PHT 540: Drug Delivery Systems

1. King Saud University College of Pharmacy Department of Pharmaceutics PHT 540:Drug Delivery Systems Transdermal Drug Delivery Systems From theory to clinical Practice

2. Outlines • Introduction • Theoretical Aspects of TDD • Experimental Design • Chemical Modulation of TDD • Physical and Technological Modulation • of TDD • Topical and Transdermal Formulations

3. Introduction • Human skin in a uniquely engineered organ that permits terrestrial life by regulating heat and water loss from the body whilst preventing the ingress of noxious chemicals or microorganisms. • It is the largest organ of the human body, providing around 10% of the body mass of an average person. • Human skin is a highly complex organ though in many transdermal drug delivery studies it is often regarded somewhat simplistically as merely a physical barrier.

4. Introduction…(cont.) • In vivo, skin is in a process of continual regeneration and it has immunological and histological responses. • Due to experimental and ethical difficulties, most transdermal drug delivery studies tend to utilize skin ex vivo (in vitro) which inherently reduces the complexity (regeneration stops, immune responses cease and metabolic activity is usually lost in these studies). • It should always be borne in mind that data obtained from excised skin may not translate directly to the in vivo situation.

5. Introduction…(cont.) • For the purpose of transdermal drug delivery, we can examine the structure and function of human skin categorized into four main layers: • Innermost subcutaneous fat layer (hypodermis) • The overlying dermis • Viable epidermis • Outermost layer of the tissue (a non-viable epidermal layer) the stratum corneum

7. Introduction …(cont.) • Innermost subcutaneous fat layer (hypodermis): • The subcutaneous fat layer, or hypodermis, bridges between the overlying dermis and the underlying body constituents. • This layer of adipose tissue principally serves to insulate the body and provide mechanical protection against physical shock. • It also provides a readily available supply of high-energy molecules, whilst the principle blood vessels nerves are carried to the skin in this layer.

8. Introduction…(cont.) • The dermis: • It is typically 3-5 mm thick and is the major component of human skin • Composed of a network of connective tissue providing support and elastic tissue providing flexibility. • This layer is essentially gelled water, and thus provides a minimal barrier to the delivery of most polar drugs which becomes even more significant when delivering highly lipophilic drugs. • It has numerous structures embedded within it; blood and lymphatic vessels, nerve ending, piolsebaceous unit (hair sweat glands follicles and sebaceous glands) and sweat glands.

9. Introduction…(cont.) • The dermis…(cont.): • It is important for delivering oxygen and nutrients to the tissues and toxins and waste products. • For transdermal delivery of most drugs, the blood supply thus maintains a concentration gradient that provides the driving force for drug permeation. • The appendages (hair follicles, sweat gland) may offer a potential route for some drugs without have to traverse barrier provided by the stratum corneum. These so called “shunt routes”.

11. Introduction…(cont.) • The epidermis: • It contains no blood vessels and hence nutrients and waste products must diffuse across the dermo-epidermal layer. • It contains four distinct layers: stratum germinativum, stratum spinosum, stratum granulosum and stratum corneum. • Stratum corneum is composed of dead cells, provides the main barrier to transdermal delivery of drugs.

12. Factors affecting TDD • Physiological factors: • Skin age: repeated exposure to chemicals or radiation, age-related alterations: blood flow, drug flux (a major limiting step). • Body site: site-to-site variation in permeability is complex. For example, the stratum corneum is thicker on the palms of the hands and feet. • Race: few literature reports examining racial similarities or differences show there are significant differences in the stratum corneum water contents between races.

13. Factors affecting TDD • Pathological factors: • Eruptions: in such cases, the barrier properties of the stratum corneum are compromised, allowing easier passage of drugs and potentially toxic materials into and through the skin: psoriasis and eczema. • Infections: commonly found skin bacteria include staphylococcal species. One example is impetigo. • Ichthyoses: defined as disorders of keratinization and epidermal differentiation and characterized by dry and scaly skin.

14. Advantages of TDDS • Effective systemic delivery (vs. GI) • High patient compliance • Constant rate release (membrane-based) • Easily terminated (patch removal)

15. Disadvantages of TDDS

16. Disadvantages of TDDS…(cont.) b)Stratum corneum is hydrophobic: (limits drug penetration) c) Epidermis is hydrophilic d) Main entry to vasculature via pores: (small % of surface) e) Drugs bind to skin: desorption becomes rate-limiting step f) Allergic reaction: triggered by adhesive

17. Theoretical Aspects of TDD • a) Partition coefficient: a permeant must first • partition into the membrane log P(octanol/water) It is considered that rate limiting step in the permeation process. • According to the oil and water phases solubility: • log P(octanol/water) 1-3:intercellular route predominates • log P(octanol/water) > 3:intercellular route is the only route • log P(octanol/water) <1:transcellular route

19. Theoretical Aspects of TDD b) Molecular size: the second major factor in determining the flux of a material through human skin is the size and shape of the molecules. Selected candidate for TDD should fall within (100-500 Dalton). c) Solubility/melting point d) Ionization e) Other factors: binding forces, particle size,…etc.

