Novel drug delivery systems, 2 nd edition, by Y.W. Chein page no.: 338 – 380. - PowerPoint Presentation

Novel drug delivery systems, 2nd edition, by Y.W. Chein page no.: 338 – 380. 1 REFERENCES Transdermal drug delivery systems Patch

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. 2 Transdermal drug delivery system

POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY (ADVANTAGES) Easy to use. Avoid GIT absorption problems for drugs. Avoids First Pass 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 . 3

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. 4

TDDSs may be constructed of a number of layers, including :an occlusive backing membrane to protect the system from environmental entry and from loss of drug fromthe system or moisture from the skin.A drug reservoir or matrix system to store and release the drug at the skin site. (c) a release liner, which is removed before application and enables drug release. (d) an adhesive layer to maintain contact with the skin after application. Two types of adhesive layers, theperipheral adhesive and the face adhesive,

6Basic components of Transdermal drug delivery 6

BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEMCOMPONENT OF TRANSDERMAL DEVICE INCLUDE:1) POLYMER MATRIX 2) THE DRUG 3) PERMEATION ENHANCER 4) OTHER EXCEPIENTS 7

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. 8

LIST OF POLYMERS USEDNATURAL 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 9

DRUGFor 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 10

Ideal molecular properties for drugpenetration- A low molecular weight (generally less than 500 Daltons)- An adequate solubility in oil and water- A balanced partition coefficientA low melting pointPotent drug (maximum 10 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.

 Hormones Estradiol and progesterone Avoid hepatic metabolism Cardiovascular drugs Hypertension and angina Betablockers : timolol, propranolol Hepatic metabolism of propranolol Analgesics Control of chronic pain by transdermal therapy  Antihistamines Treatment of allergy E.X Chlorpheniramine Maintain histamine-receptor antagonism while reducing CNS side effects such as drowsiness  Central nervous system drugs Physostigmine : cholinesterase inhibitors To inhibit breakdown of acetylcholine by 30 to 40% over 4days DRUG

PERMEATION ENHANCERS13Vehicle or device to maximize drug partition into the skin Incorporate penetration enhancer into formulation\ penetration enhancer 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 Optimization of Percutaneous Absorption:

IDEAL CHARACTERISTIC OF PENETRATION ENHANCERSIT SHOULD BE INERT NON-TOXIC, NON- IRRITATING ACTION SHOULD BE IMMEDIATE& PREDICTABLE SHOULD NOT CAUSE REMOVAL OF BODY FLUIDSHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS A SUITABLE SOLVENT FOR DRUG SPREAD WELL ON THE SKIN COSMETICALLY ACCEPTABLE ODORLESS, TASTELESS, COLORLESS & CHEAP 14

SOLVENTS The compounds increase penetration possibly by swelling the polar pathway and fluidizing the lipid e.g.. Methanol, ethanol, pyrolidiones, propylene glycol, glycerol etc.. SURFACTANTS They enhance polar pathway transport of hydrophillic drugsANIONIC SURFACTANTS : Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide NON -IONIC SURFACTANTS : Pluronic F127 , pluronic F58 15

The Theory for 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 16

17Backing 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 . 17

Technically, TDDSs may be categorized into two types: Monolithic and Membrane-controlled systems.Monolithic systems incorporate a drug matrix layer between the backing and the skin surface . The drug matrix layer is composed of a polymeric material in which the drug is dispersed. The polymer matrix controls the rate at which the drug is released for percutaneous bsorption. Types of Transdermal Drug DeliverySystems

The matrix may be of two types, either with or without an excess of drug with regard to its equilibrium solubility and steady-state concentration gradient at the stratum corneum . In types having no excess, drug is available to maintain the saturation of the stratum corneum only as long as the level of drug in the device exceeds the solubility limit of the stratum corneum. As the concentration of drug in the device diminishes below the skin’s saturation limit, the transport of drug from device to skin declines . In systems with excess drug in the matrix, a drug reserve is present to ensure continued saturation at the stratum corneum. In these instances, the rate of drug decline is less than in the type having no reserve.

Membrane-controlled transdermal systems are designed to contain a drug reservoir, or pouch, usually in liquid or gel form; a rate-controlling membrane; and backing, adhesive, and protecting layers .

