Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 14th December 2012 KLE College of.
Download ReportTranscript Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 14th December 2012 KLE College of.
Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 14th December 2012 KLE College of Pharmacy, Nipani. 1 CONTENTS Introduction Objectives of TDDS Advantages & disadvantages Mechanism of percutenious absorption Permeation through skin Kinetics of transdermal drug delivery system Factors affecting permeation Basic components of TDDS Formulation approaches used in development of TDDS and their evaluation Permeation enhancer. References 14th December 2012 KLE College of Pharmacy, Nipani. 2 TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS) When one hears the words transdermal drug delivery, what comes to mind? More than likely one thinks about a simple patch that one stick onto skin like an adhesive bandage such as nicotine patch. 14th December 2012 KLE College of Pharmacy, Nipani. 3 Brief History of TDDS • The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections. • Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms. • Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms 14th December 2012 KLE College of Pharmacy, Nipani. 4 Brief History of TDDS • Transdermal drug delivery system was first introduced more than 20 years ago. • The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. • First transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules. 14th December 2012 KLE College of Pharmacy, Nipani. 5 INTRODUCTION • Definition: Transdermal drug delivery is defined as a self contained discrete dosage form, which when applied to the intact skin, will deliver the drug at a controlled rate to the systemic circulation. 14th December 2012 KLE College of Pharmacy, Nipani. 6 • • • • • • • • • POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY (ADVANTAGES) Easy to use. Avoid GIT absorption problems for drugs. Avoids FP hepatic metabolism of drugs. More improved and convenient patient compliance. Rapid termination in case of toxicity is possible. Self medication is possible. Reduces frequency of dosing. Maintains therapeutic level for 1 to 7 days. Controlled delivery resulting in more reliable and predictable blood levels. 14th December 2012 KLE College of Pharmacy, Nipani. 7 DISADVANTAGES • • • • • • • Daily dose of more than 10mg is not possible. Local irritation is a major problem. Drug requiring high blood levels are unsuitable. Drug with long half life can not be formulated in TDDS. Uncomfortable to wear. May not be economical. Barrier function changes from person to person and within the same person. • Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily. 14th December 2012 KLE College of Pharmacy, Nipani. 8 STRUCTURE OF SKIN • Epidermis: Stratum corneum (Horny cell layer) Stratum lucidum (Clear layer) Stratum granulosum ( Granular Layer) Stratum spinosum (Prickly layer) Stratum germinativum • Dermis: • Hypodermis or Subcutaneous layer: 14th December 2012 KLE College of Pharmacy, Nipani. 9 STRUCTURE OF SKIN Epidermis: The outer layer of skin is made up of Stratified Squamous epithelial cells. Epidermis is thickest in palms and soles. The stratum corneum forms the outer most layer (1015µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells. Keratin contains cells called as Corneosites. Stratum corneum layer forms permeability barrier for external environment. 14th December 2012 KLE College of Pharmacy, Nipani. 10 STRUCTURE OF SKIN Water content of stratum corneum is around 20%. The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness. It consists of Cermides and neutral lipids such as Sterols, free fatty acids and triglycerides. The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption. 14th December 2012 KLE College of Pharmacy, Nipani. 11 STRUCTURE OF SKIN It is made up of three layers in thicker parts stratum granulosum, stratum lucidum,stratum spinosum. Removal of these layers permeability and water loss. 14th December 2012 results KLE College of Pharmacy, Nipani. in increased 12 STRUCTURE OF SKIN DERMIS: The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations . This network or the gel structure is responsible for the elastic properties of the skin. It is supplied by blood to convey nutrients, remove waste & regulate body temp. Drug is well absorbed by this route. Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings. 14th December 2012 KLE College of Pharmacy, Nipani. 13 STRUCTURE OF SKIN SUBCUTANEOUS TISSUE: This is a sheet of the fat containing areolar tissue known as the superficial fascia attaching the dermis to the underlying structures . SKIN APPENDAGES: Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat. HAIR FOLLICLES They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene. 14th December 2012 KLE College of Pharmacy, Nipani. 