Transdermal Drug Delivery System, Unit-III BP704T: NDDS, Sem-VII, Final Year B. Pharm (SPPU2019P).pptx

Unit III
Transdermal Drug Delivery Systems: Introduction, Permeation through skin, factors affecting permeation, permeation enhancers, basic components of TDDS, formulation approaches.

1. TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS) Ms. Kartiki M. Bhandari Assistant Professor (Pharmaceutics)

2. INTRODUCTION TDDS also k/a “ patch ,” is painless system designed to deliver therapeutic amount of API systemically across patient’s skin by applying formulation onto intact, healthy skin. API penetrates through skin & absorb systemically by dermal micro-circulation. Alternative to injectables & oral routes by increasing patient compliance & avoiding 1 st pass metabolism. Provides controlled & constant input of drugs with short T ½ thereby eliminating pulsed-entry of drug into systemic circulation, which often causes side effects.

3. ADVANTAGES

4. DISADVANTAGES

5. PERCUTANEOUS ABSORPTION It is a step-wise process of penetration of substance & permeation across layers of skin into systemic circulations; divided in 3 parts : Penetration: entry of substance in particular layer . Permeation: permeation from one layer into another , which is different both functionally & structurally from 1 st layer. Absorption: uptake of substance into systemic circulation .

6. PERMEATION THROUGH SKIN

7. BASIC COMPONENTS Polymer Matrix (Membrane) Drug Permeation Enhancer Pressure Sensitive Adhesives (PSA) Backing Laminate Release Liner Other Excipients A) Drug + adhesive = matrix (without polymer) B) Drug + polymer = reservoir (with separate adhesive) C) Drug + adhesive = reservoir (without polymer) D) Drug + polymer = matrix (with separate adhesive)

8. POLYMER MATRIX / MEMBRANE Polymer controls the drug release from device. Possible useful polymers for TDDS are: Natural Polymers: C ellulose derivatives, Zein (prolamin-rich protein found in protein bodies/ endosperm of corm kernel), Gelatin, Shellac (resin secreted by female lac-bug on trees), Waxes, Proteins, Gums & their derivatives, Natural rubber, Starch, etc. Synthetic Elastomers: Polybutadiene , Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrene butadiene rubber, Neoprene, etc. Synthetic Polymers: P olyvinyl alcohol (PVA), Polyvinyl chloride (PVC), Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinyl pyrrolidone (PVP), Polymethyl methacrylate, Epoxy, etc.

9. DRUG For successfully developing TDDS, drug should be chosen with great care. Desirable physico-chemical properties of drug for TDDS: MW approx. < 1000 Da. Affinity for both lipophilic & hydrophilic phases ; Extreme partitioning characteristics are not favorable for successful drug delivery via skin. Low melting point. Potent, having shorter T ½ & be non-irritating.

10. PERMEATION ENHANCER These are compounds which promote skin permeability by altering the skin ; which act as a barrier to the flux of desired penetrant (drug). Penetration enhancers are added into formulation to improve diffusivity & solubility of the drugs through skin that would reversibly reduce the barrier resistance of skin. These includes: water, pyrolidones, fatty acids, alcohols, glycols, essential oils, terpenes & derivatives, sulfoxides like DMSO & their derivatives, urea & surfactant.

11. PERMEATION ENHANCER The flux (J) of drug across the skin can be written as: Where, J = Flux, D = Diffusion coefficient, C = Concentration of the diffusing species (API), X = Spatial co - ordinate. J = D [dc/dx]

12. FACTORS AFFECTING PERMEATION

13. FACTORS AFFECTING PERMEATION

14. FACTORS AFFECTING PERMEATION

15. FACTORS AFFECTING PERMEATION

16. IDEAL PROPERTIES OF PERMEATION ENHANCER It should be pharmacologically inert. It is should be non-toxic, non-irritating, & non-allergenic to the skin. It should produce rapid, predictable & suitable duration of action for the drug used . Following removal of the enhancer, the SC should immediately & fully recover its normal barrier property.

17. IDEAL PROPERTIES OF PERMEATION ENHANCER The barrier function of skin should decrease in one direction only i.e., they should permit entry of API into body & efflux of endogenous materials should not occur. It should be chemically & physically compatible with DDS. It should be non-damaging to viable cells. They should be inexpensive & cosmetically acceptable .

