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  2. 2. Nasal drug delivery is attractive not because it is BETTER than injectable therapy…… BUT …Because it is SAFER! ...No needle …NO needle stick risk! 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 pr
  3. 3. Nasal Epithelial Characteristics Surface Sections Cells / Functions Stratified squamous and keratinized epithelial cells with nasal hairs / Support and protection Stratified squamous cells / Support Area Vestibule Atrium Respiratory region Olfactory region Vascularization Permeability ≈ 0.6 cm2 Low Poor NF Low Reduced Very high Good Pseudostratified cells / Support Columnar non ciliated cells / Support ≈ 130 cm2 Columnar ciliated cells / Support and muciliary clearance Globet cells / Mucus secretion Basal cells / Progenitors of other cell types Sustentacular cells / Support and ≈ 15 cm2 synthetic Olfactory receptor cells / Olfaction perception Basal cells / Progenitors of other cell types High Direct access
  4. 4. 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.
  5. 5. (1) Spheno palatine artery (2) Greater palatine artery (3) Superior labial artery (4) Anterior and posterior ethmoidal artery
  6. 6. 1) Drugs that are orally not absorbed can be delivered to the systemic circulation by means of nasal drug delivery. 2) Hepatic first pass metabolism is avoided. 3) Easy accessibility and needle free drug application without the necessity of trained personnel facilitates self medication, thus improving patient compliance compared to parenteral routes. 4) Drug degradation that is observed in the gastrointestinal tract is absent. 5) The bioavailability of large drug molecules can be improved by means of absorption enhancer or other approach. 6) Rapid drug absorption and quick onset of action can be achieved. 7) The nasal bioavailability for smaller drug molecules is good.
  7. 7. 8) Drug possessing poor stability in GIT fluids are given by nasal route. 9) Studies so far carried out indicate that the nasal route is an alternate to parenteral route, especially, for protein and peptide drugs. 10) Polar compound exhibiting poor oral absorption may be particularly suited for this route of delivery. 11) Convenient for the patients, especially for those on long term therapy, when compared with parenteral Medication.
  8. 8. 1) Nasal cavity provides smaller absorption surface area when compared to GIT. 2) Relatively inconvenient to patient when compared to oral delivery system since there is a possibility of irritation. 3) 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. 4) There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of improper technique of administration. 5) Certain surfactants used as chemical enhancers may disrupt and even dissolve the membrane in high concentration.
  9. 9. Nasal Drug Absorption Characteristis of the drug Properties of the formulation Nasal Drug Absorption Prodrugs, Enzymatic Inhibitors Absorption enhancers Mucoadhesive drugdelivery systems Novel formulation forms
  10. 10. STRATEGIES TO INCREASE NASAL DRUG ABSORPTION……….. Strategy Examples 1. Nasal enzyme inhibitors Bestatin, amastatin, boroleucine, fusidic acids and bile salts 2. Nasal permeation enhancers Cyclodextrins, surfactants, saponins, phospholipids 3. Prodrug approach Cyclic prodrugs, esters, derivatization of C and N termini 4. Nasal mucoadhesive drug delivery Carbopol, polycarbophil, cellulose derivatives, lecithin, chitosan 5. Particulate drug Microspheres, nanoparticles, liposomes
  11. 11. STRATEGIES TO INCREASE NASAL DRUG ABSORPTION CONT…. Problem Challenge Solution Poor physicochemical Improve physicochemical Prodrugs properties of drug and/or properties of drug Cosolvents formulation and/or formulation Cyclodextrins Pharmaceutical excipients Novel drug formulations Enzymatic degradation Reduce drug affinity to nasal Prodrugs enzymes Enzymatic inhibitors Inhibit nasal enzymes Protect drugs from Prodrugs nasal enzymes Cosolvents Low permeability through Increase drug permeability Prodrugs nasal membrane and dissolution Cosolvents Absorption Modify nasal membrane enhancers Absorption enhancers Mucoadhesive systems Enhance drug residence time Gelling/Viscosifying agents in nasal cavity
  12. 12. Name of compound Surfactants Example Sodium dodecyl sulphate (SDS), Polyoxy ethylene-9-lauryl ether, Phosphatidylcholines Complexing and Ethylene diamine tetraacetic acid Chelating agents (EDTA) Cyclodextrins and α-, β-, γ-cyclodextrin, DMβ-, HPβ- derivatives cyclodextrin Fusidic acid Sodium tauradihydrofusidate derivatives (STDHF) Bile salts Sodium taurocholate, Sodium glycocholate Dry microspheres Degradable starch microsphere, Dextran microspheres
  14. 14. Pathways for nasal absorption Nose brain pathway Absorption through the olfactory neurons - transneuronal absorption. Olfactory epithelium is considered as a portal for substances to enter CNS  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. Brain Brain CSF CSF Brain CSF Highly vascular mucosa nasal
  15. 15. Lipophilicity Non-lipophilic Lipophilic molecules Cell Membrane “Lipid Loving”  Cellular membranes are composed of layers of lipid material.  Drugs that are lipophilic are easily and rapidly absorbed across the mucous membranes.