20. Experimental Design • Preparation of skin membranes: • In vitro/in vivo studies • Animal membrane: hairless mouse, guinea pig and mammalian skin • Artificial membrane: - More simplistic model - No regional variability - Advantages of reproducibility and control - Simple permeation process - Used for quality control purposes or for testing formulation variables

21. Experimental Design…(cont.) • Diffusion cell for in-vitro studies: • Comprise of two compartments: donor and receptor sections • The receptor section of a fixed volume is kept at controlled T at 37 ºC and the fluid is agitated • A portal from the receptor compartment allows removal of receptor fluid at required time intervals.

26. Chemical Modulation of TDD • Chemical penetration enhancers: • Increasing the permeability of the stratum corneum by using chemical agents known as penetration enhancers or absorption promoters. • It partition into the stratum corneum and interact with tissue components to reduce the barrier properties of the membrane without causing damage to the underlying skin cells. • Penetration enhancers should act reversibly; that is, the reduction in stratum corneum barrier properties should be temporary. • Dimethylsulfoxide (DMSO), azone, pyrrolidine derivatives, fatty acids, alcohol, surfactants, urea, phospholipids and cylcodextrins

27. Physical and Technological Modulation of TDD

28. 1)- Vesicles • Liposomes What are Liposomes? They are simply vesicles or ‘bags’ in which an aqueous volume is entirely enclosed by a membrane composed of lipid (fat) molecules, usually phospholipids. In other words: A liposome is a spherical vesicle with a membrane composed of a phospholipid and cholesterol bilayer. Liposomes can composed of naturally-derived phospholipids with mixed lipid chains.

30. 1)- Vesicles…(cont.) • Liposomes …(cont.) Liposomes are used for drug delivery due to their unique properties. A liposome encapsulates a region on aqueous solution inside a hydrophobic membrane; dissolved hydrophilic solutes can not readily pass through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way liposome can carry both hydrophobic molecules and hydrophilic molecules. To deliver the molecules to sites of action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus delivering the liposome contents.

31. 1)- Vesicles…(cont.) • Liposomes …(cont.) - Their relatively low toxicity, existing safety record and experience with marketed intravenously administered liposome products (amphothericin B, doxoroubicin, daunorubicin) - The presence of a relatively large aqueous core, which is essential to stabilize the structural features of many proteins - The possibility to manipulate release characteristics of liposome associated proteins

32. 1)- Vesicles…(cont.) • Non-ionic surfactant vesicles (niosomes) • Niosomes are ionic surfactants which are considered as the novel forms of liposomes. • They are mostly formed by cholesterol incorporation as an excipient. • Niosomes have more penetrating capability than emulsions.

33. 1)- Vesicles…(cont.) • Non-ionic surfactant vesicles (niosomes) • They are structurally similar to liposomes in having a bilayer, however, the materials used to prepare niosomes makes them more stable and thus niosomes offer many more advantages over liposomes. • Niosomes are a novel drug delivery system that are finding application in: 1) Drug Targeting 2) Antineoplastic Treatment 3) Leishmaniasis Treatment 4) Delivery of Peptide Drugs 5) Studying immune response 6) Transdermal drug delivery systems.

34. 1)- Vesicles…(cont.) • Non-ionic surfactant vesicles (niosomes) • The vesicle suspension being water based offers greater patient compliance over oil based systems • Can be used for a variety of drugs. • The characteristics such as size • The vesicles can act as a depot to release the drug slowly and offer a controlled release. • They are stable and They increase the stability of the entrapped drug • Handling and storage of surfactants do not require any special conditions • Can enhance the skin penetration of drugs • They can be used for oral, parenteral as well topical use

35. 2)- Electrical methods • Iontophoresis • A non-invasive method of propelling high concentrations of a charged substance, normally medication or bioactive agents, transdermally by repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle. • To clarify, one or two chambers are filled with a solution containing an active ingredient and its solvent, termed the vehicle. The positively charged chamber, termed the anode will repel a positively charged chemical, while the negatively charged chamber, termed the cathode, will repel a negatively charged chemical into the skin.

37. 2)- Electrical methods • Iontophoresis • Iontophoresis is well classified for use in transdermal drug delivery. Unlike transdermal patches, this method relies on active transportation within an electric field. • In the presence of an electric field electromigration and electroosmosis are the dominant forces in mass transport. These movements are measured in units of chemical flux

38. 3)- Other methods • Ethosomes • Othersomes • Needleless injection • Ultrasound • Electroporation