18. METHODS FOR PERMEATION ENHANCEMENT M ethods employed for modifying barrier properties of SC to enhance drug penetration & absorption through skin can be categorized as: 1) Chemical Enhancers Relaxation of Lipids Interaction with aqueous domain Addition of co-enhancer / co-solvent Establishment of drug reservoir 2) Physical Enhancers Electroporation Iontophoresis Ultrasound Magnetophoresis Thermophoresis Microneedle-based devices Needleless injection “ MINUTE M ” “ LACR ”

19. 1) CHEMICAL ENHANCERS Chemical permeation enhancers exert their effect through following modifications in the skin structure : Relaxation of the extremely ordered lipid structure of the SC. Interacting with aqueous domain of lipid bilayer / Solvent swelling . Enhanced partitioning of drug into SC, by addition of co-enhancer or solvent . Promoting penetration & establishing drugs reservoir in the SC.

20. 1) CHEMICAL ENHANCERS Chemical permeation enhancers interact with polar head groups on skin surface through hydrogen bonding & ionic interactions. Resultant disruption of lipid bilayer & changes in head group properties causes relaxation at polar head portion of the skin. This relaxation decrease resistance of this lipid-enriched domain for polar molecules.

21. 1) CHEMICAL ENHANCERS Another aspect is increasing volume of water layer in DDS resulting in more water flow to tissue, process k/a “ solvent swelling ” , leading to increased cross sectional area for diffusion of polar molecules. This makes portion of free water available at lipid interface. This process can also occur due to simple hydration. Some of the most widely studied permeation enhancers are dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), & diethyltoluamide (DEET), propylene glycol (PG). DMSO, urea & surfactants , can also interact with the keratin filaments present in corneocytes which leads to disruption within cell thereby increasing diffusion coefficient & permeability.

22. 2) PHYSICAL ENHANCERS ELECTROPORATION: Use of electro-permeation as a method of enhancing diffusion across biological barriers dates back as far as 100 years. Electroporation involves the application of high-voltage pulses (≥100 V) for a short period (milliseconds) to induce skin perturbation. It has been successfully used to enhance the skin permeability of molecules with differing lipophilicity & size (small molecules, proteins, peptides, & oligonucleotides).

23. 2) PHYSICAL ENHANCERS IONTOPHORESIS: This involves enhancing permeation by application of low-level electric current , either directly to the skin or indirectly via the dosage form. Generated current develop +ve / -ve charges which attract oppositely-charged molecules & repel likely-charged molecules. Increased drug permeation by this method is attributed to either one or combination of: “ electro-repulsion” (for repulsion in like-charged solutes in DDS), “ electro-osmosis” (for osmotic movement of uncharged solutes), & “ electro-perturbation” (for permeation of both like-charged & uncharged) mechanisms. Anode Cathode

24. 2) PHYSICAL ENHANCERS ULTRASOUND : Ultrasound involves use of ultrasonic energy to enhance permeation of solutes either simultaneously or through pre-treatment . F requently referred as “ sonophoresis. ” Proposed mechanism behind increased skin permeability is attributed to formation of gaseous cavities within intercellular lipids on exposure to ultrasound, resulting in disruption of SC .

25. 2) PHYSICAL ENHANCERS MAGNETOPHORESIS : Involves application of magnetic field that acts as external driving force to enhance repulsion & thereby diffusion of diamagnetic solute (non-magnetic) across the skin. Exposure to magnetic field might also induce structural alterations in SC which contribute to increased permeability. THERM OPHORESIS : Skin’s surface temperature is usually maintained at 32°C (steady) in humans by range of homeostatic controls.

26. 2) PHYSICAL ENHANCERS MICRONEEDLE-BASED DEVICES : One of the 1 st patents filed on drug delivery device for percutaneous drug administration is based on this method. Micro-needles of length 50-110 mm will penetrate SC & epidermis to deliver the drug from reservoir. NEEDLE-LESS INJECTION : Needleless injection (jet-gun injection) is pain-free method of administering drugs to the skin that avoids issues of safety, pain, & fear associated with hypodermic needles.

27. 2) PHYSICAL ENHANCERS

28. PRESSURE SENSITIVE ADHESIVES (PSA) Fastening of TDDS to skin can be done by using PSA, positioned on face of the device or in back of the device & extending peripherally. 1 st approach involves development of new polymers , which include hydrogel hydrophilic polymers, & polyurethanes. 2 nd approach is modifying the physical / chemical characters of currently used PSAs (such as silicones, & acrylates). Physical modification refers to formulating base adhesives with some unique additives, drug & excipients in the system formulation, resulting in enhanced adhesion property & drug delivery. Chemical modification involves chemically incorporating or grafting functional monomers to the conventional PSA polymers to improve drug delivery rates.

29. BACKING LAMINATE Backings laminates are selected for appearance, flexibility & need for occlusion. Examples of backings are polyester film, polyethylene film & polyolefin film, & aluminum vapor coated layer. B ut the backing additives may leach out causing diffusion of drug or compositions, through the backing . Over emphasis on chemical resistance may lead to stiffness & high occlusivity to moisture / vapor; which possibly lifts the skin & causes irritation during long-term use.

