Topical route_Dr. Mansij Biswas

topical route of drug administration

1. Topical Route of Drug Administration And Dosage Forms Dr. Mansij Biswas, FYR Department of Pharmacology & Therapeutics Seth G S Medical College & KEM Hospital 19 April 2014 1

2. defined as the application of a drug containing formulation to the skin or mucous membrane, to treat specific cutaneous disorders (e.g. acne) or cutaneous manifestations of a generalised disease (e.g. psoriasis ), with the intent of containing the pharmacological effect of the drug only to the surface or within the layers of skin or mucous membrane. 19 April 2014 Ansel H.C., Allen L.V., “Pharmaceutical Dosage Forms and Drug Delivery System”, 7th edition, Lippincott Willlams and Wilkens , Baltimore, 2000, 244-246,249-251, 253-255,264-265 2

3. Includes two basic types: External - that are spread or dispersed on the cutaneous surface covering the affected area. Internal - that are applied to the mucous membrane of eye (conjunctiva), ear, oropharyngeal cavity, nasal cavity, vagina or   anorectal region for local activity . Classification Based on physical state- (A) Solid : Powder, Aerosol, Plaster (B) Liquid : Lotion, Liniment, Solution, Emulsion, Suspension, Aerosol (C) Semi - solid: Ointment, Cream, Paste, Gel, Jelly, Suppository 19 April 2014 3

4. Advantages of Topical Drug Delivery System: Avoidance of first pass metabolism E asy application Avoidance of  the risks and inconveniences of administration and the varied conditions of absorption, like pH changes, presence of enzymes, gastric emptying time etc in enteral or parenteral routes Achievement of efficacy with lower total daily dosage of drug by continuous drug input Avoids fluctuation in drug levels, inter- and intra-patient variations E asy termination of medications, when needed 19 April 2014 4

5. Advantages: contd … Relatively large area of application Drug can be delivered more selectively to a specific site Avoidance of gastro-intestinal incompatibility Provide utilization of drugs with short biological half- life & narrow therapeutic window Improved physiological and pharmacological response Improved patient compliance S uitable for self- medication 19 April 2014 Surver , C. and Davis, F.A., Bioaviability and Bioequivalence, In Walter, K.A..(Ed. ) , Dermatological and Transdermal Formulation , Marcal   Dekker, INC. NewYork , 119,2002,pp. 403,323,326,327,403 5

6. Disadvantages of Topical Drug Delivery System: Skin   irritation / contact   dermatitis due  to  drug and/or excipients Poor permeability of some drugs  through  the  skin Possibility of  allergic   reactions Can be used only for those drugs which require low plasma concentration for action Enzymes in epidermis may denature the drugs Drugs  with  larger particle size are difficult to  get absorbed through  the skin 19 April 2014 6

7. Cross Section of Human Skin: 19 April 2014 7

8. Absorption through skin: Two principal absorption route are identified: A) Trans-epidermal absorption: P rincipally responsible for diffusion across the skin. The resistance encountered along this pathway mostly arises in the stratum corneum . Maybe trans-cellular or inter-cellular. B) Trans-follicular (shunt pathway) absorption: The skin’s appendages, mainly sebaceous glands, sweat glands, hair follicles offer secondary avenues for permeation, which are considered as shunts bypassing the trans-epidermal route. Basic principle of permeation - initial transient stage- shunt pathway predominates , b ut when a steady state has been reached, diffusion through stratum corneum becomes the dominant pathway. 19 April 2014 8

9. Factors Affecting the Extent and Rate of Topical and Percutaneous Drug Absorption and Transportation:- skin physiology & pathology:- hydration, blood flow, lipid content p hysico -chemical properties of drugs and excipients :- Partition coefficient pH-condition Drug solubility Concentration Particle size Polymorphism Molecular weight fabrication and design of the delivery systems:- release characteristics, composition, nature of vehicle, presence of penetration enhancers The rate of drug transport across the stratum corneum follows Fick’s Law of Diffusion 19 April 2014 9

10. Topical Dosage Forms:- Ointment :- Viscous semisolid preparation Applied externally to skin or mucous membrane (eye, nose, vagina, rectum ) 19 April 2014 10