14 Mechanism of absorption through skin Mechanism involved is passive diffusion This can be expressed by FICK’s LAW of DIFFUSION dq = D K A ( c1 – c2 ) dt h dq /dt = rate of diffusion D = diffusion co-efficient K = partition co- efficient A = surface area of membrane H = thickness of membrane 14th December 2012 KLE College of Pharmacy, Nipani. 15 Routes of drug absorption through skin Trans follicular route Trans epidermal route 14th December 2012 KLE College of Pharmacy, Nipani. 16 Routes of drug absorption through skin Trans follicular route: • Fractional area available through this route is 0.1 % • Human skin contains 40-70 hair follicles, 200 to 250 sweat glands on every sq.cm. of skin area. • Mainly water soluble substance are diffused faster through appendages than that of other layers. • Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum. 14th December 2012 KLE College of Pharmacy, Nipani. 17 Routes of drug absorption through skin Trans Epidermal route Epidermal barrier function mainly resides in horny layer The viable layer may metabolize, inactivate or activate a prodrug. Dermal capillary contains many capillaries so residence time of drug is only one minute. Within stratum corneum molecule may penetrate either transcellularly or intercellular. Intracellular region is filled with lipid rich amorphous material. 14th December 2012 KLE College of Pharmacy, Nipani. 18 Routes of drug absorption through skin 14th December 2012 KLE College of Pharmacy, Nipani. 19 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Physico chemical properties of parent molecule Solubility and partition co- efficient pH condition Penetrant concentration Physico chemical properties of drug delivery system Release characteristic Composition of drug delivery system Permeation enhancer used 14th December 2012 KLE College of Pharmacy, Nipani. 20 Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature Effect of vehicle Pathological injury to skin Biological factors Skin age Thickness of S. Corneum Skin condition 14th December 2012 KLE College of Pharmacy, Nipani. 21 Solubility and partition co- efficient: Solubility of a drug influences its ability to penetrate the skin. pKa is index of solubility of drug in vehicle and ST corneum has influence on transfer of drug from vehicle to skin. Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption. Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility. Drug which is lipid & water soluble is favored. 14th December 2012 KLE College of Pharmacy, Nipani. 22 pH & penetration concentration: Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin. Higher the concentration of the drug in vehicle faster the absorption. At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time. 14th December 2012 KLE College of Pharmacy, Nipani. 23 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Physico-chemical properties of drug delivery system Release characteristic Solubility of drug in vehicle determines the release rate. Composition of drug delivery system It not only effects the rate of drug release but also the permeability of STC by means of hydration mixing with skin lipids. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption. 14th December 2012 KLE College of Pharmacy, Nipani. 24 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Physiological and pathological condition of skin Lipid film: It acts as protective layer to prevent removal of moisture from skin. Defeating of this film will decrease TD absorption. Skin hydration: It can be achieved by covering skin with plastic sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity. 14th December 2012 KLE College of Pharmacy, Nipani. 25 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Effect of vehicle: A vehicle can influence absorption by its effect on physical state of drug and skin. Example greases, paraffin bases are more occlusive while water in oil bases are less. Humectants in bases will dehydrate the skin and decrease percutaneous absorption. 14th December 2012 KLE College of Pharmacy, Nipani. 26 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Biological factors: Skin age: Skin of foetus, young ones and elders is more permeable than adult tissue. Skin metabolism: Viable epidermis is metabolically active than dermis. If topically applied drug is subjected to biotransformation during permeation local and systemic bioavailability is affected. 14th December 2012 KLE College of Pharmacy, Nipani. 27 BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEM COMPONENT OF TRANSDERMAL DEVICE INCLUDE: 1) POLYMER MATRIX 2) THE DRUG 3) PERMEATION ENHANCER 4) OTHER EXCEPIENTS 14th December 2012 KLE College of Pharmacy, Nipani. 28 Basic components of Transdermal drug delivery 14th December 2012 KLE College of Pharmacy, Nipani. 