Membrane-controlled systems have the advantage over monolithic systems in that as long as the drug solution in the reservoir remains saturated, the release rate of drug through the controlling membrane remains constant . In membrane systems, a small quantity of drug is frequently placed in the adhesive layer to initiate prompt drug absorption and pharmacotherapeutic effects on skin placement. Membrane-controlled systems may be prepared by preconstructing the delivery unit, filling the drug reservoir,and sealing or by lamination, a continuous process of construction, dosing, and sealing

FORMULATION APPROACHES FOR DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEM 22

1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM 23

The drug reservoir is sandwiched between a drug impermeable backing laminate and a rate controlling polymeric membrane.The drug molecules are permitted to release only through the membrane.The drug reservoir compartment: The drug is: Dispersed in solid polymer matrix (polyisobutylene )Suspended in unleachable viscous liquid (silicone fluid) to form paste like suspension. Dissolved in a releasable solvent (alkyl alcohol) to form a clear drug solution 24 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM

The membrane:Microporous or non porous ploymeric (ethylene -vinyl acetate 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. 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 anginaScopolamine-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. 26

The intrinsic rate of the drug release from this type of drug delivery system is defined by dq CR dt 1/pm + 1/pa = 27

Pm and pa respectively defined as…. pm km/r . Dm hm ka/m . Da ha = = pa 28

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 h a are the thickness 29

Substituting the pm and pa equation in equation 1 dq km/r . Ka/m . Dm . Da dt km/r . Dm. ha + ka/m . D a . h m Which define the intrinsic rate of drug release from a membrane moderated drug delivery system.If the membrane is porous, porosity and tortuosity of the membrane should be taken inconsideration. = c r 30

2. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM31 31

The drug reservoir:Homogeneous dispersion of the drug solids in hydrophilic or lipophilic polymer matrix, and the medicated polymer is then molded into medicated discs with defined surface area and thickness.Then mounted onto impermeable plastic backing.The adhesive polymer is applied to the circumference of the patch.

E.g. of this type of system is nitro-dur I and nitro-dur 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. 33

The rate of drug release from this type of system is defined as:A is the initial drug loading dose dispersed in the polymer matrix and C p and Dp are the solubility and diffusivity of the drug polymer respectively.Since only the drug species dissolved in the polymer can release , Cp is equal to C R . At steady state, Q versus t 1/2 drug release profile is obtained. (non zero order release). 1/2 = dq AC p D p dt 2t 34

3. ADHESIVE DISPERSION-TYPE SYSTEM35

e.g. of adhesive polymer is poly(isobutylene) or poly(Acrylet) adhesiveE.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. 36

The rate of drug release in this system is defined by: dQ ka/r . Da dt hawhere,K a/r is partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. = c r 37

4. GRADIENT CONTROLLED TDDSDrug – impermeable metallic plastic laminateDrug reservoir gradient layersR1>R2>R 3 R 1 R 1 R 2R 3 } 38

The rate of drug release from this drug reservoir gradient controlled system is given by: dQ ka/r . Ds dt ha (t)Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t) E.g. Nitroglycerine TDD patch A (h a ) = 39

To overcome the non zero order release, the drug loading level in the reservoir is varied incrementally.The thickness of the diffusional path increases with time, to compensate for this, the drug loading level in the multilaminate adhesive layer is increasedDeponit system: nitroglycerin releasing TDDS.

5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM rim 41

Hybrid of reservoir and matrix dispersion type.The drug is suspended in aqueous solution of water miscible drug solubilizer, then dispersing the drug suspension in a lipophilic polymer by shear mechanical force to form thousands of microscopic drug reservoirs. The medicated disc is then mounted at the center of an adhesive pad. It is successfully utilized in the preparation of nitro-disc, 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.

ADVANCED RESEARCHESMICROARRAY NEEDLEAdvanced micro-needle Patch transdermal system allowing continuous delivery through the skin of proteins and water-soluble drugs. 43

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. 44 ADVANCED RESEARCHES

45 MICRONEEDLE ARRAY

MICRO TRANSApplications : 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 DNA- based. Fluid sensing of glucose, hormones, blood gases, and therapeutic drug levels. 46

Liposomes and vehicles Liposome are colloidal particles formed as concentric bimolecular layers that are capable of encapsulating drugs. There are many examples of cosmetic products in which the active ingredients are encapsulated in vesicles. These include humectants such as glycerol and urea, sunscreening and tanning agents, enzymes, etc. Phosphatidylcholine from soybean or egg yolk is the most common composition although many other potential ingredients have been evaluated . Cholesterol added to the composition tends to stabilize the structure thereby generating more rigid liposomes.

Solid lipid nanoparticles Solid lipid nanoparticles (SLN) have recently been investigated as carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide and glucocorticoids. It is thought their enhanced skin penetration is primarily due to an increase in skin hydration caused by the occlusive film formed on the skin surface

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.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 skin in the chosen area. Find an appropriate place to put the patch 49

50Find an appropriate place to put the patch