of the nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth. The drug solution is delivered to the nasal cavity through the nostril or through the cannulation tubing. Femoral vein is used to collect the blood samples. As all the probable outlets of drainage are blocked, the drug can be only absorbed and transported into the systemic circulation by penetration and/or diffusion through nasal mucosa. 61

62. RABBIT MODEL The rabbit offers several advantages as an animal model for nasal absorption studies: It is relatively cheap, readily available and easily maintained in laboratory settings. The blood volume is large enough (approx. 300ml). To allow frequent blood sampling (l-2ml). Thus, it permits full characterization of the absorption and determination of the pharmacokinetic profile of a drug. 62

63. Procedure Rabbits (approx. 3 kg) are either Anaesthetized or maintained in the conscious state. In the anaesthetized model, intramuscular injection of a combination of ketamine and xylazine is given to anasthetized rabbit. The rabbit's head is held in an upright position and nasal spray of drug solution is administered into each nostril. The body temperature of the rabbit is maintained at 37°C during experiment with the help of a heating pad. The blood samples are collected by an indwelling catheter in the marginal ear vein or artery. 63

64. 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. 64

65. Ex vivo nasal perfusion models Surgical preparation is the same as that is for in vivo rat model. During the perfusion studies, to minimize the loss of drug solution a funnel is placed between the nose and reservoir. 65

66. The drug solution is placed in a reservoir maintained at 37°C and is circulated through the nasal cavity of the rat with a peristaltic pump. The perfusion solution passes out from the nostrils (and runs again into the reservoir. The drug solution in the reservoir is continuously stirred. The amount of drug absorbed is estimated by measuring the residual drug concentration in the perfusing solution. Rabbit can also be used as the animal model for ex vivo nasal perfusion studies. 66

67. In-vivo bioavailability studies In-vivo bioavailability study is conducted on healthy male rabbits. Study consists of three groups each containing six rabbits and fasted for 24 h. One group treated with conventional preparation, second group kept as control (i.e. not received any test substances) and third group of test formulation. Water is given during fasting and throughout the experiment. 67

68. For the collection of blood samples the marginal ear vein of the rabbits used and sample of about 2 ml collected in heparinized centrifuge tubes at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 h after the drug administration. The blood samples are centrifuged at 3000 rpm for 15 min to obtain the plasma and stored at -20°C until analysis. The extraction of drug from plasma can be carried and then analyze using the HPLC system. 68

69. Pharmacokinetic analysis Pharmacokinetic parameers are derived from the plasma concentration vs. time plot. The area under the curve ( tAUC ), the peak plasma concentration ( Cmax ) and the time to attain peak concentration ( tmax ) can be obtained from these plots. The elimination rate constant ( Ke ) is determined from the semilogarithmic plot of plasma concentration vs. time. 69

70. Previous year questions Intra nasal delivery systems Describe the preparation and evaluation of nasal drug delivery system Describe types, preparation, evaluation of nasal drug delivery system 70

71. References Y. W Chien , Novel drug delivery systems, 2 nd edition, revised and expanded, Marcel Dekker., New York, 1999. Appasaheb PS, Manohar SD, Bhanudas SR, Anjaneri N. A review on intranasal drug delivery system. Journal of Advanced Pharmacy Education & Research Oct-Dec. 2013 Oct;3(4). 71