29 29 POLYMER MATRIX Following criteria to be considered in selection a polymer: Molecular weight, physical of polymer must allow diffusion of drug at desired rate. Polymer must be non-reactive, inert, non-toxic, easy to manufacture, inexpensive. It should not decompose on storage of the device & not deteriorate when large amount of active ingredient is in corporated into it. 14th December 2012 KLE College of Pharmacy, Nipani. 30 LIST OF POLYMERS USED NATURAL POLYMERS: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Gums & Natural rubber SYNTHETIC ELASTOMER POLYBUTADIENE: Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle, Butyl rubber, Styrene butadiene rubber. SYNTHETIC POLYMER Poly vinyl alcohol, Poly vinyl chloride, Polyethylene, Poly propylene, Poly urea, PVP, Polymethacrylate 14th December 2012 KLE College of Pharmacy, Nipani. 31 DRUG For successful developing transdermal delivery, drug should be chosen with great care physicochemical properties 1. Mol. wt. less than 1000 Daltons 2. Affinity for both lipophilic & hydrophilic phase 3. Drug should have low melting point 14th December 2012 KLE College of Pharmacy, Nipani. 32 BIOLOGICAL PROPERTIES It should be potent with daily dose of few mg/ day. Half life of drug should be short. Non irritant to skin. Drug prone to ‘first pass effect’ and which degrade in GIT are ideal candidate. 14th December 2012 KLE College of Pharmacy, Nipani. 33 Ideal properties of drug candidate PARAMETER PROPERTIES Dose Sh’d be low( < 20mg/day) Half life 10 or less Molecular weight < 400 Skin permeability co- efficient > 0.5 X 10 -3 cm/ hr Skin reaction Non irritating & non sensitizing Oral Bioavailability low Therapeutic index low 14th December 2012 KLE College of Pharmacy, Nipani. 34 PERMEATION ENHANCERS These are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrant. Flux J across the skin can be given by J= D. dc/dx D= diffusion coefficient C= concentration x=Spatial coordinate D is function of size, shape, flexibility of diffusing drug molecule 14th December 2012 KLE College of Pharmacy, Nipani. 35 Activity of penetration enhancers Interaction with the polar head groups of lipid via hydrogen and ionic bonding Change in hydration sphere of lipids and affect packing at the head region Increase volume of the aqueous layer hydration the swelling and Protein modification- open up the dense keratin structure and make it more permeable 14th December 2012 KLE College of Pharmacy, Nipani. 36 Backing membrane They are flexible and provide a good bond to the drug reservoir, prevent the drug from leaving the dosage form through top. It is an impermeable membrane that protects the product during the use on the skin. Contains formulation throughout shelf-life and during wear period Must be compatible with formulation (non adsorptive) Printable E.g.: Metallic plastic laminate , plastic backing with adsorbent pad adhesive foam pad. 14th December 2012 KLE College of Pharmacy, Nipani. 37 37 Schematic Skin absorption of drug 14th December 2012 KLE College of Pharmacy, Nipani. 38 38 Topical application-absorption & action of drugs LOCALIZED DRUG IN DELIVERY SYSTEM PHARMACOLOGICAL RESPONSE TOPICAL DRUG IN TARGET TISSUE RELEASE DRUG IN SKIN SECRETION FLUIDS, SWEAT, SEBUM, pH 4.5--5.5 ABSORPTION TRANSDERMAL DISTRIBUTION DRUG IN BLOOD CIRCULATION ELIMINATION SYSTEMIC 14th December 2012 KLE College of Pharmacy, Nipani. 39 FORMULATION APPROACHES FOR DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEM 14th December 2012 KLE College of Pharmacy, Nipani. 40 TYPES OF FORMULATION PLATFORM FOR THE DRUG: • Liquids • Semisolids : ointments and gels • Non flowing material That is … Polymeric film or rubbery gels and Solid-state platform 14th December 2012 KLE College of Pharmacy, Nipani. 41 TYPES OF PLATFORM MONOLITH : slabs, reservoir, vehicle, film, polymer matrix FILMS : Natural or synthetic Porous and non porous ADHESIVES: viscoelastic materials which remains permanently tacky E.g. Natural or synthetic rubber, polyacrylates and silicon elastomer 14th December 2012 KLE College of Pharmacy, Nipani. 42 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM 14th December 2012 KLE College of Pharmacy, Nipani. 43 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM RCM made up of EVA copolymer A thin layer of drug compatible, hypoallergenic adhesive polymer e.g. Silicon or polyacrylet adhesive may be applied to the external surface. Rate of drug release affect by varying the polymer composition, permeability coefficient and thickness of rate limiting membrane and adhesive. 14th December 2012 KLE College of Pharmacy, Nipani. 44 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM Accidental breakage of the rate controlling membrane can result in dose dumping or a rapid release of the entire drug content. E.g. Nitroglycerine releasing trans dermal system for once a day medication for angina 14th December 2012 KLE College of Pharmacy, Nipani. 