11. Vehicle of an ointment is known as ointment base 1) Hydrocarbon (oleaginous) bases: Emollient, occlusive, greasy, non water washable, prolonged contact period E.g.- white/yellow petrolatum 2) Absorption (anhydrous) bases: P ermits the incorporation of additional quantities of aqueous solutions E.g. - Lanolin 3) Water removable Bases: Oil in water type, non occlusive, less greasy, creamy in appearance, water - washable. 4) Water soluble Bases : D o not contain oleaginous components , completely water- washable, greaseless, mostly used for the incorporation of solid substances. E.g.- Polyethylene Glycol 5) Simple base: Wool fat (5%) + hard paraffin (10%) + yellow soft paraffin (85%) 19 April 2014 11

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13. 19 April 2014 13 Methods of preparation of ointments: a) Trituration : finely subdivided insoluble medicaments are evenly distributed by grinding with a small amount of the base followed by dilution with gradually increasing amounts of the base . b) Fusion : the ingredients are melted together in descending order of their melting points and then stirred to ensure homogeneity . Difficult to measure precise dose - by weighing the tube before & after use or measuring the length of the ribbon squeezed. Only the medicine that is touching the skin will work, so thin layer is always preferred to thick layer.

14. Cream: Viscous semisolid emulsion- medicaments dissolved or suspended in water removable bases. Applied to skin or mucous membrane (vagina, rectum) Most are O/W (small droplets of oil dispersed in a continuous aqueous phase), only cold creams and emollients are W/O (small droplets of water dispersed in a continuous oily phase). O/ W ( vanishing) - water washable, non greasy, non occlusive, more cosmetically acceptable. W/ O ( oily) - for some hydrophobic drugs, more emollient. 19 April 2014 14

15. Advantages over ointment :- 1 . Less greasy 2 . Spreads easily 3. S oothing sensation 4. Easily washable Uses : - Physical or chemical barrier to protect the skin e.g. sunscreens Cleansing agent Emollient Retention of moisture (especially water-in-oil creams) Vehicle for drug substances such as local anaesthetics , anti-inflammatory agents, hormones, steroids, antibiotics , antifungals or counter-irritants 19 April 2014 15

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17. Paste:- Pastes are basically ointments into which a high percentage of insoluble solids have been added L ess greasy than ointments Provide protective coating on skin due to it’s stiff consistency P oorly occlusive, so suited for application around moist areas A bsorb secretion from the oozing lesions Forms an unbroken , water impermeable, opaque film on the skin Effective sun filter & prevent excessive wind dehydration (windburn ) 19 April 2014 17

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19. Gels & Jellies : Semisolid systems- dispersions of small or large molecules in an aqueous liquid vehicle by addition of gelling agent G elling agents- either Synthetic macromolecules ( Carbomer 934) or Cellulose derivatives ( Carboxymethylcellulose ) Non greasy, moisture rich C ompatible with many substances May contain penetration enhancers for anti-inflammatory and some other medications 19 April 2014 19

20. Types : - · Single phase : macromolecules are uniformly distributed throughout a liquid with no apparent boundaries between the dispersed macromolecules and the liquid . · Double phase : Gel mass consists of floccules of small distinct particles, often referred to as a magmas . Gel rich in liquid is called jelly P repared from either natural gums such as pectin , alginate etc. or from synthetic derivatives of natural substance such as methylcellulose 19 April 2014 20

21. Applications: sustained -release delivery system dressings for healing of burn or other hard-to-heal wounds reservoirs in topical drug delivery, particularly ionic drugs, delivered by iontophoresis e.g . Diclofenac gel, Lignocaine jelly 19 April 2014 21

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23. Lotion : Clear solution /suspension/ emulsion containing 25-50% alcohol Low to medium viscosity M ay contain extract of witchhazel , menthol, glycerin, boric acid, alum , chloroform etc but NOT camphor Applied without friction Can be applied on abraded /wounded skin or on mucous membrane Antiseptic, anti inflammatory, astringent, emollient, cooling , moisturizing or protective actions e.g . Calamine lotion 19 April 2014 23

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25. Liniment (Balm) : Low - to medium- viscosity emulsions Formulated from quickly evaporating solvents , contain aromatic chemical compounds As a rule contain camphor Always applied with friction Applied only on unbroken skin, never on mucus membrane Mechanism of action: Rubefacient Local irritant Counter irritant Typically used to relieve pain and stiffness such as from sore muscle cramp or arthritis e.g . Turpentine 19 April 2014 25