30. RELEASE LINER During the storage, patch is covered by protective liner that is removed & discarded before application of patch to the skin. Since the liner is in intimate contact with TDDS, it should be chemically inert. Liner is composed of base layer which may be non-occlusive ( e.g. paper fabric) or occlusive ( e.g. polyethylene, polyvinylchloride) & release coating layer made up of silicon or teflon. Other materials used for TDDS liners include, polyester foil & metalized laminate .

31. OTHER EXCIPIENTS Various solvents such as chloroform, methanol, acetone, isopropanol & dichloromethane are used to prepare drug reservoir. In addition, plasticizers such as dibutyl-phthalate, triethyl citrate, polyethylene glycol & propylene glycol are added to provide plasticity to transdermal patch. Flavours, perfumes & sweeteners are NOT required in TDDS as the formulation is applied topically on external surfaces of the body.

32. FORMULATION APPROACHES Polymer Membrane P ermeation- C ontrolled TDDS: Drug reservoir sandwiched between drug impermeable backing laminate & rate controlling polymeric membrane. In drug reservoir compartment drug is dispersed homogeneously in a solid polymeric matrix (e.g. polyisobutylene), suspended in a unleachable viscous liquid medium (e.g. silicon fluid) to form a paste-like suspension. Rate controlling membrane is either micro-porous or porous polymeric membrane e.g. ethylene-vinyl acetate copolymer.

33. FORMULATION APPROACHES Polymer Membrane P ermeation- C ontrolled TDDS: Examples of this type of patches: Estraderm ( twice a week in treatment of postmenopausal syndrome), Duragesic (management of chronic pain for 72 hrs). Intrinsic rate of drug release from this type of DDS is defined by- dq /dt = Cr / [(1/Pm)+(1/Pa)] Where, Cr = Concentration of drug in drug reservoir, Pa & Pm = Permeation Co-efficient of adhesive layer & rate controlling membrane respectively.

34. 1) Polymer Membrane P ermeation- C ontrolled TDDS

35. FORMULATION APPROACHES 2) Polymer Matrix D iffusion- Controlled TDDS : D rug reservoir is prepared by homogeneously dispersing drug particles in hydrophilic / lipophilic polymer matrix. Resulting polymer matrix is then molded into discs with defined surface area & controlled thickness. This medicated disc is then molded onto an occlusive base plate in compartment made up of drug impermeable backing. Finally, adhesive polymer is spread along the circumference of the film.

36. FORMULATION APPROACHES 2) Polymer Matrix D iffusion- Controlled TDDS : Example: Nitro-glycerin releasing TDDS with a daily dose of 0.5 g/cm² for angina pectoris. Rate of drug release in this system is given by equation- dq /dt = ( A.Cp.Dp /2t)½ Where, A= Initial drug loading dose dispersed in polymer matrix, Cp = Solubility of drug in Polymer, Dp = Diffusivity of drug in Polymer.

37. 2) Polymer Matrix D iffusion- Controlled TDDS

38. FORMULATION APPROACHES 3) Adhesive Dispersion-Type TDDS: Simplified form of membrane permeation-controlled s ystem where drug & other selected excipients are directly incorporated into adhesive solution. They are then mixed & casted as thin films & solvent is evaporated by drying the film. The drug reservoir film is the then sandwiched between the banking laminate & rate-controlling adhesive polymer membrane.

39. FORMULATION APPROACHES 3) Adhesive Dispersion-Type TDDS: Examples: Isosorbide dinitrate-releasing TDDS for 24 hr to treat Angina Pectoris, Verapamil-releasing TDDS for 24 hrs to treat Hypertension. Rate of drug release from this system is given by- dq /dt = Cr . (K a/r . Da / ha) Where, Cr = Concentration of drug in drug reservoir, K a/r = Partition co-efficient of drug in adhesive layer & reservoir layer, Da = Diffusivity of drug, ha = Thickness of membrane.

40. 3) Adhesive Dispersion-Type TDDS

41. FORMULATION APPROACHES 4) Micro-Reservoir D issolution-Controlled TDDS: H ybrid system of reservoir & matrix dispersion type DDS. Drug matrix is formed by suspending the drug in aqueous solution of water-miscible drug solubilser e.g. PEG. Above drug suspension is then homogeneously dispersed with water-soluble lipophilic polymer by high shear mechanical force to form thousands of unleachable microscopic drug reservoir suspended in solubilizer fluid.

42. 4) Micro-Reservoir D issolution-Controlled TDDS

43. ANY QUESTIONS…??