45 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM Scopolamine-releasing transdermal system for 72 hr. prophylaxis of motion sickness. Clonidine releasing transdermal system for 7 day therapy of hypertension. Estradiol-releasing transdermal system for treatment of menopausal syndrome for 3-4 days. 14th December 2012 KLE College of Pharmacy, Nipani. 46 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM The intrinsic rate of the drug release from this type of drug delivery system is defined by dq dt 14th December 2012 = CR 1/pm + 1/pa KLE College of Pharmacy, Nipani. 47 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM Pm and pa respectively defined as…. pm = km/r . Da hm pa = 14th December 2012 ka/m . Da ha KLE College of Pharmacy, Nipani. 48 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM Where, Km/r and ka/m are the partition coefficient for the interfacial partitioning of the drug from reservoir to the membrane and from the membrane to adhesive layer respectively. Dm and Da are diffusion coefficient and hm and ha are the thickness 14th December 2012 KLE College of Pharmacy, Nipani. 49 1.POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM Substituting the pm and pa equation in equation 1 dq dt km/r . Ka/m . Dm . Da = km/r. Dm. ha + ka/m . Da . hm cr Which define the intrinsic rate of drug release from a membrane moderated drug delivery system. 14th December 2012 KLE College of Pharmacy, Nipani. 50 2. ADHESIVE DISPERSION-TYPE SYSTEM 14th December 2012 KLE College of Pharmacy, Nipani. 51 2. ADHESIVE DISPERSION-TYPE SYSTEM e.g. of adhesive polymer is poly(isobutylene) or poly(Acrylet) adhesive E.g. of this type of system is isosorbide dinitrate releasing transdermal therapeutic system for once a day medication of angina pectoris. It is used for the administration of verapamil. 14th December 2012 KLE College of Pharmacy, Nipani. 52 2. ADHESIVE DISPERSION-TYPE SYSTEM The rate of drug release in this system is defined by: dq dt = ka/r . Da cr ha where, Ka/r is partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. 14th December 2012 KLE College of Pharmacy, Nipani. 53 3. GRADIENT CONTROLLED TDDS Drug – impermeable metallic plastic laminate R11 R2 R3 14th December 2012 } KLE College of Pharmacy, Nipani. Drug reservoir gradient layers R1>R2>R3 54 3. GRADIENT CONTROLLED TDDS The rate of drug release from this drug reservoir gradient controlled system is given by: dq dt ka/r . Ds = h (t) a A (ha) Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t) E.g. Nitroglycerine TDD patch 14th December 2012 KLE College of Pharmacy, Nipani. 55 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM 14th December 2012 KLE College of Pharmacy, Nipani. 56 56 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM E.g. of this type of system is nitro-dur I and nitrodur II. for continuous transdermal fusion of nitroglycerine at a daily dose of 0.5 mg/cm2 for therapy of angina pectoris. Nitro dur II is modified version of I in which the drug is dispersed in acrylic based polymer adhesive with a resinous cross linking agent which result in much thinner and more elegant patch. 14th December 2012 KLE College of Pharmacy, Nipani. 57 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM The rate of drug release from this type of system is defined as: dq ACp Dp = dt 2t 1/2 A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are the solubility and diffusivity of the drug polymer respectively. Since only the drug species dissolved in the polymer can release . 14th December 2012 KLE College of Pharmacy, Nipani. 58 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM rim 14th December 2012 KLE College of Pharmacy, Nipani. 59 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM Silicon elastomer the lipophillic polymer is used for dispersion technique to form unleachable microscopic sphere of drug reservoir. The quick stabilization occur by cross linking of the polymer chain which produced medicated polymer disc with a constant surface area and fixed thickness according to requirement of drug release. 14th December 2012 KLE College of Pharmacy, Nipani. 60 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM Extra coating is available as a biocompatible polymer to modify the mechanism and rate of drug release. A trans dermal therapeutic system is produced by positioning the medicated disc at the centrally and surrounded bit with an adhesive rim. 14th December 2012 KLE College of Pharmacy, Nipani. 61 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM It is successfully utilized in the preparation of nitrodisc, a nitroglycerine releasing trans dermal therapeutic system used in angina pectoris. This system followed zero order release of drug without the danger of dose dumping. 14th December 2012 KLE College of Pharmacy, Nipani. 62 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM The rate of release of drugs of the micro reservoir system is defined by, DISl (1-n) 1 dq Dp .Dd .m .kp 1 = n.Sp + hI kI km dt Dphd+Ddhpmkp 14th December 2012 KLE College of Pharmacy, Nipani. 