26. Poultices/Cataplasms:- Now obsolete Heated & spread on dressing & applied as hot as the patient can bear Heat is retained, soothing in pain and inflammation Ingredients may have counter-irritant/ absorptive properties e.g. Kaolin poultice 19 April 2014 26

27. Solution : Solutions are liquid preparations of soluble chemicals dissolved in solvents such as water, alcohol or propylene glycol E.g : ·   Tincture of iodine ·   Sterile Indian ink for surgical procedures   19 April 2014 27

28. Emulsion : T wo -phase preparations - the dispensed ( internal) phase is finely dispersed in the continuous ( external) phase Because there are two incompatible phases in close conjunction, a physical stabilizing system is needed- surfactant (ionic or nonionic), polymers, polyelectrolytes etc Types - ·   Water-in-oil emulsion ·   Oil-in-water emulsion ·   Water-in-oil-in-water emulsion ·   Oil-in-water-in-oil emulsion 19 April 2014 28

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30. Suspension : H eterogeneous system consisting of two phases: The continuous or external phase is generally a liquid or semisolid The disperse or internal phase is made up of particulate matter that is dispersed throughout the continuous phase Almost all suspension systems get separated on standing, the rate of settling and ease of resuspendability is the concern A satisfactory suspension must remain sufficiently homogenous for at least the time necessary to remove and administer the dose after shaking its container Types: ·   Flocculated ·   Deflocculated 19 April 2014 30

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32. Medicated shampoos :- e.g . Selenium sulphide , Cetrimide , Ketoconazole Paints:- Applied to broken skin/mucus membrane Applied in throat with an applicator e.g. Mandl ’ s paint Nail lacquers :- e.g . Amorolfine (a newer antifungal) for tinea unguium 19 April 2014 32

33. 19 April 2014 33 Collodion :- Protective , occlusive, water repellant film on the skin surface following evaporation of the solvent S eals small cuts and scratches Occlusion prolongs contact with active medicaments C ontains pyroxylone ( a nitrocellulose ) in an ether alcohol mixture Applied using a brush or applicator e.g . Salicylic acid collodion

34. Eye/Ear Drops :- Solution / suspension Relatively brief contact time with absorbing surface pH, tonicity, viscosity important for local comfort. Sterile; require aseptic handling Use droppers with attached or separate plastic nozzle, avoid touching the application surface Use: to prevent or treat infections E.g. Ciprofloxacin eye/ear drop, Artificial tear 19 April 2014 34

35. Ophthalmic strips :- Used for delivering diagnostic dyes topically for eye, by simply touching the conjunctival surface e.g. Fluorescein sodium Ocular insertion :- Continuous release multilayered polymeric insertion in conjunctival fornix Ocusert ( pilocarpine - for treatment of glaucoma), Lacrisert (artificial tear substitute- for treatment of dry eye) Not available in India 19 April 2014 31

36. Medicated plaster, dressing, sticks:- 19 April 2014 36 Belladonna plaster, Keratolytic plaster, neocapsicum plaster Framycetin dressing

37. Suppository : Solid dosage forms intended to deliver medicine into rectal, vaginal or urethral orifice Prepared by cold compression or fusion technique An appropriate base is selected for its compatibility, stability, melting point, and aesthetics . Commonly used bases are cocoa butter, glycerin, hydrogenated vegetable oils, and polyethylene glycol 19 April 2014 37

38. Advantages : Bypasses first pass metabolism Suitable when oral route cannot be used (e.g. patient unconscious, excessive nausea, vomiting, malabsorption disorder) Suitable when drug is not suitable for oral use (unstable in GI tract, degraded by digestive enzymes ) Disadvantages : Absorption slower & unpredictable (BA ~50%) Inconvenient & embarrassing The contained fat often melts at the high temperatures of the tropics Used in kids only where controlled delivery possible 19 April 2014 38

39. 19 April 2014 39 Rectal Suppository : Tapered at one or both ends (torpedo shape is most common), weight= 2g They are meant for local (e.g. OTC preparation for hemorrhoids containing a moisturizer or vasoconstrictor; Glycerin or Bisacodyl as laxative ) and for systemic (e.g. Paracetamol , Aminophylline, Promethazine) effects Active ingredient(s) usually mixed with a suitable base which is solid at room temperature to assist insertion, but melts at body temperature to enable dispersion