  16. 16. Absorption through the supporting cells & the surrounding capillary bed - venous drainage
  17. 17. •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
  18. 18. •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
  19. 19. Designing of nasal formulation depends upon the therapeutic need of the particular drug molecule, duration of action and duration of therapy. Both controlled release and conventional release drug delivery are possible through nasal route.(38) 1. Nasal drops 2. Nasal powders 3. Nasal sprays (solution/suspension) 4. Nasal mucoadhesive particulate delivery (micro/nanoparticles, liposomes) 5. Nasal gel 6. Nasal ointments 7. Nasal microemulsions
  20. 20. Drug Molecule * Molecular weight and size: <1000 Da * Solubility: Higher to get dissolved in the nasal fluid and thereby to get permeated (important for particulate drug delivery).(29) * Compound lipophilicity: Should be high for better absorption (through transcellular route), although hydrophilic small molecular weight compounds absorb through aqueous channels.(30) * Partition coefficient and pKa: Unionized molecules easily permeate, although ionized species also permeate through different pathways. * Therapeutic dose: <25 mg per dose(31)
  21. 21. Drug concentration: Higher the concentration, higher the permeation (up to certain extent)(32) * Dose volume: 0.05 - 0.15 ml per dose * Formulation pH: 4.5 – 6.5 to avoid nasal irritation. (nasal surface pH is 7.39 and pH of nasal secretions is 5.5 – 6.5)(33) * Osmolarity: Isotonic formulation (less irritant), higher salt concentration increases permeability but is irritant to nasal mucosa.(34) * Viscosity: Higher the viscosity, longer the residence time of formulation. But it also hinders normal physiological functions like ciliary beating and mucociliary clearance, thus affecting permeability.(35)
  22. 22. Nasal gels are high-viscosity thickened solutions or suspensions. Until the recent development of precise dosing devices, there was not much interest in this system. The advantages of a nasal gel include the reduction of post-nasal drip due to high viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing/emollient excipients and target delivery to mucosa for better absorption. The deposition of the gel in the nasal cavity depends on the mode of administration, because due to its viscosity the formulation has poor spreading abilities. Without special application techniques it only occupies a narrow distribution area in the nasal cavity, where it is placed directly. Recently, the first nasal gel containing Vitamin B12 for systemic medication has entered the market.
  23. 23. Nanoparticles may offer an improvement to nose to brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation, and extracellular transport by P-gp efflux proteins. This would increase CNS availability of the drug. A high relative surface area means that these vectors will release drug faster than larger equivalents, a property desirable where acute management of pain is required. Their small diameter potentially allows nanoparticles to be transported transcellularly through olfactory neurones to the brain via the various endocytic pathways of sustentacular or neuronal cells in the olfactory membrane. Surface modification of the nanoparticles could achieve targeted CNS delivery of a number of different drugs using the same ‘platform’ delivery system which has known and well characterised biophysical properties and mechanism(s) of transit into the CNS.
  24. 24. POLYMER USED IN N ASAL GEL PREPARATION Pluronic PF 127(Poloxamer 407 ) Pluronic (PF 68) HPMC K4M PVP-K-30 Carbopol 934P
  25. 25. POLYMER USED IN N ASAL GEL PREPARATION Sr No. Polymer Category 1 Pluronic PF 127(poloxamer 407 ) Thermoreversible polymer 2 Pluronic (PF 68) Thermoreversible polymer 3 Hpmc K4m Bioadhesive polymer 4 Pvp-k-30 Bioadhesive polymer 5 Carbopol 934P Bioadhesive polymer 6 7
  26. 26. Pluronics are surfactants (oxyethylene-polyoxypropylene) exhibiting each copolymers – poly thermoreversible of poly (oxyethylene) property. (BASF Wyandotte, Product brochure). Pluronic has been accorded GRAS status and has high solubilizing capacity. (Schmolka et al., 1991). Aqueous pluronic dispersions (20 – 35 %) are solutions at low temperature and are converted into semisolid gel at higher (or body) temperature. There useful physiochemical properties of pluronics have been evaluated for controlled release of drugs for topical, rectal and ophthalmic routes.
  27. 27. Preparation of nasal gel formulations: Nasal gel using different concentration of pluronic F-127 and pluronic F-68 and various formulation additives were prepared by cold method described by schomolka et al. (Schomolka et al., 1972). Briefly, the method involved slow addition of polymer, drug and other additive in cold water with continuous agitation. The formed mixtures were stored overnight at 4oC. The nasal gel formulation showing satisfactory gelation temperature (30oC 37oC) were selected as optimized formulation. On this optimized formulation further study was carried out and additional amount of bioadhesive polymer namely methyl cellulose and hydroxy propyl methyl cellulose (HPMC K 4 M) were added in the concentration 0.5,1, and 1.5 % w/w.
  28. 28. Preformulation studies 1)Determination of λmax of API A stock solution of 100 μg/ml of MCP HCl was prepared by dissolving 10 mg in 100 ml of deionized distilled water. The resulting solution was scanned between 200 nm to 400 nm using double beam UV-visible spectrophotometer. 2)Differential scanning calorimetry Differential scanning calorimetry (DSC) was used to evaluate the thermal behavior of pure drug and physical mixture of the drug and excipients. Five-ten milligrams of samples were weighed and sealed in standard aluminum pans and then scanned over a temperature range from 50 to 300°C at a heating rate of 10°C/min.
  29. 29. Characterization OF NASAL GEL 1)Gelation point 2)pH of the gels 3)Content uniformity 4)Rheological studies (Viscosity) 5)Gel strength determination 6)Determination of mucoadhesive strength 7) Spreadability