63 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM Where, m=a/b is the ratio of the bulk of the elution medium over drug solubility of the same medium and b is the ratio of drug concentration at the outer edge of the polymer coating for the drug solubility in the same polymer composition. n is the ratio of the drug concentration at the inner layer of the interfacial barrier over drug solubility in the polymer matrix. 14th December 2012 KLE College of Pharmacy, Nipani. 64 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM Dl, Dp and Dd and hl, hp and hd; are diffusivities and thickness of liquid layer surrounding the drug particle, polymer coating membrane surrounding the polymer matrix and the hydrodynamic diffusion layer surrounding the polymer coating . Kl, km and kp are the partition coefficient for the interfacial partitioning of the drug from the liquid compartment to the polymer matrix, from the polymer matrix to the polymer coating membrane and from the polymer coating membrane to the elution solution respectively. 14th December 2012 KLE College of Pharmacy, Nipani. 65 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM Sl and SP are the solubility of the drug in the liquid compartment and in the polymer matrix respectively. The release of drug from this system can follow either a partition control or matrix diffusion control process depending upon the relative magnitudes of Sl and SP 14th December 2012 KLE College of Pharmacy, Nipani. 66 6. POROPLASTIC TYPE SYSTEM Poroplastic film consists of ultra micro porous membranes which are not sensitizing to skin and are fairly stable at higher than normal temperature and at biological pH. It is made utilizing the concept of water coagulation of cellulose triacetate solution in organic acid at low temperature. The coagulation is performed under controlled condition. 14th December 2012 KLE College of Pharmacy, Nipani. 67 7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE Macromolecules such as Hormones, interferons, bioactive peptides can be delivered by Trans dermal delivery system. The devices used for this purpose are divided in to two categories…. 1. Devices based on ethylene vinyl acetate copolymers (EVAc). 2. Devices based on silicone elastomer. 14th December 2012 KLE College of Pharmacy, Nipani. 68 7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE This both the system utilize one common concept i.e. Matrix must have channel to facilitate the release of macro molecule This device is used as implants 14th December 2012 KLE College of Pharmacy, Nipani. 69 8. OTHER TDDS IONTOPHORESIS Built-in battery layer Comparable in size to a normal transdermal patch The Lectro Patch, General Medical Co. Treatment time : 20 min Recommended maximum current : 4mA Lidocaine (local anesthesia), dexamethasone (arthritis), hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc. 14th December 2012 KLE College of Pharmacy, Nipani. 70 IONTOPHORESIS 14th December 2012 KLE College of Pharmacy, Nipani. 71 8. OTHER TDDS Sonophoresis: The application of high frequency ultrasound to enhance drug penetration. Examples:. Lidocaine, hydrocortisone, salicylic acid. Electroporation: Transient high-voltage electrical pulses, to cause rapid permeabilization of the stratum corneum through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts. 14th December 2012 KLE College of Pharmacy, Nipani. 72 8. OTHER TDDS Reverse iontophoresis: Current passage causes ions and other molecules to move in both directions under both electrodes. Hence it is possible to sample an analyte in the body, and to provide a drug in response to the analyte level, e.g., sugar, glucose. 14th December 2012 KLE College of Pharmacy, Nipani. 73 Trandermal Matrix patch designs Matrix Reservoir Drug in adhesive Multilaminate Backing 14th December 2012 Drug Membrane Adhesive KLE College of Pharmacy, Nipani. Liner / skin 74 Transdermal Production Process 14th December 2012 KLE College of Pharmacy, Nipani. 75 Transdermal Controlled-Release Products and Devices Drug Trade Name Type of Devices Indication Scopolamine Transderm-Scop Reservoir Motion sickness Nitroglycerine Transderm-Nitro Reservoir Angina Nitro-Dur Monolithic Nitrodisc Monolithic Estraderm Reservoir and ethanol enhancer Estradiol 14th December 2012 KLE College of Pharmacy, Nipani. Hormone treatment 76 Transdermal Products under Development Drug Trade name Producer-Marketer Minocycline Sunstar American Cyanamide, Takeda Estradiol+Noret Estracombi histerone TIS Ciba-Geigy, Alza DHEA Pharmedic Fentanyl Triamcinolone acetonide 14th December 2012 Whitby Pharm. KLE College of Pharmacy, Nipani. 