40. Vaginal suppositories/ pessaries : Globose or oviform, weight=5g Mostly meant for local effects ( clotrimazole , miconazole , metronidazole) Urethral suppository/ bougies : Cylindrical, longer for males than for females, obsolete now a days 19 April 2014 40

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42. Douche:- Douche is a device used to rinse any body cavity but usually applies to vaginal irrigation Vaginal douches may consist of water, water mixed with vinegar, or even antiseptic chemicals Disadvantage: Can lead to irritation, pelvic inflammatory disease (PID), fertility problems Use - Treatment of bacterial vaginosis with a vaginal douche containing a strain of L. acidophilus 19 April 2014 42

43. Medicated Vaginal R ings:- Doughnut-shaped polymeric drug delivery devices designed to provide controlled release of drugs to the vagina over extended periods of time Vaginal ring products are used for the treatment of vaginal atrophy, relief of hot flashes and as a contraceptive Vaginal ring technology is currently being developed for the controlled release of microbicides and vaccines for the prevention of HIV/HPV infection 19 April 2014 43

44. Intra uterine Devices:- An intrauterine device is a small contraceptive device, often 'T'-shaped, containing either copper (Cu-T) or levonorgestrel (LNG-IUS), inserted into the uterus most effective types of reversible birth control 19 April 2014 44

45. Aerosol : A system that depends on the power of compressed or liquefied gas to expel the contents from the container. Topical pharmaceutical aerosols utilize hydrocarbon (propane, butane, and isobutene) and compressed gases such as nitrogen, carbon dioxide, and nitrous oxide . Advantages: Rapid onset at site delivery Less amount of drug required Less systemic absorption – less side effects No first pass effect Dose titration possible Acceptable & convenient to patient 19 April 2014 45

46. Disadvantages: Difficult to maintain particle size ≈ 2 -8 microns and moisture content ≈ 100 -300 ppm Only 10-20% drug is deposited at site Aerosol droplets facilitate microbial invasion Propellants can cause ADR Proper technique is difficult to maintain Devices: MDI ± Spacer Nebuliser Rotahaler Inhaled insulin device 19 April 2014 46

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48. Dusting Powder :- Free flowing Applied on skin, wounds, ulcers Very fine particle size produces large surface area per unit weight Mechanical protective action against irritation/itching due to friction Dries the skin by absorbing water & adsorbs toxic material Medicated powders are used for prickly heat or preventing microbial growth on skin e.g . Starch, Talc 19 April 2014 48

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50. Intranasal Drug Delivery:- This route involves administration of drugs directly into the nose Agents include nasal decongestants such as xylometazoline & corticosteroid like mometasone furoate . Desmopressin is administered intranasally in the treatment of diabetes insipidus Calcitonin , a peptide hormone used in the treatment of osteoporosis, is also available as a nasal spray Ketorolac nasal spray for pain management The abused drug, cocaine, is generally taken by intranasal sniffing Applied via drops/sprays/powder or aerosols Advantages of nasal delivery Lower dose needed More rapid attainment of therapeutic blood levels Quicker onset of pharmacological activity Fewer side effects 19 April 2014 50

51. Transdermal Drug Delivery System (TDDS) :- 19 April 2014 51

52. 19 April 2014 52 Topically administered medicaments in the form of patches or other techniques, that deliver drugs for systemic effects at a predetermined and controlled rate. Transderm Scop ® Patch, Novartis,1979- first FDA approved- opened the door to the current TDDS as a successful alternative to systemic drug delivery. TDDS use the percutaneous route for systemic drug delivery, but the skin is not the primary target organ, active ingredient is moved across the layers of skin for subsequent systemic distribution.