77 Recently approved transdermal contraceptive Recently approved by FDA (Ortho-McNeil) Once a week for three weeks, fourth week patch free 99 percent effective when used as directed Combination estrogen and progestin One-and-three-quarter inch square applied to the lower abdomen, buttocks or upper body. Skin irritation or detachment reported in 2-5% of patients 14th December 2012 KLE College of Pharmacy, Nipani. 78 EVALUATION 14th December 2012 KLE College of Pharmacy, Nipani. 79 1.EVALUATION OF ADHESIVE A. Peel adhesion properties Peel adhesion is the force required to remove an adhesive coating from a test substrate. This properties are affected by the molecular wt. of the adhesive polymer, the type and amount of additives, and polymer composition. 14th December 2012 KLE College of Pharmacy, Nipani. 80 1.EVALUATION OF ADHESIVE It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a 180o angle. 14th December 2012 KLE College of Pharmacy, Nipani. 81 1.EVALUATION OF ADHESIVE B. Tack properties: Tack is ability of the polymer to adhere to substrate with little contact pressure. It is dependent on the molecular weight and composition of polymer as well as the use of tackifying resin in the polymer. Tests for tack include.... 14th December 2012 KLE College of Pharmacy, Nipani. 82 a. Rolling ball test: This test involves measurement of the distance that a stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the farther the ball will travel. 14th December 2012 KLE College of Pharmacy, Nipani. 83 b. Quick-stick (or peel-tack) test: The peel force require to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90o at a speed at 12 inch/min. The force is recorded as the tack value and is expressed in ounce or grams per inch width with higher values indicating increasing tack. 14th December 2012 KLE College of Pharmacy, Nipani. 84 1.EVALUATION OF ADHESIVE 14th December 2012 KLE College of Pharmacy, Nipani. 85 c. Probe tack test: Here, the force required to pull a probe away from an adhesive at a fixed rate is recorded as tack (in grams) Adhesive film Annular weight Probe Dial 14th December 2012 KLE College of Pharmacy, Nipani. 86 C. Shear strength properties: Shear strength is the measurement of the cohesive strength of an adhesive polymer. It is affected by molecular weight as well as the type and amount of tackifier added. Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate 14th December 2012 KLE College of Pharmacy, Nipani. 87 1.EVALUATION OF ADHESIVE Stainless steel plate Adhesive coated tape Weight 14th December 2012 KLE College of Pharmacy, Nipani. 88 2. IN-VITRO DRUG RELEASE EVALUATION In these studies, excised skin is mounted on skin permeation cells. Skin of hairless mouse is used rather than human cadaver skin. In-vitro system should be designed in such way that the intrinsic rate of release or permeation which is theoretically independent of the in-vitro design can be accurately determined. 14th December 2012 KLE College of Pharmacy, Nipani. 89 2. IN-VITRO DRUG RELEASE EVALUATION Several designs of the in-vitro membrane permeation cell, the Jhawer-Lord (J-L), Valia-Chien (V-C) Cell, Ghannam-Chein (G-C) membrane permeation enhancer, Franz Diffusion Cell and the KeshryChien(K-C) Cell. K-C Cell has an effective receptor volume 12ml, skin surface area of 3.14cm2. the receptor solution is stirred by star-head magnet rotating at a constant speed of 600rpm driven by 3W synchronous motor. 14th December 2012 KLE College of Pharmacy, Nipani. 90 Franz Diffusion Cell 14th December 2012 KLE College of Pharmacy, Nipani. 91 ADVANTAGES It can help in investigating the mechanism of skin permeation of the drug before it can be developed in TDDS. Time needed to attain steady state permeation and the permeation flux at steady state can be obtained. It is use to optimize the formulation before more expensive in vivo studies are performed. Studies on skin metabolism can also be performed. 14th December 2012 KLE College of Pharmacy, Nipani. 92 ADVANTAGES It includes also ease of methodology, analytical assay since there are no complication arising from the disposition of the drug in the body and better control over experimental condition than is possible in vivo. 14th December 2012 KLE College of Pharmacy, Nipani. 93 3. EFFECT OF SKIN UPTAKE AND METABOLISM In this study, a piece (3cm by 3cm) of full thickness skin (human cadaver skin) or stripped skin freshly excised from a hair less mouse, 5-7 week old, was mounted between the two compartments of each V-C permeation cell. It was mounted in such a way that either the stratum corneum or the dermis faced the drug solution and the other side of the skin was protected with impermeable aluminum foil. 14th December 2012 KLE College of Pharmacy, Nipani. 94 3. EFFECT OF SKIN UPTAKE AND METABOLISM The compartment with the skin surface uncovered was filled with a saturated solution of drug in normal saline and the compartment with the skin surface covered with aluminum foil remained empty. Both the compartment were maintained isothermally at 37oC. Samples were withdrawn from solution compartment at predetermined times and assayed for drug and any possible metabolite. 