53. Advantages of TDDS:- Consistent serum drug levels as IV The lack of peaks in plasma concentration Drugs that require relatively consistent plasma levels are very good candidates Convenience and high adherence non invasive usually once weekly /once in 15/30 days application removal of the patch in case of toxicity Avoids FPM and GI irritation Great advantage in patients who are nauseated or unconscious Useful for drugs that are degraded by the enzymes and acids in the gastrointestinal system 19 April 2014 53

54. Disadvantages:- local irritation r otation to minimize i f severe allergic reactions- discontinue skin's low permeability limits the number of drugs that can be delivered after removal, most patches contain at least 95% of the total amount of drug initially in the patch - patients must exercise care when disposing of patches Damage to a transdermal patch p atients should be advised to discard a patch if the outer packaging or the patch itself appears damaged or altered in any way 19 April 2014 54

55. Design of TDDS: Patch design is the first & commonest type Factors influencing:- 1. Properties of the drug- Systemic absorption of transdermal is better with low dose low molecular weight lipid soluble drugs Desired delivery profile Target patient group -- determine which design is best for a given application 19 April 2014 55

56. Components of a TD patch:- Liner - protects the patch during storage, removed prior to use Drug reservoir- drug solution in direct contact with release liner Adhesive - adhere the components of the patch together and to the skin Membrane – controls release of the drug from reservoir and multi-layer patches Backing - protects the patch from the outer environment 19 April 2014 56

57. Types of TD patch:- Single layer drug in adhesive Multi -layer drug in adhesive - immediate drug release layer Vapour patch - for releasing of essential oils in decongestion Reservoir system - liquid drug solution containing reservoir is embedded between an impervious backing layer and a rate controlling semi permeable membrane Matrix system - similar to that of the reservoir, but the drug is instead provided as a semisolid formulation , and there is no membrane layer 19 April 2014 57

58. Advanced designs for TDDS:- Jet injectors:- Jet injectors are hand-held devices that deliver a high-pressure liquid stream through a small nozzle orifice 19 April 2014 59

59. Iontophoresis : - Technique involving the transport of ionic or charged molecules into tissue by the passage of direct or periodic electric current through an electrolyte solution Limitations : Hair follicle damage is possible E.g. Pilocarpine Iontophoresis in sweat test for Cystic Fibrosis 19 April 2014 60

60. Ultrasound ( Phonophoresis / Sonophoresis ):- Skin is made permeable under the influence of ultrasonic waves Sonophoresis : involves the usage of the low frequency ultrasound waves. The ultrasonic energy disturbs the lipid packing in stratum corneum by cavitation Phonophoresis : movement of drugs through living intact skin and into soft tissues under the ultrasound perturbation. The technique involves placing an ultrasound-coupling agent on the skin over the area to be treated and massaging the area with an ultrasound source 19 April 2014 61

61. Microfabricated Microneedles Technology:- This technology employs micron-sized needles (10 to 200 μm in height and 10 to 50 μm in width) made of silicon . These microneedles after insertion into the skin create conduits for transfer of drug through the stratum corneum . The drug after crossing stratum corneum diffuses rapidly through deeper tissues and are taken up by capillaries for systemic action 19 April 2014 62

62. Penetration or Permeation Enhancers:- Chemical penetration enhancers: reversibly reduce the barrier resistance of the stratum corneum without damaging the skin cells E.g . Dimethyl sulphoxides , long chain alkanes, pyrrolidone , urea, alcohol, surfactants Skin ablation: doubling of the TEWL (Trans Epidermal Water Loss) using surgical tapes Microsecond thermal ablation- a promising mechanism to increase permeability of the skin's outer barrier layer of stratum corneum while sparing deeper living tissues to aid skin permeation 19 April 2014 63

63. Novel Topical Drug Delivery System: Aerosol Foams:- b ecoming increasingly popular topical formulation vehicle base is of liquid or semi- solid, sharing the same physicochemical characteristics of conventional vehicles maintains desirable properties such as moisturizing/ fast-drying effects , higher drug bioavailability aerosol is dispensed through a gas-pressurized can In acne, foams may be preferred for application on large hairy surfaces or on the face as they are easy to apply 19 April 2014 64

64. Liposomes:- frequently used as vehicle for controlled and optimized delivery to skin layers spherical phospholipid vesicles whose membrane consists of amphiphilic lipid (hydrophilic on outer side and lipophilic on the inner side) that enclose an aqueous core thus they may encapsulate hydrophilic substances in their aqueous core and lipophilic substances in their lipid bilayer. unique dual release capability enables the delivery of two types of substances simultaneously once they are applied on the skin, which may enhance the desired therapeutic benefit 19 April 2014 65