14th December 2012 KLE College of Pharmacy, Nipani. 95 4.IN-VIVO EVALUATION a. Animal models: The rhesus monkey is the most reliable model for in vivo evaluation of transdermal drug in man. Standard radiotracer methodology is used. The application site is generally the forearm or abdomen which are the least hairy sites on the animal’s body. 14th December 2012 KLE College of Pharmacy, Nipani. 96 4. IN-VIVO EVALUATION Limitation of using this animal include cost and handling capabilities required. Ethical consideration also limit the use of rhesus monkey. Other animals are weanling pig and human skin grafted nude mouse. Difficulties in using these animals are their non availability and the facilities and skill required for their handling. 14th December 2012 KLE College of Pharmacy, Nipani. 97 4. IN-VIVO EVALUATION b. Human models: Procedure for in vivo evaluation in humans were first described by feldmann and maibach in 1974. They involve the determination of cutaneous absorption by an indirect method of measuring radio activity in excreta following topical application of the labelled drug. This method is used since plasma level following trans dermal administration of a drug are too low to use chemical assay procedure. 14th December 2012 KLE College of Pharmacy, Nipani. 98 4. IN-VIVO EVALUATION The % of dose absorbed transdermally is calculated by Total radioactivity excreted after topical adm. % Drug absorbed = Total radioactivity excreted after i.v. adm. Various modification have been made for this method, it is given below. 14th December 2012 KLE College of Pharmacy, Nipani. 99 RESERVOIR TECHNIQUE It is simple technique, short exposure of the skin to the compound (radio-labelled) under study followed by removal of the stratum corneum. From this analysis, it is possible to predict the amount of drug that will penetrate over a longer period of time. LIMITATION: o Invasive nature of the technique due to the tape stripping required. o The single measurement obtained which does not allow detailed kinetic analysis & adm. of large dose of radio active material is required. 14th December 2012 KLE College of Pharmacy, Nipani. 100 5. CUTANEOUS TOXICOLOGICAL EVALUATION CONTACT DERMATITIS: It can be either I. Contact irritant dermatitis or II. Contact allergic dermatitis I. Contact irritant dermatitis: It results from direct toxic injury to cell membrane, cytoplasm or nuclei. 14th December 2012 KLE College of Pharmacy, Nipani. 101 5. CUTANEOUS TOXICOLOGICAL EVALUATION Two types of protocols are used o Ten days primary irritation test & o Twenty one days irritation test II. Contact allergic dermatitis: It involves a host immunological reaction to an antigen. It can be screened by the guinea pig maximization test. 14th December 2012 KLE College of Pharmacy, Nipani. 102 ADVANCED RESEARCHES MICROARRAY NEEDLE Advanced micro-needle Patch transdermal system allowing continuous delivery through the skin of proteins and water-soluble drugs. 14th December 2012 KLE College of Pharmacy, Nipani. 103 ADVANCED RESEARCHES • The device create painlessly micropores in the S.C. known as microstructered arrays or microneedles. • These devices have about 400 microneedles. • The solid silicone needles (coated with drug) or hollow metal needles (filled with drug solution) penetrate the horny layer without breaking it or stimulating nerves in deeper tissues. • Flux increase up to 1,00,000 fold are reported. 14th December 2012 KLE College of Pharmacy, Nipani. 104 MICRONEEDLE ARRAY 14th December 2012 KLE College of Pharmacy, Nipani. 105 Multidose Transdermal Drug Delivery System It is comprises a laminate composite with a plurality of compartments. Each compartment is a reservoir for a unit dose of a drug active to be transdermally administered. Individual seals are provided for resealably enclosing the drug active in each of the reservoirs. The individual enclosing seals are removable to release the unit dose into contact with the skin of the patient and are actuable to control the transdermal absorption of the drug actives. 14th December 2012 KLE College of Pharmacy, Nipani. 106 MICRO TRANS Applications : Delivery of large proteins, fragile antibodies, and hormones. Delivery of small molecules, particularly those with difficulty diffusing through skin layers. Delivery of vaccines, both conventional and DNAbased. Fluid sensing of glucose, hormones, blood gases, and therapeutic drug levels. 14th December 2012 KLE College of Pharmacy, Nipani. 107 Crystal reservoir technology 14th December 2012 • This system makes oversaturation of adhesive polymer with drug forcing partial crystallization. • Presence of both molecular and solid state, allow higher conc. & consistent supply of drug. • As skin absorbs dissolved drug, crystals redissolve to maintain drug at solubility limit (max. thermodynamic activity) at the site of contact. • This results in smaller thinner patches with better patient acceptability. Clinical trials with this technology with β2 adrenergic agonist tulobutarol confirmed superiority of TDDS formulation over oral formulation KLE College of Pharmacy, Nipani. 108 PERMEATION ENHANCERS These are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrate Flux J across the skin can be given by J = D dc dx D = diffusion coefficient C = concentration D is function of size, shape, flexibility of diffusing drug molecule 14th December 2012 KLE College of Pharmacy, Nipani. 109 Activity of penetration enhancers Interaction with the polar head groups of lipid via hydrogen and ionic bonding. Change in hydration sphere of lipids and affect the packing at the head region. Increase volume of the aqueous layer:swelling and hydration. Protein modification- open up the dense keratin structure and make it more permeable. 14th December 2012 KLE College of Pharmacy, Nipani. 110 IDEAL CHARACTERISTIC OF PENETRATION ENHANCERS 1) IT SHOULD BE INERT 2) NON-TOXIC, NON- IRRITATING 3) ACTION SHOULD BE IMMEDIATE& PREDICTABLE 4) SHOULD NOT CAUSE REMOVAL OF BODY FLUID 5) SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS 6) COSMETICALLY ACCEPTABLE 7) ODORLESS, TASTELESS, COLORLESS & CHEAP 14th December 2012 KLE College of Pharmacy, Nipani. 111 SOLVENTS The compounds increase penetration possibly by swelling the polar pathway and fluidizing the lipid e.g.. Methanol, ethanol, DMSO, DMA, DMF, pyrolidiones, propylene glycol, glycerol etc.. SURFACTANTS They enhance polar pathway transport of hydrophillic drugs 14th December 2012 KLE College of Pharmacy, Nipani. 112 ANIONIC SURFACTANTS Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide CATIONIC SURFACTANTS Pluronic F127, pluronic F58 14th December 2012 KLE College of Pharmacy, Nipani. 113 BINARY SYSTEMS • These systems open up the multilaminate path way as well as the continuous path way e.g. Propylene glycol-oleic acid. 1,4, butane diol- linoleic acid. MISCELLANIOUS CHEMICALS e.g. Urea, N,N- dimethyl m- toluamide 14th December 2012 KLE College of Pharmacy, Nipani. 114 Key Features Simple for patient to use, and fully disposable. Unique manufacturing techniques result in very low cost. Accurate, reliable delivery of drug to epidermis or dermis, circumventing the stratum corneum. Passive or active drug delivery profiles. Can be used with Valeritas' e-Patch and h-Patch™ device to deliver a wide range of drug volumes under various extended or time-release profiles 14th December 2012 KLE College of Pharmacy, Nipani. 115 Find an appropriate place to put the patch Choose a dry, unbroken, non-hairy part of your skin. The buttocks, lower abdomen, lower back, and upper arm (outer part) are good choices. If the area you choose has body hair, clip (do not shave) the hair close to the skin with scissors. Make sure that the area is clean. If there is any oil or powder (from bath products, for example), the patch may not stick properly. Attach the adhesive side of the patch to your skin in the chosen area. 14th December 2012 KLE College of Pharmacy, Nipani. 116 Find an appropriate place to put the patch A stiff protective liner covers the sticky side of the patch - the side that will be put on your skin. Hold the liner at the edge and pull the patch from the liner. Try not to touch the adhesive side of the patch. Throw away the liner. Press the patch firmly on your skin with the palm of your hand for about 30 seconds. Make sure the patch sticks well to your skin, especially around the edges. If the patch does not stick well, or loosens after you put it on, tape the edges down with first aid tape. Wash your hands after applying the patch. 14th December 2012 KLE College of Pharmacy, Nipani. 117 Find an appropriate place to put the patch 14th December 2012 KLE College of Pharmacy, Nipani. 118 Product Development Challenges Flux sufficient but manageable size Adequate skin adhesion Adequate shelf life stability Non-irritating Aesthetically pleasing Easy to handle and use Comfortable Unobtrusive Product cost 14th December 2012 KLE College of Pharmacy, Nipani. 119 REFERENCES Transdermal controlled systems medication by Y.W. Chein. Controlled drug delivery – Fundamental and Application, 2nd edition, by Joseph R. Vincent, H.C. Lee page no.: 524 – 589. Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop K. Khar page no.: 411 – 447. 14th December 2012 KLE College of Pharmacy, Nipani. 120 REFERENCES Novel drug delivery systems, 2nd edition, by Y.W. Chein page no.: 338 – 380. The Eastern Pharmacist delivery system”, vol.34,1991 “Transdermal drug http://www.google.com 14th December 2012 KLE College of Pharmacy, Nipani. 121 THANKING YOU E-mail: [email protected] Cell No: 00919742431000 14th December 2012 KLE College of Pharmacy, Nipani. 122