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66. Niosomes :- Niosomes are microscopic lamellar structures composed of non-ionic surfactants and cholesterol Carrier + surfactant = Proniosomes Proniosomes + water = Niosomes Niosomes and liposomes have similar application in drug delivery but chemically differ in structure units. Niosomes constitute of non-ionic surfactant whereas liposomes comprise of phospholipids Mixture of acorbyl palmitate , cholesterol and highly charged lipid diacetyl phosphate leads to the construction of vesicles named aspasomes . Aspasomes are first hydrated with water/aqueous solution and then sonicated to attain the niosomes 19 April 2014 67

67. Nano-emulsions:- class of emulsions - water-in-oil or oil-in- water, dispersion of very small- sized droplets (5-200 nm) when mixed require unique thermodynamic conditions, specialized manufacturing processes, and specific surfactants that can stabilize the nano droplets suitable for the transport of lipophilic compounds into the skin- ideal vehicle for use in acne to increase the penetration of the active compounds inside the lipophilic environment in addition, they do not clog the pores & can produce additional therapeutic effects, such as increased skin hydration and viscoelasticity 19 April 2014 68

68. Polymers:- large molecules consisting of repeating structural units or monomers connected by covalent chemical bonds i n pharmaceutical industry, there are new acrylic-acid polymers that turn into a gel in the presence of water by trapping water into microcells. Inside these aqueous microcells, hydrophilic compounds can remain in a solution, whereas hydrophobic compounds may be dispersed in suspension. The result is a stable gel like formulation that is easy to use and releases the active compound(s) once they are applied on the skin. m oreover , these polymer-based gels can be mixed with other excipients, such as moisturizers and emollients, to provide additional clinical benefits. r ecently introduced anti-acne formulations that combine clindamycin 1% with benzoyl peroxide 5% utilize this novel polymer-based gel technology that exhibits efficacy and excellent tolerability. 19 April 2014 69

69. Microsponges :- biologically inert particles made of synthetic polymers with the capacity to store a volume of an active agent up to their own weight the particles serve to protect the entrapped active compound from physical and environmental degradation more frequently manufactured as gels once applied on the skin, they slowly release the active agent(s ) 19 April 2014 70

70. Emulsifier -free Formulations:- growing area of development for dermatologic and cosmetic products most skin care products are emulsions - mixture of 2 or more materials that are not miscible with each other, thus requiring addition of surfactants (emulsifiers) that stabilize the formulation to guarantee an adequate shelf life once these surfactant agents are applied on the skin, they tend to emulsify and remove the natural lipids of the epidermis consequently , the pharmaceutical industry has been developing surfactant-free emulsions as alternatives by using stabilizers, in order to yield sufficiently stable products with a cosmetically pleasant appearance 19 April 2014 71

71. Fullerenes:- molecules composed entirely of carbon that resemble a hollow sphere Rouse , et al., showed that once fullerenes come into contact with the skin, they migrate through the skin intercellularly , as opposed to moving through cells t herefore , a fullerene could be used to “trap” active compounds and then release them into the epidermis once they are applied on the skin moreover , fullerenes, themselves, are thought to be potentially potent antioxidants t hey are well tolerated & hold substantial promise in dermatologic and cosmetic applications. 19 April 2014 Rouse JG, Yang J, Ryman-Rasmussen JP, et al. Effects of mechanical flexion on the penetration of fullerene amino acid- derivatized peptide nanoparticles through skin. Nano Lett 7(1):155-60 (2007 Jan) 72

72. 19 April 2014 73 Conclusion:- Topical preparations are used for the localized effects at the site of their application by virtue of drug penetration into the underlying layers of skin or mucous membranes The main advantage of topical delivery system is to bypass first pass metabolism Avoidance   of  the risks and inconveniences of parenteral therapy and of the varied conditions of absorption, like pH changes, presence of enzymes, gastric emptying time are other advantage of topical preparations Iontophoresis , Electroporation, Sonophoresis , Phonophoresis , Vesicular concept and Microfabricated microneedles technology are some advanced technique which are being used to increase delivery through skin Semi -solid formulation in all their diversity dominate the system for topical delivery, but foams, spray, medicated powders, solution, and medicated adhesive patches are also widely used              

73. Thank You…